B number and titleProposal summary
B2534 - Assessing causality in the association between maternal pre-pregnancy obesity and child neurodevelopment observational - 02/10/2015

Aims: to assess causality in the association between maternal pre-pregnancy body mass index and child neuropsychological by performing an observational analysis of birth cohorts (meta-analysis) and a mendelian randomization (MR) analysis in those cohorts with genetic data available. Further, we will use paternal BMI as a negative control exposure and test the role of the child BMI genetic score.

B2532 - Abnormal metabolic measures in adolescents with pyschotic experiences - 24/09/2015

To examine whether people with psychotic experiences at age 18 are more likely to have abnormal metabolic measures in the period preceding the onset of such symptoms, and at what time point are these abnormalities evident. If there will be evidence of an association between metabolic disorders and psychotic experiences, we will then examine whether this association is specific to psychotic experiences or occurs across a range of psychiatric disorders.

B2516 - The genetic architecture of pro-social behaviour - 03/09/2015

Human social interaction plays an important role in social success, adjustment and development. This involves also altruistic and prosocial behaviour1, which supports creating and maintaining social bonds, an important quality of functioning societies2. Prosocial behaviour is one of the most heritable social skills with twin heritabilities rising from 0.32 during early childhood to 0.61 during middle childhood3. It is strongly associated with social cognition and intelligence, and prosocial motivation is one of the three major cognitive components, which have been hypothesized to underlie empathyADDIN ZOTERO_ITEM CSL_CITATION{"citationID":"16tvof0ais","properties":{"formattedCitation":"{\rtf\super4\nosupersub{}}","plainCitation":"4"},"citationItems":[{"id":3140,"uris":["http://zotero.org/users/8513/items/9AICVEX6"],"uri":["http://zotero.org/users/8513/items/9AICVEX6"],"itemData":{"id":3140,"type":"article-journal","title":"Theneuroscience of empathy: progress, pitfalls andpromise","container-title":"Nature Neuroscience","page":"675-680","volume":"15","issue":"5","source":"www.nature.com","abstract":"Thelast decade has witnessed enormous growth in the neuroscience of empathy. Here,we survey research in this domain with an eye toward evaluating its strengthsand weaknesses. First, we take stock of the notable progress made by earlyresearch in characterizing the neural systems supporting two empathicsub-processes: sharing others' internal states and explicitly considering thosestates. Second, we describe methodological and conceptual pitfalls into whichthis work has sometimes fallen, which can limit its validity. These include theuse of relatively artificial stimuli that differ qualitatively from the socialcues people typically encounter and a lack of focus on the relationship betweenbrain activity and social behavior. Finally, we describe current researchtrends that are overcoming these pitfalls through simple but importantadjustments in focus, and the future promise of empathy research if thesetrends continue and expand.
View fulltext","DOI":"10.1038/nn.3085","ISSN":"1097-6256","shortTitle":"Theneuroscience of empathy","journalAbbreviation":"NatNeurosci","language":"en","author":[{"family":"Zaki","given":"Jamil"},{"family":"Ochsner","given":"KevinN."}],"issued":{"date-parts":[["2012",5]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"}4. The neurobiological basis of pro-social behaviour and empathy is complex. Empathic cognition has been linked to multiple subcortical regions such as the limbic system, the putative mirror system, a proposed mentalising network 5,6, as well as the septal area, which has also been associated with prosocial motivation e.g. ADDIN ZOTERO_ITEM CSL_CITATION{"citationID":"XIZroMmB","properties":{"formattedCitation":"{\rtf\super7,8\nosupersub{}}","plainCitation":"7,8"},"citationItems":[{"id":3151,"uris":["http://zotero.org/users/8513/items/W9689QEU"],"uri":["http://zotero.org/users/8513/items/W9689QEU"],"itemData":{"id":3151,"type":"article-journal","title":"Neuralcorrelates of giving support to a lovedone","container-title":"PsychosomaticMedicine","page":"3-7","volume":"74","issue":"1","source":"PubMed","abstract":"OBJECTIVE:Social support may benefit mental and physical well-being, but most researchhas focused on the receipt, rather than the provision, of social support. Weexplored the potentially beneficial effects of support giving by examining theneural substrates of giving support to a loved one. We focused on a prioriregions of interest in the ventral striatum and septal area (SA) because oftheir role in maternal caregiving behavior in animals.
METHODS: Twentyromantic couples completed a functional magnetic resonance imaging session inwhich the female partner underwent a scan while her partner stood just outsidethe scanner and received unpleasant electric shocks.
RESULTS: Support giving(holding a partner's arm while they experienced physical pain), compared withother control conditions, led to significantly more activity in the ventralstriatum, a reward-related region also involved in maternal behavior (p valuesless than .05). Similar effects were observed for the SA, a region involved in bothmaternal behavior and fear attenuation. Greater activity in each of theseregions during support giving was associated with greater self-reported supportgiving effectiveness and social connection (r values = 0.55-0.64, p values less than .05). In addition, in line with the SA's role in fear attenuation (presumablyto facilitate caregiving during stress), increased SA activity during supportgiving was associated with reduced left (r = -0.44, p less than .05) and right (r =-0.42, p less than .05) amygdala activity.
CONCLUSIONS: Results suggest thatsupport giving may be beneficial not only for the receiver but also for thegiver. Implications for the possible stress-reducing effects of support givingare discussed.","DOI":"10.1097/PSY.0b013e3182359335","ISSN":"1534-7796","note":"PMID:22071630","journalAbbreviation":"PsychosomMed","language":"eng","author":[{"family":"Inagaki","given":"TristenK."},{"family":"Eisenberger","given":"NaomiI."}],"issued":{"date-parts":[["2012",1]]},"PMID":"22071630"}},{"id":3177,"uris":["http://zotero.org/users/1947403/items/PSZ5IXEX"],"uri":["http://zotero.org/users/1947403/items/PSZ5IXEX"],"itemData":{"id":3177,"type":"article-journal","title":"Impairmentof prosocial sentiments is associated with frontopolar and septal damage infrontotemporaldementia","container-title":"NeuroImage","page":"1735-1742","volume":"54","issue":"2","source":"PubMedCentral","abstract":"Poets and philosophers have longacknowledged moral sentiments as key motivators of human social behavior.Prosocial sentiments, which include guilt, pity and embarrassment, enable us tocare about others and to be concerned about our mistakes. Functional imagingstudies have implicated frontopolar, ventromedial frontal and basal forebrainregions in the experience of prosocial sentiments. Patients with lesions of thefrontopolar and ventromedial frontal areas were observed to behaveinappropriately and less prosocially, which could be attributed to ageneralized emotional blunting. Direct experimental evidence for brain regionsdistinctively associated with moral sentiment impairments is lacking, however.We investigated this issue in patients with the behavioral variant offrontotemporal dementia, a disorder in which early and selective impairments ofsocial conduct are consistently observed. Using a novel moral sentiment task,we show that the degree of impairment of prosocial sentiments is associatedwith the degree of damage to frontopolar cortex and septal area, as assessedwith 18-Fluoro-Deoxy-Glucose-Positron Emission Tomography, an establishedmeasure of neurodegenerative damage. This effect was dissociable fromimpairment of other-critical feelings (anger and disgust), which was in turnassociated with dorsomedial prefrontal and amygdala dysfunction. Our findingssuggest a critical role of the frontopolar cortex and septal region in enablingprosocial sentiments, a fundamental component of moralconscience.","DOI":"10.1016/j.neuroimage.2010.08.026","ISSN":"1053-8119","note":"PMID:20728544
PMCID:PMC2997153","journalAbbreviation":"Neuroimage","author":[{"family":"Moll","given":"Jorge"},{"family":"Zahn","given":"Roland"},{"family":"deOliveira-Souza","given":"Ricardo"},{"family":"Bramati","given":"IvaneiE."},{"family":"Krueger","given":"Frank"},{"family":"Tura","given":"Bernardo"},{"family":"Cavanagh","given":"AlysonL."},{"family":"Grafman","given":"Jordan"}],"issued":{"date-parts":[["2011",1,15]]},"PMID":"20728544","PMCID":"PMC2997153"}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"}7,8. In addition, several neuropsychiatric disorders show abnormal social functioning. Understanding the neural basis of prosocial behaviour has remained however challenging due to the diversity of cognitive assessments, developmental changes in genetic architecture of prosocial and cognitive skills and the wide range of often costly neuroimaging technologies.

B2488 - Dairy intake in pregnancy anthropometry in infancy and childhood - 16/07/2015

AIMS: To investigate associations between intake of dairy foods in pregnancy with anthropometric measures at birth, infancy, early and late childhood

B2487 - Using genetic data to understand the relationship between growth and cardiometabolic health - 16/07/2015

Genome-wide association studies (GWAS) have uncovered multiple single nucleotide polymorphisms (SNPs) that are associated with height[1], adiposity[2, 3], cardiometabolic diseases[4] and intermediate cardiometabolic phenotypes.[5, 6] However, most GWAS have been carried out in caucasian adults, and the association between the SNPs and phenotypes in different ethnic groups and at different stages of the life course remains uncertain.

Within epidemiology, observational data are often used to assess the association between an exposure and a health outcome of interest in situations where a randomized controlled trial (which provides stronger evidence of causality) is not possible or not ethical. These studies are, however, plagued with difficulties due to bias and confounding.[7, 8] Mendelian Randomization[9] (MR) is a technique that uses genetic variants related to an exposure of interest to obtain an estimate of the exposure-outcome association that is not affected by confounding or reverse causality.

This PhD proposal will 1) further understanding of the genetic architecture of anthropometry and cardiometabolic traits, and 2) use MR to advance understanding of the causal relationships between anthropometry and cardiometabolic health.

B2486 - Using a healthy population to explore the biological pathways underlying inflammatory bowel disease - 16/07/2015

AIMS:

To investigate the downstream effects of genetic variants associated with inflammatory bowel disease (IBD) in healthy indiviuduals, focusing particularly on metabolites and metabolic pathways.

B2484 - The association of paternal depression with childrens school behaviour and academic achievement a mediational analysis - 16/07/2015

The proposed research aims to answer the following questions: 1) Do children of parents with high levels of depressive symptoms score lower on measures of academic achievement and positive school behaviours? 2) Does parenting and chronicity of parental depressive symptoms explain the link between parental depression and children's outcomes? 3) Does children's intellectual functioning moderate the link between parental depressive symptoms and child outcomes so that children with higher IQ do better at school despite exposure to parental depression?

B2483 - The Causal Effect of Body Mass Index on Blood Pressure Using Mendelian Randomization with Invalid Instruments - 16/07/2015

The purpose of using the ALSPAC data is to demonstrate the new methods on real Mendelian randomization studies done using ALSPAC. ALSPAC is one of the largest repositories of data used for Mendelian randomization. More importantly, ALSPAC contains individual-level values, a necessity for Kang et al.'s methods. Utilizing ALSPAC data would allow us to validate some of the causal conclusions already made with ALSPAC using the new robust methods as well as allow opportunities for novel causal effects that were previously not possible due to the presence of invalid instruments.

B2482 - Association between dietary measures and later development of psychotic symptoms in the ALSPAC cohort - 17/07/2015

Essential fatty acids and risk of psychotic symptoms in the ALSPAC cohort outline

Aim:

To investigate whether essential fatty acids intake both perinatally and in childhood and is associated with the later development of psychotic symptoms or disorder in adolescence.

B2477 - Qualitative research on attitudes around commercial access to health biomedical and genetic data - 09/07/2015

The Wellcome Trust has commissioned Ipsos MORI to undertake qualitative social research to explore the attitudes of patients, the public, cohort participants and healthcare professionals around commercial organisations accessing health, biomedical and genetic data. We would like to recruit up to 20 ALSPAC cohort participants to form the 'cohort' demographic for this research.

Aim: The aim is to understand attitudes around commerical access and identify governance, safeguarding and communications actions that could help: improve the trustworthiness of research uses and protections of data; and enable public trust in access to data to be developed over time. We are interested to establish whether cohort participants' attitudes differ to those of patients and the general public.

B2473 - The Relationship Between Cognitive Function and Later Depression A Systematic Review and Meta Analysis - 02/07/2015

To conduct a systematic review and meta-analysis on the longitudinal relationship between cognitive function and depression, including potential confounds and moderating factors.

B2472 - Uncommon and rare genetic variants associated with vitamin D levels - 25/06/2015

GWAS has sucsessfuly identified common candidate loci associated with vitamin D levels. However, these loci account for only a small proportion of heritability in vitamin D levels. These studies did not assess for uncommon or rare variants. Access to whole genome sequencing data and deeper imputation based on the UK10K/1000G panel means that it is now possible to test a greater range of uncommon and rare variants. This approach has been previously used to re-evaluate existing phenotypes and has lead to new variants being discovered, e.g. for triglyceride and thyroid hormone levels. The consortium consists of the following European ancestry cohorts:

1. Twins UK

2. ALSPAC

3. Framingham Heart Study

4. Rotterdam Study

5. SOF

The analysis for the ALSPAC cohort will be conducted by Tom Dudding and Simon Haworth both IEU members, under Nic Timpson's supervision.

Aims. The IEU has been approached by an international consortium to participate in analysis. The overall consortium aims are to identify uncommon and rare genetic variants associated with vitamin D levels.

B2471 - Diet and Myopia - 25/06/2015

A) Relationship between glycemic index, dietary protein and myopia.

The Cordain theory [3] proposes that myopia occurs as a result of environmental conditions associated with modern civilisation, which came about after the Palaeolithic era. The prevalence of myopia is very low in hunter-gatherer populations compared to more "advanced" populations (less than 2% vs. greater than 20%) [1]. In Eskimos, increasing acculturation during the 1960's led to a marked increase in myopia prevalence [2]. The typical Palaeolithic diet is characterised as being high in protein, low in fat and low in carbohydrates, particularly low glycaemic index carbohydrates: which are slowly absorbed in the blood stream and produce a gradual and minimal rise in plasma glucose and insulin levels when compared to higher glycaemic foods . As well as being implicated in metabolic syndrome, the modern - lower protein/higher glycaemic index - diet has also been suggested as a potential risk factor for myopia [3].

Dietary protein has also been considered as a possible risk factor for myopia, because protein generally results in lower rises in both plasma glucose and insulin when compared to carbohydrate.

In a number of studies, Gardiner [4,5], indicated that myopic individuals consumed significantly lower amounts of animal protein than non-myopes. Further, in an intervention study (albeit a non-rigorous one) he was able to show that increasing the level of animal protein in the diets of myopic children slowed progression of their myopia when compared to a control group receiving no dietary modification [6].

B) Exploratory analysis: Dietary copper

Normal copper metabolism is essential to ocular tissue health and is associated with myopic refractive error development in some studies [7,8]. A recent study found that mutations in the SCO2 gene were associated with autosomal-dominant high-grade myopia. SCO2 encodes for a copper homeostasis protein influential in mitochondrial cytochrome c oxidase activity. Mutations of SCO2 were associated with a destabilisation of protein structures which in turn may result in modulation of oxidative toxicity-particularly in the retina, leading to retinal neuronal thinning. In addition, mutations can affect copper metabolism, which may result in an imbalance of copper enzymatic support activity and oxidative levels within eye tissues [9]. Proper copper metabolism is essential for cell differentiation, development, and maintenance. One study demonstrated the protective effect of copper supplements in individuals with myopia, restoration by capsule injection of copper compounds resulted in increased scleral copper concentration and improved scleral tissue elasticity with cessation of myopic refractive error development [10].

C) Exploratory analysis: Breastfeeding

Observational studies have suggested that breast-feeding benefits the visual development of infants, which has been attributed to the presence of DHA in breast milk but not most formula milks.

In a cross-sectional study of 797 children (ages 10-12 years) in Singapore, the prevalence of myopia was significantly lower in children who had been breastfed than in those who had not (62% vs. 69.1%; p=0.04). The duration of breastfeeding (three months or less versus more than three months) was not associated with myopia risk. However, since the incidence of myopia in children in Singapore is among the highest in the world, it is not clear whether these findings can be generalised to other populations [11].

Analyses of data from three large British birth cohorts showed that there were no differences in visual outcome in childhood or adolescence among those initially breastfed for greater than 1 mo compared with those formula fed. Rates of breastfeeding fell across successive cohorts considerably, but there was no evidence of a subsequent increase in adverse visual outcome in childhood, although, there was a small increase in adverse visual outcome in adolescence from 1946 to 1970. However, the latter did not take into consideration important confounding factors, especially the age at which vision was assessed. (12)

B2470 - Metabalomic profile of vitamin D deficiency - 25/06/2015

Aims:

1) To assess the how serum vitamin D concentration affects metabalomic profile

2) To identify a genetic instrument for metabolites that are associated with vitamin deficiency

B2469 - Sexual Health Need in Avon - informing the Joint Strategic Needs Assessment - 25/06/2015

Overall Aim:

To calculate prevalence estimates of a range of self-reported key sexual health indicators and behavioural patterns as assessed in the ALSPAC cohort between the ages of 17 and 22 years of age in order to better understand the sexual health needs of young people in the Bristol area.

B2466 - Genetic and epigenetic influences on Research Domain Criteria Domains influencing risk for psychiatric disorders - 11/06/2015

Aims

To unravel the genetic and longitudinal epigenetic and environmental influences on National Institute of Mental Health (USA) Research Domain Criteria (RDoCs) Domains (http://www.nimh.nih.gov/research-priorities/rdoc/index.shtml) including: positive and negative valence and social process systems that contribute to the development of psychiatric disorders in children and young adults. In doing so, we will focus on the RDoCs Domains that have not been extensively studied in relation to genetic and epigenetic influences such as reward prediction error.

B2465 - An analysis of the environments which promote the development of early speech and language skills - 18/06/2015

AIM:

This aim of this research proposal is to understand the impact that children's early physical and communication environments have on their developing speech and language skills. The findings will be of use to parents, health visitors, health promotion and public health, early years practitioners and educationalists with regard to which environments and behaviours are most helpful in promoting early speech and language development and which can have a deleterious effect. This is particularly important given recent changes in society which mean that children are being brought up in homes where there are numerous devices which can be used to occupy them rather than engage them in conversation. Moreover, other lifestyle factors could also be having an impact but to date have been subject to minimal investigation (e.g. central heating, forward facing buggies, eating together). Whilst there is much evidence on the importance of parent child interaction on the development of speech and language in young children, there has not been the opportunity to date to investigate how this interacts with these other factors relating to the physical environment.

The findings of this study will also be of interest to the government. A recent DfE report based on data from the original ALSPAC sample (Roulstone, Law, Rush, Clegg, Peters, 2011, DFE RR134) found that vocabulary scores at age 2 years old were associated with baseline scores on entry to primary school, which are themselves related to academic outcomes later on. Low academic outcomes and persistent speech and language impairment are both associated with poor social and economic outcomes and a greater cost to the nation. This study will aim to identify factors early on in the child's development, including data collected in the child's home, which could impact on vocabulary at age 2 and language skills and academic skills beyond.

In the course of collecting data on variables which impact on early speech and language development, normative data will be collected using tools which have been developed in the US and for which UK norms are not currently available. These data will be of help to health visitors and early years practitioners in the future as they will assist in the process of early identification of children at risk of speech and language impairment. Currently, children are not typically identified until age 2 at the earliest.

B2464 - The genetic landscape of speech language and communication skills - 11/06/2015

We would like to use the extensive ALSPAC resource to carry out investigations on common genetic influences and genetic overlaps between speech, language and communication related during childhood. These analyses will inform subsequent meta-GWAS within the framework of the GenLang Consortium

B2463 - Causal role of NMR metabolites in reading and spelling measures - 11/06/2015

Lipids in general and fatty acids in particular have been implicated in brain development (Simopoulos 2011, Molecular Neurobiology), cognitive ability (Swanson 2012, Advances in Nutrition), and dementia (Reitz 2011, Nature Reviews Neurology). Specific fatty acids, such as DHA, are believed to have a direct effect on cell integrity, development, maintenance, and function in the brain (Bazan 2011, Annual Review of Nutrition). These essential polyunsaturated fatty acids can only be obtained through diet with high levels found in cold water fatty fish, seed oils and green-leafed plants.

Spelling and reading are markers of learning ability and cognitive function (Taylor 2013, Psychological Bulletin). As both diet and learning ability are strongly influenced by socioeconomic level we will use a Mendelian randomisation approach to estimate the causal effects of lipid metabolites and fatty acids on brain function, in children aged seven, as this is measured through spelling and reading tests. For this we will use the identified polymorphisms affecting the metabolites of interest as reported in Ketunnen et al 2012 Nat Genet.

Depending on the results of this effort we will try to obtain funding for a more detailed characterisation of fatty acids in order to gain a better understanding of the mechanisms involved

B2462 - Collection of new non-cognitive skill measures in ALSPAC via questionaire - 11/06/2015

During this project we will study the development of non-cognitive skills across the life-course. Non-cognitive skills encompass a diverse range of skills including: motivation, perseverance, emotional intelligence, resilience, and self-regulation. We will investigate the genetic architecture of these skills, and particularly how these skills develop over time. ALSPAC has existing measures of non-cognitive skills measured repeatedly across childhood. Further measures are being collected in the Focus @24/25 YP clinic as part of Marcus Munafo's research. During this project we would like to collect further measures of non-cognitive skills via a questionnaire during 2016 or 2017. We will collect comparable measures to other major cohort studies, including the English Longitudinal Study of Aging and The Health and Retirement Study in the US, which will enable the data to be used in a large GWAS consortia. As part of the project comparable data will be collected in TEDS.

B2461 - Age at menarche and lung function A Mendelian randomisation analysis - 04/06/2015

We will perform a MR study to estimate the effect of age at menarche on parameters of lung function indicative of both restriction (FVC) and obstruction (FEV1/FVC). For this we would like to use ALSPAC lung function data from 16-year old women.

B2460 - Using linked routine and bespoke data to better understand inequity in the use of health care services among children - 11/06/2015

Using linked routine and bespoke data to better understand inequity in the use of health care services among children.

B2458 - Exploring associations between childhood pet ownership GCSE results hyperactivity anxiety and depression at age 15-16 - 04/06/2015

Aims

The aims of this study are to quantify the effect of pet ownership (all pets and individual species will be considered separately) during childhood (whilst controlling for confounders) on the following measures at age 15-16 years: GCSE results, Hyperactivity, Anxiety, Depression.

B2457 - Locating the neighbourhood effect on cervical cancer diagnosis - 19/06/2015

Aims and Objectives, Context and Significance of the Research:

The aim of the project is to locate neighbourhood mechanisms through which the effects of area deprivation impact the likelihood to receive cervical cancer diagnosis. Variables will be chosen in line with the causal mechanisms suspected to explain the relationship which has often been explored as an outcome of individual over neighbourhood poverty, using a cross-sectional methodology (Singh et al., 2004), adopting traditional approaches and thereby reporting statistical not causal inference. In adopting a methodology which seeks to make use of neighbourhood histories, as well as employing a mechanisms based approach, the research will directly acknowledge and respond to gaps within existing neighbourhood effects literature, as well as articulating a more rigorous and fine-grained analysis, resulting in effective neighbourhood interventions.

B2454 - An EWAS of Anti-Mullerian Hormone - 04/06/2015

The aim of this study is to identify differential methylation in cord blood that is associated with AMH levels in female and male adolescents (separately) 15 years of age.

B2453 - NutriCog Use of ALSPAC data to identify dietary factors associated with cognitive functioning - 04/06/2015

The overall objective of our research is to identify dietary components associated with better health and quality of life. For this project in particular, we focus on the relationship of foodgroups, foods, and nutrients and cognitive performance. ALSPAC is a rich source of diet and nutrition data throughout childhood and there is already existing evidence that food intake patterns in early childhood are associated with children's IQ. We wish to extend upon the existing research to investigate how nutrient and food intakes (including dietary patterns) throughout childhood but particularly in the early school years relate to more specific measures of children's cognition (atttentional control and other executive functions), to overall school performance and to parents' ratings of child behavior. The findings from this study will be used to inform the design of nutrition-based interventions in school children in the two other participating countries (Germany and Spain).

B2452 - Signature pathways of early life nutritional environment - 21/05/2015

This proposed project aims to:

1. Identify CNS and blood signature pathways altered by early life high-fat/high-sugar diet exposure in mice.

2. Assess whether these signature pathways identify individuals at risk of adult metabolic or cardiovascular disease in human cohort data.

B2450 - Building a longitudinal picture of early life adversity and life course health - 21/05/2015

This is a five year fellowship which aims to assess the importance of early life adversity for health at different points in the life course using good quality, prospective data from Great Britain and Sweden.

AIM - the aim of the research is to assess whether early life adversity is associated with biomarkers of stress in childhood amongst children in Great Britain.

B2449 - Frequency association statistics and LD lookups of 6 variants associated with height to fine map a Sardinia GWAS signa - 21/05/2015

This proposal is specifically to look up the allele frequency and height association summary statistics of 6 SNPs.

B2448 - Schizophrenia risk genes immune markers and cognition - 21/05/2015

The purpose of this study is to determine whether the effects of schizophrenia related risk genes on cognitive performance are mediated via changes in pro- and anti-inflammatory cytokines.

B2447 - Characterising the psychological and neurobiological alterations associated with APOE-e4 - 21/05/2015

A. To obtain new cognitive data in ALSPAC focused on online psychological tasks proposed to be sensitive to early life brain changes associated with APOE-e4

B. To understand how performance on these tasks is moderated by factors, such as cognitive reserve, gender and lifestyle, as well as whether there are associations with inflammation, as measured by elevated pro-inflammatory markers

B2446 - Inferring whole-phenome architecture of complex traits - 21/05/2015

Developing methods in estimation of the phenomic components of complex traits, which seeks to address the causal influence of different 'omic data sets on various complex traits.

B2445 - Outcomes in late adolescence in children with Developmental Coordination Disorder - 21/05/2015

The aim of this project is to assess the associations between DCD at age 7 years and difficulties in a number of psychosocial measures, and educational outcomes, at age 15-18 years. We intend to use multi-variate logistic regression to investigate how DCD affects outcomes in late adolescence in three main domains: psychological, social and education.

B2444 - Exploiting the existing biomarker data available in CLOSER social position age and allostatic load - 21/05/2015

Rationale:

Ageing, Social science and allostatic load

Many physiological systems are proposed as the mediators that allow social processes to "get under the skin". Allostatic load is conceptualised as the 'wear and tear' associated with the response to chronic or repeated stress (Mcewen and Stellar 1993). The concept has been adopted in many analyses of the association of the social environment with health as it represents the impact on a multiple physiological systems including 'primary' stress pathways and secondary 'intermediate' pathways (Seeman et al., 2001). A number of studies within CLOSER and others that have detailed measures of the social environment have used the concept of allostatic load to examine social, psychological and other exposures (Babosa-Solis et al., 2015, Read & Grundy, 2015; Rod et al., 2015; Robertson et al., 2015). Allostatic load is generally measured through a composite index of indicators that reflect this multi-system approach and include neuroendocrine, metabolic, immune and cardiovascular markers. However operationalisation of allostatic load varies across surveys as it is limited to the availability of biomarkers within studies. Consequently, it is difficult to compare analyses across cohorts. While there are a few studies in younger age groups (Brody et al., 2014), studies that have examined allostatic load are generally conducted in older age groups (Seeman et al., 2010; Gruenwald et al., 2012; Read and Grundy, 2014). It is unclear that the allostatic load construct remains stable by age or by other factors such as medication status (Booth et al., 2014). A number of studies have suggested that allostatic load varies by social position (Seeman et al., 2010; Gruenwald et al., 2012). Again a majority of these studies are conducted in older age groups and, while one suggests that social differences in allostatic load are apparent in those aged under 75 y only (Robertson et al., 2014), further work is required to understand when in the lifespan the association of allostatic load with measures of social position emerges.

Plan of analyses

1)We will catalogue the biomarkers in the component studies within CLOSER and other studies such as Whitehall II, Twenty-07 and ELSA. In doing this we will highlight valuable analytes for social-biological research, and provide guidance on the key issues that need to be considered in their analysis.

2) We would scope the literature to examine which biological markers are typically included in the construction of Allostatic load. Examine which of the identified markers have been collected across the CLOSER studies with a focus on categorising them as components of primary or intermediate and markers. We will then examine how the inclusion/exclusion of typical plus additional markers might affect our understanding of the construct and its social patterning.

Finally we propose three substantive research questions:

1)to operationalise 'allostatic load' across the cohorts with varying inclusion criteria and by medication status.

2)to capitalise on the on-going work package in CLOSER, which has harmonised measures of social position across the CLOSER studies and examine how social position is related to 'Allostatic load'.

3)to capitalise on the wide age range available in with CLOSER studies to examine how allostatic load evolves across the age span.

B2443 - Methodological toolkit for using digital devices to capture predictive patterns of health behaviours in cohort studies - 14/05/2015

Aims

This project will develop new methods for capturing and analysing health behaviour data from digital devices in cohort studies. It will address specific research questions around identifying patterns of behaviours that predict the start and stop of certain behaviours, including smoking, drinking and snack eating. The underlying methods will be developed in ALSPAC and one other ERSC resourced cohort study (e.g. Understanding Society), and will be designed such they can, through the ESRC's National Centre for Research Methods (NCRM), be adopted by a wider set of cohort studies.

B2442 - Association of mtDNA SNPs with anthropometric and glycemic traits integration with the CHARGEmtDNA consortium - 15/05/2015

a. To perform association of adipose and glycemic traits with mtDNA SNPs in ALSPAC.

b. To perform the association of adipose and glycemic traits with nucmtDNA SNPs in ALSPAC.

c. To meta-analyse the results on all CHARGEmtDNA+ cohorts

B2441 - A Bayesian mixture framework for epigenetics - 15/05/2015

To further develop a statistical framework to model the epigenetic effects of maternal tobacco smoking on offspring and explore changes in the epigenetic profile over time.

B2440 - Are prenatal metabolites nutrients and toxins linked to lung function in adolescence via DNA methylation - 14/05/2015

Are prenatal metabolites, nutrients, and toxins linked to lung function in adolescence via DNA methylation?

B2439 - Social educational and medical outcomes in young adults on renal replacement therapy in the UK - 08/05/2015

Identify broad social outcomes for young adults on renal replacement therapy

B2438 - Metabalomic profile of alcohol consumption in adolescents - 01/01/1900

Aims:

1) To assess the how alcohol consumption affects metabalomic profile

2) To identify a genetic instrument for metabolites that are associated with alcohol consumption

B2437 - Epigenome-wide association study of atopic dermatitis - 07/05/2015

To identify and assess the causal nature of associations between epigenome-wide methylation levels and atopic dermatitis

B2436 - PI-MZ genotype effects on human complex traits including respiratory capacity and height and possible mechanisms - 07/05/2015

PI-MZ genotype: effects on human complex traits including respiratory capacity and height, and possible mechanisms.

B2435 - Methods for dealing with missing data in longitudinal latent class models - 30/04/2015

To establish methods for best practice when dealing with missing data within the context of longitudinal mixture modelling.

B2434 - Pilot study to measure arsenic exposure in ALSPAC participants - 21/05/2015

The aim of this pilot project is to determine the extent to which ALSPAC participants are exposed to arsenic. To carry out this aim, we propose to select 50 urine samples from ALSPAC participants to analyze for methylated arsenic species (inorganic arsenic, monomethylarsonic acid, dimethylarsinic acid). This will allow us to initially characerize the level of exposure to inorganic arsenic and determine whether it is scienitifcally worthwhile to pursue additional analyses on a larger pool of participants to test specific scientific hypotheses.

B2432 - Genome-wide association analysis of 2D4D finger ratio - 30/05/2015

Genome-wide association analysis of 2D:4D finger ratio

B2431 - Positive mental wellbeing in emerging adulthood - 23/04/2015

The aim of this project is to collect a battery of positive wellbeing measures in the ALSPAC young adult sample.

B2430 - PARENTAL SEPARATION AS A RISK FACTOR FOR ADOLESCENT DISORDEREDEATING EXPLORING EXPLANATORY MECHANISMS IN A BRITISH COHORT - 23/04/2015

The study will consider the role of several family-related variables in the association between divorce and

disordered eating

B2429 - The fetal childhood and adolescent effects of prenatal exposure to caffeine - 23/04/2015

This proposal is to assess the associations of caffeine intake with outcomes in pregnancy

B2428 - Youths Resilience and Vulnerability to Maladaptation - 30/04/2015

Aim: To look at the moderating effect of resilience on the effect of neighbourhood deprivation on educational outcomes and externalising problem behaviours.

Resilience is a dynamic developmental process, encompassing the attainment of positive adaptation within the context of adversity (Cicchetti, 2010). Youths with different individual characteristics respond differently to environmental stress, leading either to pathological or resilient developmental outcomes. To explore differences in vulnerability and resilience to environmental adversities, we propose to examine the interaction effects between three important individual psychological and biological characteristics

B2427 - Exploring changes to cardiometabolic risk factors during the menopause - 23/04/2015

To determine the extent to which menopausal age/or chronological age influence cardiometabolic risk factors in women during mid-life (mid-forties to early mid-fifties)

B2426 - The developmental role of Behavioural and Neurobiological Dimensions in predicting Eating Disorders in adolescence/young - 23/04/2015

Eating Disorders (ED) are serious mental health disorders affecting approximately 5-10% of adults (Hudson et al., 2007; Swanson et al., 2011) and have a peak of onset in adolescence between the ages of 15-19 (Micali et al., 2013; Field et al., 2012). The etiology of ED remains poorly understood, though and interplay of genetic and environmental factors is likely to be at play. Research into the clarification of risk factors has been hampered by uncertainties about clear phenotypic distinctions across ED categories, and by a lack of integrative studies using a longitudinal approach to clarify risk for ED. This study aims to focus on how cognitive, emotional and social processes cause ED behaviors in adolescence and young adulthood in interaction with environmental factors from infancy onwards. Cross-sectional studies have identified cognitive, emotional and social difficulties that are associated with ED.

There is cross-sectional evidence that anorexia nervosa (AN) is associated with emotional and social communication difficulties and that specific cognitive profiles characterize bulimic type disorders.AN shares common features with anxiety (Silberg & Bulik, 2005; Micali et al, 2011); and a range of social communication deficits, including interpersonal problems and poor emotion recognition, are present in individuals with AN (Tchanturia et al., 2012; Treasure et al., 2012). Bulimic-type ED are cross-sectionally associated with specific cognitive profiles characterized by poor attention (Dobson & Dozois, 2004; Faunce, 2002) and low inhibition (Galimberti, et al., 2012; Rosval et al., 2006).

Most of the studies cited above are cross-sectional and have often focused on one specific area of behavior or cognition. Large genome-wide studies of psychiatric disorders have highlighted genetic similarities across disorders, indicating either poor specificity of genetic markers or poor specificity of categorical classification systems. The purpose of this study is to investigate the contribution of attention, anxiety and social communication difficulties as well as their biologicla counterparts, genetic data and their interaction with environmental factors to the risk for ED behaviors (restrictive eating, excessive exercise, bingeing, purging at ages 13,14, 16, 18, 24) in a longitudinal developmental fashion.

We propose to use data collected prospectively (and carry out a new wave of data collection) from ALSPAC to investigate the prospective association of anxiety and social communication and AN-type behaviors (restrictive eating and excessive exercise); and cognitive control and attention and BN-type behaviors (bingeing, purging).

B2425 - The effect of antenatal depression and anxiety on adolescent conduct behaviour - 16/04/2015

The aim of the study is to look at antenatal factors affecting behavioural outcome in children of 15 years therefore a longitudinal study was deemed the only appropiate method to use. ALSPAC have obtained the data that is needed for this study, for the nature of this study no other method would be suitable to use.

B2424 - A Longitudinal Study on the Impact ofStressful Life Events on Obsessive-Compulsive Disorder Symptomatology - 16/04/2015

Logistic regressions will be used to examine the association between stressful life events (SLEs) and OCD symptomatology. Additional logistic regressions will be conducted adjusting for sex, social economic status, depressive symptoms severity obtained from the SDQ at 81 months, maternal depression and marital status.

I will also investigate the impact of missing data using multiple imputation.

B2423 - Team Grant Developmental Origins of Health and Disease - Implications for Men Women Boys and Girls - LOI 2015-04-13 - 16/04/2015

Overview. While fetal exposure to toxic elements has been associated with metabolic disease, and some of these associations are sex-specific, it is unclear if these associations are causal. The overall goal of MET-DETOX is to provide causal evidence as to whether fetal exposure to toxic ele- ments predisposes to type 2 diabetes (T2D) and components of the metabolic syndrome. This will be achieved by identifying maternal and fetal genetic and gene x environmental determinants of toxic elements in fetal cord blood and using this information to undertake Mendelian randomization (MR) studies. Since levels of environmental toxicants are modifiable, understanding their etiologic role could support key public health interventions to decrease the burden of metabolic disease in Canada.

B2422 - Psychosocial stress and eczema persistence - 16/04/2015

The link between psychosocial stress and eczema (aka atopic dermatitis) was identified at least a half-century ago when eczema was designated one the seven classic psychosomatic disorders.[1] The allostatic model of chronic stress proposes that dysregulation of normal homeostatic mechanisms may lead to chronic hyperarousal or hyporesponsiveness.[2] Mechanistic evidence comes from the field of psychoneuroimmunology linking the nervous system, endocrine system, and immune system.[3,4] Stress may also lead to disease-exacerbating behaviors related to diet, sleep, exercise, bathing practices, and treatment adherence.[5] In epidemiologic studies, self-reported stress levels have been shown to correlate with eczema incidence, and stress-reducing modalities have been found to improve eczema symptoms.[6,7]

Various factors are involved in a stress response and will be included in our analyses: exposure to a stressor, resilience/ the use of social supports, and the emotional and behavioral response.[2] We will also include family-related distress such as caregiver stress, maternal panic disorder or depression and family conflict because these have been reported to have immunological effects on younger subjects.[8]

Aim: To examine the association between stress and eczema.

Hypothesis: Higher rates of distressing life events, poor social supports, and psychological distress will each be associated with more persistent eczema.

All patients in the ALSPAC cohort with follow-up data available through age 18 will be included in a longitudinal cohort study. Because the relationship between stress and eczema is likely bidirectional,8 we will model the relationship between each measure of stress and repeated measures of eczema persistence using a marginal structural model and stabilized inverse probability-of-treatment weights to avoid conditioning on stress through its inclusion as a predictor in the outcome model.[9] We will have 90% power to detect an odds ratio as small as 1.23 at a 0.05 significance level in a design with 5 repeated measurements, assuming 15% eczema prevalence.[10,11] We will carefully evaluate missingness and will conduct sensitivity analyses using multiple imputations.[12,13] The results of this study promise to disentangle the individual experience of stress from group-level factors that may be associated with stress including race, socioeconomic status, and environmental factors.

B2421 - Psychosocial Costs of Mens Appearance and Physical Performance-Motivated Behaviors - 16/04/2015

This study relates to a previous (approved) proposal regarding the investigation of eating disorder behaviors in ALSPAC by childhood and adolescent gender expression and adolescent report of sexual orientation. We have additionally proposed the collection for new data concerning current gender expression and sexual orientation, as well as engagement in a wider array of appearance and physical performance-motivated behaviors than has previously been examined in ALSPAC (see accompanying QPF). The collection of new ALSPAC data and analysis of new and existing ALSPAC data will be covered by funding from K01DA034753 (PI: Dr. Calzo) and an R01 from NIH that Dr. Calzo will apply for in October 2015. Analyses of ALPSAC data will complement analyses of data from the Growing Up Today Study and Nurses' Health Study III Men's Cohort in the United States, thus providing a cross-cultural analysis of the comorbidity and costs of appearance and physical performance-motivated behaviors in men's lives from adolescence through middle age.

B2420 - NMR-based Metabolomics pilot on Lymphoblastoid Cell Lines LCLs - a case/control study for Niemann-Pick Type C1 diseas - 16/04/2015

This is a pilot study with the following research aims:

1.) Generation of NMR-based metabolomics data on Niemann-Pick Type C1 (NPC1) disease for identification of metabolic (diagnostic) markers for NPC1 disease at different ages.

2.) Development of methodology to facilitate future work on metabolomics of LCLs.

3.) Evaluation of a 700MHz NMR spectrometer with 1.7mm cryoprobe for metabolomics on mass-limited samples. This instrument is the first of its kind in the UK and offers significant potential for novel metabolomics research. A comparison will be made to data acquired on more standard NMR spectrometers (600MHz with 5mm nitrogen-cooled (Prodigy) probe).

Niemann-Pick type C disease is a complex disorder characterized by elevated cholesterol, glycosphingolipids and sphingosine in endosomal compartments. In the majority of patients lipids are stored due to a defective protein NPC1 a membrane spanning late endosomal protein. A minority (5%) of patients have mutations in a lumenal late endososmal protein NPC2. Although much is known regarding the clinical aspects of NPC disease, the cellular mechanisms leading to neurodegeneration are, to date, poorly understood, and the precise function of the NPC1 and NPC2 proteins remains unknown or speculative. NPC disease has one EMA-approved therapy (Miglustat) which is disease-modifying; however, new, additional therapeutic approaches are urgently required. In order to evaluate these, the identification of novel, clinically-relevant biomarkers for the monitoring of this disease and its progression are necessary.

B2419 - Developing novel online cognitive tests ofspatial perception and memory for use in UK population cohorts - 16/04/2015

We study the potential importance of early life cognitive and brain alterations associated with apolipoprotein (APOE)-?4, an allele linked to increased risk of later life Alzheimer's disease (AD, Genin et al., 2011). With colleagues at Cambridge University, we have recently elicited behavioural differences in young undergraduate APOE-?4 carriers (versus non-carriers) on a novel spatial learning task (Hodgetts et al., in prep). Testing the reliability of this finding, and examination of potential moderators (e.g., gender), now requires larger-scale representative samples. With ALSPAC, therefore, we are writing grants to facilitate new brain imaging and behavioural data collection, as well as analysis of retrospective data. These will address pressing questions about the relationship between early life brain/behavioural changes and later-life cognitive decline.

Here, we propose pilot data collection designed to strengthen a Wellcome Collaboration Award (WCA) between Bristol, Cambridge and Oxford Universities. In the WCA, one key objective is to carry out online data collection using versions of the cognitive paradigms we have established - in smaller scale studies - to be sensitive to APOE-?4 status. This move towards online cognitive tasks (applicable throughout the lifespan and in different cohorts), and large-scale population-level analysis, is new to our research. We do not yet have pilot data that shows, unequivocally, our ability to (a) develop cognitive tasks to enable sensible and robust behavioural assessment and (b) apply these in populations, specifically ALSPAC, underpinning our proposed WCA.

B2418 - EWAS of IL6 - 16/04/2015

IL-6 is an inflammatory cytokine with diverse roles in chromic inflammation and autoimmunity. It is thought to play a role in a diverse array of health outcomes, including auto-immune conditions, allergic conditions, brain diseases and even depression. Therefore, increased understanding of the mechanisms that influence it, and that it influences, could have far reaching health implications.

Aim: EWAS of interleukin-6 measured in the children at age 9, to identify CpG sites where methylation levels are correlated with IL-6 levels.

B2417 - Characterisation of the common and rare genetic architecture of head circumference during childhood and adolescence - 16/04/2015

Within our study, we aim to analyse common and rare genetic variation for association with head circumference within a total sample of 6284 unrelated 7-year-old ALSPAC children with phenotypic information (mean(SD)=52.5(1.5) cm). For this, we will carry out a meta-analysis in collaboration with other cohorts such as GenR, HELIC and QIMR. Specifically, we aim at the detection of novel rare but also single point variants. In addition, we will search for an enrichment of signals according to cell type and syndromic loci, where disorders have been linked to abnormal head shape (holoprosencephaly, oral clefts and others). This will be complemented by analyses of SNP heritability and genetic correlation analyses with other anthropometric traits in ALSPAC during childhood and adolescent development.

Exposure variables in ALSPAC: The analysis will be carried out within the framework of a UK10K Project (UK10K approval has already been obtained). This includes the investigation of 1867 individuals from the Avon Longitudinal Study of Parents & Children (ALSPAC), which have been whole genome sequenced (WGS) to ~6.5x coverage. The analysis will also include the remaining ALSPAC children with genome-wide SNP data (total N=8365). These data were jointly imputed using variants discovered by WGS together with those from 1000 Genomes. Outcome variables in ALSPAC: The investigated phenotype is head circumference at 7 years of age. Genetic relationships will also be explored with respect other anthropometric and bone-related variables, as well as cognitive functioning (height, weight) during childhood and adolescence (birth to 17 years).

B2415 - Mendelian Randomisation in the Presenceof Many Instrumental Variables and Many Measurements - 09/04/2015

Aim : Our aim is to develop new methods for causal inference in the context of the Mendelian randomisation (MR) framework.

We are interested in the metabolites data set because we believe it is interesting from both a methodological and biological point of view. MR being an instrumental variable method, it makes strong and untestable assumptions about the effect of genetic variants on measured variables, the 'no pleiotropy' assumption being the most restrictive (Didelez V. et al, 2010).. But one might ask whether it is possible to relax this assumption, and if so with what consequences. When the number of genetic variants and measurement increase, can it be replaced by a different set of assumptions that might be more believable in a biological context. See for example (Silva R and Evans R., 2014) and (Kang et al. 2014) who make assumptions about the strength of the confounders and the number of invalid instruments. To that end, we intend to model all variables together, a method sometimes called "network Mendelian randomisation" (Burgess S. et al, 2014). In particular, we will use recent developments in the fields of matrix recovery and graphical modelling in order to infer the effect of the confounders and identify some of the pleiotropic pathways (Candes E. et al. 2009, Chandrasekaran V., 2011). According to our power analysis, we expect to uncover 60% of the causal links at a false discovery rate of 5 %, and this in the presence of arbitrarily strong confounders. Thanks to simulations for a wide range designs, we have confirmed that our FDRs are well calibrated.

B2414 - Genetic Mutations causing congenital imprinting disorders mechanisms and consequences - 09/04/2015

Aim: to compare the DNA methylation (blood leukocyte) of patients with ultra-rare imprinting disorders, with that of batch-matched, averaged data from individuals within ALSPAC and similar cohorts.

Background

Humans harbour approximately 100 known imprinted genes, characterised by the epigenetic control of gene expression, often through parent-of-origin specific methylation that is applied in the germ line and conserved through subsequent development in all tissues. As yet, disruption of the methylation state at eight imprinted loci has been associated with imprinting disorders (IDs): Beckwith-Wiedemann syndrome (BWS; MIM #130659), Silver-Russell syndrome (SRS; MIM #180860), transient neonatal diabetes mellitus (TNDM; MIM #601410), Prader-Willi syndrome (PWS; MIM #176270), Angelman syndrome (AS; MIM #105830), matUPD14-like (Temple syndrome) and patUPD14-like (Wang-Kagami) syndromes, and pseudohypoparathyroidism 1B (PHP-1B; MIM #103580).

A proportion of patients with IDs have multi-locus imprinting disturbance (MLID) affecting different imprinted loci throughout the genome. MLID patients may have clinical features in addition to the 'classic' clinical presentation of IDs, such as developmental or behavioural problems, atypical growth patterns, or congenital anomalies; in some cases, clinical features may be nonspecific to any ID, obscuring a clinical diagnosis. We have developed a robust informatic approach for analysing epigenomewide DNA methylation, using the Illumina Infinium HumanMethylation450 BeadChip (henceforth referred to as 450k). The method requires analysis of 450k data from a single patient, compared with the averaged values from a group (optimally 20-40) batch-matched controls.

Accurate characterisation DNA methylation in MLID patients is valuable as it can underpin personalised management, and moreover can indicate the presence of an underlying genetic mutation. While in many cases the causes of MLID are unknown, and may be purely stochastic or environmental, in some cases we have identified genetic mutations causing MLID.

B2413 - Impact of environmental exposures on sperm parameters and male fertility - 09/04/2015

Infertility is a significant health problem worldwide, estimated to affect approximately 1:6 couples of reproductive age. Whilst reports of global declines in semen quality are controversial, the increasing prevalence of male subfertility stands as uncontested fact: male factor is now the leading cause of fertility problems, and accounts for almost half of all cases. Exposure to environmental toxicants, such as heavy metals, organic solvents and pesticides, as well as lifestyle choices, including obesity and poor diet, drugs (prescribed medication and otherwise) and smoking are all suggested to be contributory causes to male subfertility, but effects are poorly defined. Unexplained poor sperm motility (asthenozoospermia) is the commonest clinical abnormality in subfertile males, yet our limited knowledge of the exact workings of spermatozoa mean that this problem is incompletely understood, neither do we know how to correct it. Incredibly, there is no drug that a subfertile man can take, nor that can be added to his sperm in vitro, to improve sperm motility. Couples instead rely on Artificial Reproduction Technology (ART), such as IVF, which is expensive, invasive and not without risk. Nonetheless, year-on-year, ART is increasingly utilised worldwide. In order to tackle a global health problem, there is clearly a need to better understand the pathological processes affecting male reproductive health.

Sperm motility, calcium and CatSper

Sperm motility is arguably the most important characteristic to impact on male fertility. Increase and fluxes in intracellular calcium [Ca2+]i are fundamental to the regulation of sperm motility and function, including changes in direction, hyperactivation and chemotaxis. [Ca2+]i is regulated by at least two processes: mobilisation of Ca2+ stored in the sperm neck region and/or movement into the cell via Ca2+ permeable ion channels and transporters, mainly CatSper channels. CatSper channels are essential for male fertility and are present in the flagellum of human sperm. Landmark studies have demonstrated Ca2+ entry into human sperm in response to progesterone (a product of cumulus cells) is via CatSper channels. CatSper channels are also activated by organic molecules that apparently evoke chemotaxis, and it has therefore been proposed that this ion channel acts as a polymodal chemosensor integrating multiple chemical cues from the female reproductive tract to elicit functional responses to direct sperm towards the egg.

Environmental exposures

Xenobiotics are any alien molecules that are foreign to mammalian biological systems. Such substances include pesticides, herbicides, cosmetics, preservatives, cleaning materials and pharmaceutical products, and have worked their way into our lives in a variety of forms. Even though awareness of the biological risks of chemical toxicity has increased considerably in recent years, the majority of these chemicals have long half-lives and can still be detected in the environment decades after their release. Xenobiotics may have direct or indirect effects on sperm motility and function, including interference with physiological CatSper responses, which subsequently manifests as male subfertility. For example, dichlorodiphenyldichloroethylene (DDE) is an organochlorine pesticide, an endocrine disruptor and known reproductive toxicant to certain species of birds due to thinning of their eggshells. DDE is fat soluble, and tends to build up in the fat of animals. Due to its stability in fat, DDE is rarely excreted from the body, and body levels tend to increase throughout life. In vitro exposure to DDE affects functional sperm parameters and we have demonstrated that it activates CatSper at environmentally relevant concentrations.

Trans-generational reproductive impact

For many disease states it is now recognised that the risk of disease in adult life is determined by a combination of genetics, the intra-uterine environment, childhood exposures and adult lifestyle, but the impact of each of these components on sperm parameters and male fertility is largely unknown. The impact of environmental factors on the epigenome and male fertility, and significance of epigenetic changes/aberrations (often hypermethylation) in assisted reproduction are beginning to be understood. However, identification of the respective contribution of genetic and timecourse environmental exposures to male reproductive capacity in adulthood is not only very limited, but also very challenging, particularly due to the difficulty of obtaining data on multiple factors throughout life.

Aims

By utilising the Avon Longitudinal Study of Pregnancy and Children (ALSPAC) cohort, we aim to address the contribution of genetic and timecourse environmental exposures to male reproductive capacity in adulthood. This cohort is a huge resource and has the fantastic potential to provide prospective longitudinal data, allowing not only quantification of relative contributions of various elements, but the potential to identify critical timepoints and how these associations change with progression from fetal life, childhood, adolescence and into adult life.

B2412 - Maternal Smoking During Pregnancy andChildhood Obesity linear association or threshold effect An IPD Meta-Analysis - 09/04/2015

Aims:

A positive association between maternal smoking in pregnancy and childhood obesity has been confirmed in a number of meta-analyses of observational studies (Oken, Levitan et al. 2008, Ino 2010, Weng, Redsell et al. 2012). This empirical evidence for a causal association between intrauterine exposure to nicotine and childhood overweight later in life, however, has been questioned because of potential residual confounding (Raum, Kupper-Nybelen et al. 2011, Yang, Decker et al. 2013). Major concerns regarding possible residual confounding were based on the observation that children who were exposed to paternal or secondhand smoking while in utero as well as after pregnancy also had an increased risk of being overweight, and that this risk was similar to that observed in children with maternal intrauterine exposure to much higher levels of nicotine or other smoked products (Leary, Smith et al. 2006, Kleiser, Schaffrath Rosario et al. 2009, Plachta-Danielzik, Kehden et al. 2012, Harris, Willett et al. 2013). These results were surprising given that second-hand environmental tobacco smoke (ETS) exposure is not necessarily considered an intrauterine exposure, and the associated exposure dose of nicotine is much lower compared to that seen with direct maternal smoking (Florescu, Ferrence et al. 2007). Although mutual adjustment did not eliminate the effect of maternal smoking (Leary, Smith et al. 2006, Apfelbacher, Loerbroks et al. 2008, von Kries, Bolte et al. 2008, Kleiser, Schaffrath Rosario et al. 2009), the persistence of a similar effect size from paternal smoking either during or after pregnancy on childhood overweight raises concern about the potential of both ETS and maternal smoking in pregnancy to affect childhood overweight, and might be a reflection of a common unidentified family characteristic accounting for residual confounding, such as genetic or environmental factors, which could explain the effects of both paternal and maternal smoking during pregnancy.

An alternative explanation might be that there exists a very low threshold of smoke exposure from either father or mother leading to a priming effect that increases a child's risk to become overweight later on in life: in this case, the low exposure from ETS or paternal smoking would be sufficient for the priming effect and a linear dose effect of maternal smoking in pregnancy would not be observed. Indeed, it is still unclear whether or not a linear dose effect of maternal smoking on childhood overweight exists. Some studies suggest that a linear dose effect does exist (Power and Jefferis 2002, Hill, Shen et al. 2005), however, most confidence limits of the dose-related effect estimates overlap widely. The associations observed in other studies suggest instead a threshold effect, with a steep increase in effect at low exposure levels that flattens out at higher exposure levels (Reilly, Armstrong et al. 2005, Chen, Pennell et al. 2006).

Assuming a threshold effect, exposure to paternal smoking and ETS levels above the threshold could yield similar effects on childhood obesity as maternal smoking exposure in pregnancy, which would be compatible with the concept that low dose smoking exposure leads to an intrauterine priming effect which increases the offspring's risk to become overweight later on in life. This individual patient data (IPD) meta-analysis aims to identify whether a linear dose-effect relationship exists for maternal smoking during pregnancy on childhood obesity.

B2411 - Environmental risk factors of health-risk behaviours Using DNA to strenghten causal inference - 26/03/2015

AIMS:

Health-risk behaviours - here including alcohol, tobacco, drug use, risk taking and antisocial behaviour - are prevalent in early adulthood and highly comorbid. They constitute a major public health challenge impacting individuals, families and society. Identifying environmental risk factors causally associated with health-risk behaviours is crucial to design effective interventions.

The main objective of the proposed research project is to identify environmental risk factors causally associated with health-risk behaviours in emerging adulthood. To achieve this aim, the project will build on advances in genetics, using DNA information to strengthen causal inference.

The project will largely build on already collected data and, pending on funding may include additional data collection regarding health risk behaviours and environmental risk in early adulthood.

The project will investigate three major questions:

1. Comorbidity between health-risk behaviours: We will test whether the observed comorbidity within health-risk behaviours is due to underlying causal relationships or arises from genetic and environmental confounding (for instance alcohol use and antisocial behaviour).

2. Magnitude and consequences of gene-environment correlations: We will examine gene-environment correlations by looking at genetic influences on environmental risk factors (e.g. neighbourhood safety). We will then test to what extent the relationship between risk factors and health-risk behaviours may arise from shared genetic influences.

3. Early and concurrent environmental predictors: We will build on the longitudinal feature of the datasets to examine how early and concurrent risk-factors predict health-risk behaviours. We will contrast conventional analyses and classical techniques to examine causality with analyses using DNA information to strengthen causal inference.

B2410 - Investigating causal associations between caffeine consumption and ADHD - 26/03/2015

Aims:

An association between caffeine consumption and ADHD is well-established, but whether this is causal is harder to ascertain. In particular the direction of any causal association is unclear. We will use Mendelian randomisation to assess the association between a risk score predicting caffeine consumption and ADHD, and between a risk score predicting ADHD and caffeine consumption.

B2409 - Exploring the heritability of facial features in fathers and offspring using spatially-dense geometric morphometrics - 19/03/2015

Background

The face is a biological display of our identity and controlled in the most part by genes.1-3 There is consistent facial concordance between identical twins,4 identifiable facial features within families,5 geographic populations,6 and the sexes,7 and finally distinctive facial features associated with particular genetic conditions.8,9 This suggests that inter-individual variation in craniofacial morphology is primarily determined by genetic variation.

Studies of craniofacial heritability are performed on twin and parent-offspring databases and provide insight in the relative contribution of genetic and environmental effects on craniofacial parameters.4,5,10,11 Heritability studies allow the focus on those facial parameters displaying a strong genetic component as well as acknowledging possible environmental influences. Most if not all studies on craniofacial heritability start from sparse descriptions of facial shape using a limited set of manually indicated landmarks. Variation in these landmarks is then comprised using principal component analysis or by measuring geometric features such as distances, curvature, ratios and/or angles. Subsequently, for each principal component or geometric feature separately a heritability score is computed using correlations between parent and offspring or between twins. However, sparse representations typically overlook salient features of facial shape. Furthermore, heritability studies today do not investigate co-inheritance between different geometric features. Doing so would allow subdivision of facial shape into modules (multiple landmarks and measurements grouped together) of co-inheritance, that when analyzed as groups could reveal higher levels of inheritance.

Research Aim

The aim of this proposal is to perform a spatially-dense analysis of facial heritability and co-heritability starting with Fathers and offspring data available within ALSPAC. The study outcome is two-fold. In a first instance a spatially dense view on facial heritability per landmark will be provided. In a second instance, a subdivision of facial shape into modules of co-inheritance will be provided. Subsequently, the benefit of such a modularization will be tested in a limited association study between facial shape and known craniofacial genes based on BRIM.12

B2408 - An investigation into the determinants of fatigue in a population-based cohort of young adults - 19/03/2015

Hypotheses

1. Musculoskeletal phenotypes during adolescence (particularly pain, joint hypermobility, muscle morphology) are associated with chronic fatigue as an adult. This association will be influenced by anxiety/depression, obesity and gender.

2. There are subdivisions of the musculoskeletal fatigue phenotype with different risk factors and potentially different responses to interventions.

3. There is intergenerational transmission of fatigue vulnerability.

Aims and purpose

Aim 1: To stratify adults at aged 24 with fatigue into various fatigue phenotypes based on associated features including musculoskeletal variables, sleep disturbance, mood disturbance. We will investigate the overlap, basic descriptives and epidemiology of these fatigue phenotypes.

Aim 2: To further our understanding of the association between musculoskeletal variables (specifically musculoskeletal pain, joint hypermobility and muscle morphology) and fatigue in adults, by assessing whether musculoskeletal phenotypes at aged 13.5 are associated with fatigue in adulthood.

Aim 3: To explore causal pathways between anxiety/depression, musculoskeletal phenotypes and fatigue in adults.

Aim 4: To investigate whether the various fatigue phenotypes identified in Aim 1 (e.g. fatigue alone, fatigue+pain, fatigue+hypermobility, fatigue+obesity, fatigue+reduced muscle mass/density, fatigue+mood disturbance) have different risk factor profiles and causal pathways.

Aim 5: To produce the first population-based data on the change in prevalence (natural history) of fatigue between aged 17.8 and aged 24. We will describe the trajectories of fatigue over 6 years to define whether fatigue regresses, progresses or remains stable.

Aim 6: To carry out the first investigation of the intergenerational effects of fatigue by identifying whether parental fatigue phenotypes are transmitted to offspring, whether particular parental characteristics increase the likelihood of transmission of fatigue, and whether particular offspring characteristics increase vulnerability to transmission of fatigue.

B2407 - Effects of smoking during pregnancy on offsprings autistic traits mediation by DNA methylation - 12/03/2015

Background: Autism spectrum disorders (ASD) are neurodevelopmental disorders characterised by deficits in social interaction and repetitive and stereotyped interests and behaviours. The aetiology ot ASD comprises known genetic factors [1,2] and increasing evidence suggests a role for intrauterine environmental factors, such as exposure to maternal smoking during pregnancy [3]. Maternal smoking during pregnancy has been associated with other adverse perinatal outcome such as lower birth weight and higher risk of other neurodevelopmental disorders such as attention deficit hyperactivity disorder [5], therefore smoking during pregnancy is a biologically plausible hypothesis in the aetiology of autism but the evidence is still inconsistent. Epigenetics is one potential mechanism linking intrauterine exposures and postnatal outcomes. DNA methylation changes induced by the prenatal exposure could affect genes that are implicated in the aetiology of ASD and therefore DNA methylation could be a causal mediator for the increase risk of ASD. A recent study in the ALSPAC has shown that maternal smoking is associated to DNA methylation changes across the genome, including the replication of genes that were found in other cohorts and new targets [6]. Although an association between maternal smoking in pregnancy and autism might be plausible, there is much inconsistencies in studies to date. In particular, when investigating causal effects in observational studies there is the possibility of unobserved and residual confounding and a way to overcome this issue is by using genetic variants as proxies for the exposure as in a Mendelian Randomization framework [7]. GWAS studies have observed robust associations between smoking and a locus on chromosome 15 involving the CHRNA3 gene, as well as associations in other genes such as BDNF [8].

Aim: We aim to investigate the causal relationship between maternal smoking during pregnancy and childhood's autistic traits and whether this is mediated via DNA methylation changes at birth.

B2406 - A Mendelian Randomisation study of Skin tone and Vitamin D - 12/03/2015

In this project I will examine the association between Skin tone, Vitamin D levels and a range of health outcomes. It has been shown in previous studies using ALSPAC data (Bonilla et al 2014) that children who had genetic variants associated with fairer skin have higher vitamin D levels. I wish to test the hypothesis that children with fairer skin will have lower BMI and blood pressure once the vitamin D levels have been controlled for. In this study I will use Instrumental Variables analysis to examine the effect of Skin tone and Vitamin D levels on a range of health outcomes such as BMI and blood pressure using the genetic variants associated with skin tone and Vitamin D levels to control for potential confounding in this estimation. Due to potential confounding in this study I will also control for time spent in the sun and whether or not a child has ever been sunburnt using questionnaire results, the gender of the child and the ethnicity of the child.

In this project I would also like to use the genotype data for the mothers to test the association between the fairer skin/higher vitamin D levels and the outcomes BMI and Blood pressure in female adults using Instrumental Variable Analysis and two sample Mendelian Randomisation. This analysis will test the same hypothesis as the analysis of the child data however rather than using Instrumental Variable analysis to assess the effect of skin tone on the outcomes considered I will use two sample Mendelian Randomisation to test the hypothesis that the SNPs shown to be associated in other studies with skin tone have an effect on BMI and Blood pressure. To control for additional confounding in this analysis I will also control for the age and ethnicity of the mother.

Levels of Vitamin D in individuals vary over the year and so in each of the analyses above I intend to control for the time of year at which the Vitamin D levels where sampled in order to control for any variation caused by differences in the season of sampling. Another source of potential confounding in this data is from population stratification due to systematic differences in the frequency of alleles for skin tone across different sections of the population. Therefore, I will control for additional potential population stratification in the data using Principal Components analysis of the genotype data.

I would like to use ALSPAC for this analysis due to the availability of the phenotypes and genotypes needed for this analysis in both children and mothers enabling analysis of the relationship between skin tone, Vitamin D and BMI/blood pressure in both children and adults.

B2403 - Unravelling the link between depression and violence in adolescents - 05/03/2015

Background

Depression is one of the most widespread mental health concerns in the world (Kessler & Bromet, 2013). It is often linked to inwardly directed harm such as self-injuries and suicide (Cuijpers et al., 2014; Hawton et al., 2012; Hawton et al., 2003). The association between depression and violence against others remains uncertain. Emerging evidence is showing that depression and violent behaviours are associated. Positive depression-violence associations have been reported in cross-sectional community survey and register-based investigations (Coid et al., 2006; Wallence et al., 1998; Swanson, 1990), and longitudinal cohort studies (Arseneault et al., 2000; Monahan et al., 1983). Recent research on a total population cohort has shown that risk of violent crime was increased in individuals with depression even after adjustment for familial, socio-demographic and individual factors (Fazel et al., 2015). To date, however, evidence regarding this link has been largely limited to adult and selected samples of individuals in secondary or tertiary care. It is not clear whether the magnitude of depression-violence link is different according to the developmental stages of an individual and whether it is related to more sensitive markers of the illness course. Further, it is not known the mechanisms of any association.

Aim: This project sets out to dissect the depression-violence link with a developmental perspective. Subsequently, this project proposes to test the moderating role of situational factors (i.e., stressful life events) and the mediating role of self-regulation abilities (i.e., inhibition, locus of control), self-harm, and peer victimization. The gained knowledge will be used to facilitate the development of tailor-made prevention and intervention strategies to mitigate the link between depression and violence.

B2402 - An examination of the association between school engagement at 10-11 yrs and sexual health and behaviours at 21 yrs - 05/03/2015

Background

Identifying factors in childhood that are associated with later poor sexual health (e.g. early sexual behaviour, sexually transmitted infections, and teenage pregnancy) may be valuable in recognising and targeting populations at risk (Parkes et al., 2014). Lower school grades and school adjustment problems in childhood have been proposed as potentially important determinants of early sexual initiation (Zimmer-Gembeck et al., 2008), and recent studies using ALSPAC data found persistent school dislike in primary school to be associated with early sexual behaviour and sexual risk taking, reported at age 15 years (Parkes et al., 2014) and low educational attainment at 11 years to be associated with Chlamydia infection at 18 years (Crichton et al., 2014). We wish to extend this work, to examine the association between school academic achievement and school engagement in childhood with sexual health outcomes reported at age 21 years.

Aim

To determine if academic achievement or school engagement in Year 6 (age 10-11 years, final year of primary school) predict self-reported sexual health/behaviours at age 21 years.

B2401 - Maternal substance use in pregnancy and childs educational attainment at age 16 years - 05/03/2015

Background

Two previous studies using ALSPAC data have examined the association between prenatal alcohol exposure and educational perfomance at Key Stage 2 (the last year of primary school, aged 11 years approximately). One study contrasted maternal and paternal alcohol intake in pregnancy, and found that maternal binge drinking was associated with lower KS2 scores but paternal binge drinking was not, thus suggesting an intrauterine mechanism (Alati, 2013). In support of this, a second study found children of mothers whose genotype predisposed them to lower alcohol consumption during pregnancy had a better performance at KS2 than the children of mothers whose genotype predisposed to heavier drinking; a finding which suggests positive associations in observational studies between self-reported moderate alcohol intake in pregnancy and child's educational attainment are explained by residual confounding by factors associated with socio-economic position (Zuccolo, 2013).

Prenatal cannabis exposure has also been shown to have a negative effect on intellectual development at age 6 (Goldschmidt, 2008), resulting in lower educational attainment at age 14 years (Goldschmidt, 2012). This association has not previously been explored using ALSPAC data. Intrauterine exposure to tobacco smoke and child's IQ at 8 has been studies using ALSPAC; associations between maternal and paternal smoking and child's IQ were similar, suggesting any relationship between smoking in pregnancy and child's IQ may not explained by intrauterine exposure (Alati, 2008).

Aims

This proposed study would extend previous work to determine if any negative impact of intrauterine exposure to alcohol, cannabis or tobacco on educational attainment persists to Key Stage 4 (GCSEs, taken when aged 15-16 years). [The inclusion of cannabis as an exposure will depend on whether numbers are adequate].

B2400 - Lookup of methQTL signals for variants associated with anthropometric traits and identified in the UK10K project - 05/03/2015

The UK10K project represents one of the first large scale applications of next generation sequencing to population based epidemiological samples and the examination of complex phenotypes. The objectives of this work are to record whole genome sequence variation at and below 1% minor allele frequency, to provide an imputation reference and to use this, not only to provide a resource for the scientific community (both genotypes and phenotypes), but also to examine genetic associations across a spectrum of genetic variation.

The study is composed of two samples drawn from European population based epidemiological studies (The Avon Longitudinal Study of Parents and children and Twins UK) and forms a collection of nearly 4000 participants now with whole genome sequence data and phenotypes (along with complementary imputed internal replication data sets). A total of 1,990 individuals from TwinsUK and 2,040 individuals from ALSPAC were consented for sequencing. Variant sites and genotype likelihoods were called using samtools and genotypes were refined and phased using BEAGLE, with similar procedures to the 1000 Genomes Project.

In addition, both ALSPAC and TwinsUK consented to release phenotype data related to cardiovascular disease as a public resource for the association analyses. Twelve anthropometric traits including height, weight, BMI, waist-hip-ratio, waist-hip-ratio (BMIadj), waist circumference, waist circumference (BMIadj), hip circumference and hip circumference (BMI adj) and DXA measures (total fat mass, total lean mass and trunk fat mass) phenotypes were released. The association analyses for the anthropometric traits are currently reaching a critical phase for the singlepoint associations, and also for those more rare variants with analyses being undertaken using variant aggregation techniques such as SKAT. Consequently, we are following up possible avenues for unraveling the underlying molecular mechanism of the identified genetic associations. To this end, we are writing to seek a collaborative arrangement efforts to continue our analysis of both single point and rare variant associations using expression (already part of UK10K agreement) and methylation data.

B2399 - Association between brain anatomy and genetic risk for mental disorders in healthy volunteers - 05/03/2015

This project aims at combining multiple MRI datasets obtained in the same magnet (scanner) through very similar acquisiton procedures in order to investigate the association between anatomical markers and genetic risk factors for major mental disorders (psychosis, bipolar disorder and Alzheimer's disease) and associated polygenic pathway scores (e.g. dopaminergic transmission) in healthy participants. The combination of ALSPAC's and our own samples will constitute a unique resource to investigate neuroimaging and genetic associations, since it will include data from potentially up to 1,000 participants avoiding the counfounds of previous similar efforts from other groups using different magnets and not always equivalent data acquisition methods.

B2398 - Genomics of Neuropsychiatric Traits in Children and Adolescents MRC IEU project - 05/03/2015

Aims & Hypotheses

The overall aim of our research is to identify genetic variants associated with a neuropsychiatric traits in children using community-based samples. We are interested in three specific traits: obsessive-compulsive traits, ADHD traits and response inhibition as measured by the Stop-Signal Task. Given that response inhibition is an endophenotype for ADHD, we expect that identifying genetic variants associated with response inhibition will also help us identify genetic variants associated with ADHD.

B2397 - Metabolomic profile of Familial hypercholesterolaemia - 05/03/2015

Familial hypercholesterolaemia (FH) is an inherited condition affecting at least one in 500, although current studies suggest that the frequency is much higher (1 in 250). Affected individuals are characterised by a significant increase of LDL cholesterol levels from birth. It is ussually caused by mutations in one of three genes (LDLR, APOB or PCSK9), however recently a polygenic cause of high LDL-C has been found to mimic the clinical FH phenotype. Our preliminary results showed that individuals with the polygenic form of FH have significantly higher triglyceride levels in comparison to the monogenic FH patients, which suggest that different metabolic pathways may be involved in the development of hypercholesterolaemia in these two forms of FH. We therefore would like to:

1) Compare the metabolomic profiles of the polygenic vs the monogenic FH to see if there are different pathways involved in the two groups

2) Focus on the known FH associated loci (LDLR and APOB) and compare the FH mutations versus common occuring polymorphisms in the same locus which have previously been associated with lipids in large scale association studies. This will help us test if the FH mutations are associated with metabolic changes different to those attributed to their genes in studies using healthy population samples.

Replication will be available through UCLEB where similar information is available.

B2395 - External validation of two studies on risk factors and prediction of childhood asthma - 26/02/2015

Background: We recently published two studies in which we developed a novel and robust tool for predicting asthma at school age in preschool children with wheeze or cough (REF1), and determined the association between breastfeeding and school-age lung function (REF2). The two studies made use of population-based cohorts from children of Leicestershire, United Kingdom.

Aim: We want to externally validate the findings of those two studies using the ALSPAC data set.

B2394 - Socioeconomic gradient of smoking comparing families where one or two parents smoke - 26/02/2015

We seek approval to repeat this analysis among the four English STELAR cohorts. Data requested are (at a given timepoint) socioeconomic status, number of smoking adults in the child's house, number of adults in the house (this addresses the issue of single parent families). In some of the cohorts, these outcomes may be available at more than one time point and this would allow us to see whether these observations are static or change over time.

B2393 - Using a genetic risk score for Coronary Artery Disease to investigate casusal influences on the metabolome - 19/02/2015

Multi-locus genetic risk profiles, or genetic risk scores (GRS) aggregate data from multiple SNPs to provide a robust genetic instrument for traits of interest. They are more powerful than single SNP GWAS scores as the use of multiple sites reduces the effects of pleitropy and minor allele frequencies. GRS have been developed for many conditions including CAD and obesity. They provide a useful genetic tool for probing the causal pathways of multifactorial diseases.

In this study we intend to use multiple GRSs developed from CARDioGRAMplusC4D SNPs as a genetic instrument of CAD to investigate associations between predictors of CAD and differences in metabolite profile in ALSPAC mothers and children. GRSs are the exposure variable in this case, and altered metabolite profile is the exposure. We will use a range of GRSs developed using varied SNP significance threshlds to demnstrate the robustness of GRSs a genetic instrument, while investigating the genetic influence on the metabolism at a pathway specific and global level.

Three GRSs for CAD will be produced based on highly strict, moderate, and lenient SNP significance thresholds using CARDioGRAMplusC4D data. A selection of the most significant SNPs will also be analysed seperately. The individual SNPs and strict GRS should reveal how specific SNPs or groups of SNPs influence isolated metabolic pathways related to CAD, while the more lenient GRSs demostrate the wider influence of genetic variants on global metabolism. These GRSs will be regressed against the top ten principle components of NMR metabolite data from mothers and children. Principle components that are significantly associated can then be deconstructed to reveal specific changes in metabolite levels. By using principle components instead of individual metabolite concentrations, the number of analyses is significantly reduced, and the components themselves may represent biologically meaningful metabolic pathways.

B2392 - Long-term outcomes of children with borderline personality disorder traits at 11-12 years - 19/02/2015

BACKGROUND: Recently there has been a growing body of research examining Borderline Personality Disorder in youth, i.e., childhood and adolescence (Hawes, 2014). Nevertheless, diagnosis in this age group remains controversial, partly due to concerns regarding the validity of the construct (Griffiths, 2011). Predictive validity reflects the degree to which BPD in youth is prognostic of future impairment, and is considered a crucial aspect of the validity of a construct (Van Os et al., 2009). While, a small body of literature has considered the stability of BPD symptoms over time, there are few studies that have examined the long-term clinical and psychosocial impacts of the disorder. The few studies that have reported negative outcomes in youth with BPD symptoms in community populations (e.g., Cohen et al., 2007; Winograd et al., 2008) utilised ad hoc, self-created assessments of BPD rather than established, validated tools. Furthermore, these studies did not consider the mechanistic pathways from early BPD symptoms to outcomes in late adolescence/early adulthood (e.g., do BPD symptoms increase risk of bullying exposure, subsequently heightening risk of depression symptoms?).

AIMS: To explore to what extent BPD symptoms at 11-12 years of age are predictive of future psychopathology and negative psychosocial outcomes, and to examine mechanisms via which increased risk manifests.

B2391 - Investigating putative risk factors for Alzheimers disease using Mendelian Randomization - 19/02/2015

The aim of this study to investigate the role of potential risk factors for Alzheimer's (AD) using Mendelian Randomization. Smoking, hypertension, increased body weight, dyslipidemia and type 2 diabetes have all been suggested as risk factors for AD but the results of epidemiological studies on them have been inconclusive.

In this project we are planning to use genetic variants that are robustly associated with the above exposures to test if they have a causal effect on AD through Mendelian randomization (MR). For blood pressure, BMI, lipids and type 2 diabetes the method of analysis will be a 2-sample MR in which the "reduced-form" estimate (the coefficient for the association between the IV and the outcome) and the "first-stage" estimate (the coefficient for the association between the IV and the exposure) are obtained from non-overlapping samples (Pierce and Burgess 2013). The instrumental variables for the MR analysis will consist of an allelic score calculated based on the results of independent genome-wide association studies of the above traits.

Polygenic risk scores will be calculated based on the results of published GWAS studies. These identified risk alleles will be used to calculate a polygenic score for each individual in an independent (target) sample (ALSPAC), corresponding to the mean number of score alleles (weighted by the logarithm of the odds ratio) across the set of SNPs, using PLINK. Standard linear regression models will be used to calculate coefficients for the association of the polygenic scores with the trait of interest in the ALSPAC target sample (first-stage coefficients). The reduced-form coefficients of the genetic variants/polygenic scores will be calculated in the International Genetics of Alzheimer's Project (IGAP) sample, which is independent of the target sample where the first-stage coefficients would be calculated. The IGAP sample is a collaboration of 4 groups in Europe and USA with approximately 60,000 individuals (either with AD or controls). Genetic data are available on all of them. We have obtained permission to perform this analysis in the IGAP sample.

B2390 - A study of origins correlates and determinants of locus of control - 12/02/2015

Locus of control (LOC) refers to the connections individuals perceive between their behavior and what happens to them. If they perceive such connections they are internally controlled; but if they see their outcomes as due to luck, fate or chance they are externally controlled. Even though researchers have found an internal LOC to be related positively to important aspects of human life including academic achievement, business success, physical and mental health and, in a United Nations study of 84 countries, to happiness, little is known about how internal and external LOC develop, their stability over time or whether they can be changed. Such information is important because over the past 30 years the average locus of control score for adults and children has become more external. We need to know why, and how to change that negative trend. The data to be used in this project include measures of LOC of parents during pregnancy and 16 years later, and of their children at ages 8 and 18 on over 12000 families. It is the only large study in the world that includes multiple assessments of LOC for children and their parents linked to relevant outcome measures. Statistical analyses will provide crucial information on how to foster internality and hence develop interventions.

B2389 - Coventry Reading Engagement Self-Belief and Teaching Project - 12/02/2015

The aims of this project are to examine the links between attitudes, self-belief and literacy behaviour and attainments. It is likely that these factors form a reciprocal relationship - i.e. success at reading means that a child believes that they can do well at reading, and they are therefore motivated to a) try harder when decoding unknown words and b) read for pleasure. In turn, both of these activities are likely to improve reading attainments. Previous studies have indicated a correlation between these areas but it is difficult to establish the cause of this correlation. Large-scale longitudinal work is required to assess whether these relationships exist and whether they vary with ability or age (for example, it could be that self-belief is more important for poor readers or in adolescence)

B2386 - The development of an integrated OMICS signature that links in utero air pollution to growth and cardiovascular health - 05/02/2015

Hypotheses:

In utero particulate matter exposure has been linked to adverse pregnancy outcomes such as low birth weight and intrauterine growth retardation, which in turn have been linked to adult cardiovascular disease and metabolic abnormalities such as obesity, hypertension, insulin resistance and glucose intolerance. These findings suggest that adverse intrauterine conditions that promote reduced birthweight, such as air pollution exposure, may also promote lifelong susceptibility to cardiovascular diseases. Although it is becoming clear that in utero exposure to environmental stressors plays a role in fetal metabolic programming, the mechanisms are still unclear. The investigation of OMICS measurements at different molecular levels provides an insight into the biological pathways involved in the process linking in utero air pollution exposure to early life growth and cardiovascular development.

Aims:

The objective of this project is to derive a molecular pathway linking in utero air pollution exposure to fetal and childhood growth and to study potential consequences on the development of the cardiovascular system. I address four main objectives:

1) The investigation of prenatal and postnatal growth in association with in utero air pollution exposure.

2) The derivation of biomarkers (within in each OMICS level) linking prenatal air pollution exposure to growth trajectories in the first years of life.

3) The identification of common patterns across different OMICS levels (cross-omic analyses) in order to get an insight into the biological pathways involved in the association between in utero air pollution exposure and growth.

4) The investigation of the role of early life growth and the derived OMICS signature in the association between prenatal air pollution exposure and cardiovascular endpoints in childhood and early adulthood.

B2385 - Genome wide association study for physical activity and sedentary behaviour - 05/02/2015

This analysis will form part of an expanded meta-analysis for self-reported moderate and vigorous leisure time activity and sedentary behaviour. Our first goal is to capture a dichotomous trait corresponding to moderate and vigorous leisure activity. Such activity would not include occupation-related activity (i.e. shoveling, heavy-lifting) and/or light leisure activity (i.e. walking, gardening). The second goal is to capture all aspects of sedentary behaviour for which we defined four traits; three dichotomous traits, reflecting sedentary behaviour at work, home and during commuting, and one continuous trait: TV viewing.Separate GWAS analyses will be run for male and female offspring and the mothers. Covariates included in the models are age and body mass index.

B2384 - Novel Epidemiological Methods to Infer Causal Effects of Risk Factors on Neuropsychiatric Cardiovascular Disorder - 29/01/2015

BACKGROUND

This project focuses on developing methodological applications for analysing "omics" data resources (genome-wide genotypes, metabolomics, the epigenome), an area that has exciting prospects for observational epidemiology (Brion et al., Curr Epidem Rep 2014). We have previously published work indicating that genome-wide allelic scores can be used to data-mine large numbers of associations between biological intermediates and disease-related outcomes and screen for potentially causal relationships (Evans, Brion et al., PLoS Genetics 2013). We would like to build on this work and investigate the use of similar allelic scores in studies based on metabolomic and epigenetic measures. In addition, we would like to develop and implement novel applications of Mendelian Randomization to these genome-wide genotype, epigenetic and metabolomic measures, such as by implementing bidirectional MR (Welsh et al., J Clin Endocrin Metab, 2010) and MR for mediation (Relton & Davey Smith, IJE 2012). We would then implement these methods to test causal relationships involving blood methylation (epigenetic) markers and metabolomic measures.

AIMS

1.To develop and test novel epidemiological approaches, such as Mendelian Randomization and data-mining approaches, that exploit the availability of high throughput biological data (genome-wide single nucleotide polymorphism (SNP) data, epigenetic, metabolomic).

2.To apply these novel methods to infer the causality between risk factors, such as environmental exposures and biomarkers, with cardiovascular and psychological outcomes, through potentially mediating epigenomic and metabolomic pathways.

B2383 - MR of blood pressure and NMR metabolites - 29/01/2015

Higher blood pressure is associated with increased cardiovascular and renal disease and premature mortality. Although some of the biological pathways and disease endpoints linked to blood pressure changes are well understood, a large number of them remain unexplained. Higher blood pressure is associated with other risk factors for cardiovascular and renal disease, including dyslipideamia, hyperglycaemia and insulin resistance (referred to collectively as metabolites) and higher levels of inflammatory markers, which might mediate any causal effect of higher blood pressure on later disease. But associations with these other risk factors and their joint role in causing later disease could reflect several different alternatives:

1.Blood pressure causes variation in these other risk factors and via these effects causes later CVD and other diseases.

2.These other risk factors cause variation in blood pressure and the primary causal agents are the metabolites/inflammatory markers with blood pressure being more downstream and proximal to disease endpoints.

3.There is a bidirectional causal relationship between BP and metabolites/inflammatory markers

4.There is no causal relationship between blood pressure and metabolites/inflammatory markers, but rather the association is confounded, for example by socioeconomic position, lifestyle characteristics and obesity. .

In preliminary analyses, we have already identified a number of metabolites from the NMR platform that are strongly correlated with BP. We want to extend this work by using Mendelian randomization (MR) to determine whether the relationships are causal and if so which direction they are in (i.e. to distinguish which of the 3 alternatives listed above is most likely).

With UCLEB we can increase the number of available individuals to more than 30 000, all with blood pressure measurements, GWAS or other array genotyping, and NMR metabolites and inflammatory markers.

We will use the known BP genetic instruments to assess whether BP is causally related to the metabolites and inflammatory markers (alternative 1 or 3 above vs 4) and metabolite instruments from recent GWAS to test whether metabolites are causally related to BP (alternative 2 or 3 vs 4).

B2382 - Defining the mitochondrial DNA genetic bottleneck by studying the inheritance of low-level heteroplasmy between mothers and offspring - 12/02/2015

Our aim is to study low-level heteroplasmy in a large number of mother-child pairs using DNA samples already extracted for ALSPAC genotyping studies. We estimate that greater than 1000 pairs will be required to carry out a meaningful experiment, based on our pilot data from existing data sets. We will use ultra high depth next generation sequencing (IlluminaMiSeq) to carry out this experiment, allowing the detection of greater than 0.5% heteroplasmy from a standard genomic DNA sample. Statistical analysis will be carried out by Dr Ian Wilson at the Institute of Genetic Medicine. We will model the genetic bottleneck as done previously,7 and determine whether the background mtDNA sequence influences the rate of segregation of mtDNA heteroplasmy in healthy controls. We will then compare this to data acquired from humans transmitting pathogenic mtDNA mutations to determine whether they behave differently.8 This will advance our understanding of the underlying biology, and will be directly relevant to current work aimed at preventing the transmission of mtDNA mutations.

B2381 - Trajectories of Brain Injury in the ALSPAC cohort - 22/01/2015

Aims:

The aim of the study is to investigate the trajectories of traumatic brain injury (TBI) from childhood into adolescence using the ALSPAC cohort. In particular the study will explore the impact that a single TBI event and recurrent TBI events will have on aspects of social cognition, risk behaviour engagement and general cognition. The control groups will include participants who have had a broken bone/fracture and also participants who have never had an injury. There will be exploratory analyses conducted to see whether the detrimental effects of recurrent TBI events are greater than for a single TBI event.

Social cognition can be broadly conceived as the ability to understand other people through emotion perception and empathy and also by inferring the beliefs, intentions and feelings of others 1 Following a TBI event, many facets of social cognition have been shown to be impaired, such as the recognition of facial emotional expressions 1-4; however, current evidence is hampered by small, heterogeneous sample sizes 1.

Engagement in risky behaviour such as substance use has been implicated as an outcome of TBI 5-8. One large cohort study demonstrated that a TBI injury requiring hospitalisation between the ages of 0-5 years old increases the risk for adolescent substance use 5; while findings from another birth cohort indicate that drinking to intoxication is more common among 14 year olds who have experienced a TBI compared to those who have not 6. Ilie and colleagues 7 found that high school students who had experienced a TBI had higher odds of using illicit substances, were twice as likely to consume hazardous amounts of alcohol and were at greater risk for cannabis dependence. Likewise, in a group of incarcerated youths, those with a TBI history were found to be more likely to engage in risky alcohol and cannabis use as well as weekly use of another illicit drug prior to incarceration; this was also the case for participants reporting multiple TBI events9. In comparison to a single TBI event, individuals who have experience two or more TBI events have reported more frequent alcohol, tobacco and illicit drug use 8.

The sequelae of TBI is characterised by cognitive problems 10. Corrigan and colleagues 11 compared different characteristic profiles of TBI histories in persons with substance use disorders and found that a TBI event occurring between the ages of 6-10 may lead to slower processing speed and a greater number of cognitive complaints, while working memory was more impaired in those with a severe adult TBI, mild adolescent injury or multiple mild injuries. Elsewhere, processing speed has been found to be more impaired in participants with more than one TBI resulting in loss of consciousness than in participants who have had just one TBI 8.

Predictors of TBI from birth cohort studies include male gender 6,12, parental alcohol misuse 6, a punitive parenting style and the number of adverse life events experienced by the family 12. These will be controlled for in the proposed study.

B2380 - Metabolic effects of statin therapy longitudinal and genetic evidence - 22/01/2015

Aims: Statins are first-line therapy for cardiovascular prevention, yet the effects of statins on lipoprotein subclasses and circulating fatty acids remain unclear. Statin usage may further influence other pathways beyond lipid lowering. We aim to assess the detailed metabolic effects of starting statin therapy by quantitative NMR metabolomics profiling in 4 longitudinal cohort studies with 2 20 years of follow-up (including ALSPAC mothers).

Hypotheses: Starting statin usage is associated of all LDL lipids to a similar extend, but deviating patterns may be observed for detailed VLDL subclasses and their cholesterol and triglyceride levels. We hypothesize that statin lower all fatty acid concentrations, but more so for omega-6 fatty acids than for omega-3 and mono-unsaturated fatty acids. Finally, we will assess the effects of statins on numerous small molecules (including amino acids, glycolysis precursors and ketone bodies) to examine potential non-lipid effects of statins. Longitudinal analyses will be corroborated by genetic analysis, using established genetic instruments to proxy the effect of the statin target: HMGCoA reductase inhibition. Analyses: Associations with starting statin usage with NMR-based metabolite data will be meta-analysed in 4 cohorts including ALSPAC mothers. Genetic associations of 2 SNPs in HMGCR will be tested in 9 population-based cohorts including ALSPAC children & mothers.

Confounding variables: Longitudinal analyses will be adjusted for age and sex. Genetic analyses will be adjusted for age, gender, and population structure if available.

B2379 - Using parents experiences to investigatehow to prevent high risk primary school children developing antisocial and criminal behaviour - 22/01/2015

Aims:

The study aims to investigate what interventions, services or policies could help prevent primary-school

children with conduct problems, living in high risk families, from developing antisocial and criminal

behaviour as they grow older. The study aims to take a broad view as to what could help and has therefore

been designed in two phases. Phase One is a qualitative longitudinal interview study with ten families to

build hypotheses about what might help. I would like to use ALSPAC data in Phase Two of the study. In

Phase Two the aim is to access longitudinal data on larger samples of similarly high need families that

include a child with behaviour problems to explore issues arising from the qualitative interviews. I aim to

explore possible modifiers (referred to as 'modifying factors') of the association between risk factors and

outcomes (antisocial and criminal behaviour in later adolescence). The aim is not to identify pre-existing

protective factors but to look at changes occurring between beginning primary school and adolescence

which appear to indicate a move onto a more positive trajectory. Outcomes will be compared for matched

groups of children who have or have not experienced the modifying factor/exposure. The matching will

be based on risk factors for the ultimate outcomes of interest, i.e.antisocial and criminal behaviour at ages

16+, and it is proposed that propensity score matching be used. This matching will make use of existing

knowledge about factors associated with resilience in an effort to control for these and isolate the impact

of later occurrences (e.g. Bowen, Heron, Steer, & El Comy, 2008). The method is imperfect for looking

at effectiveness of intervention but provides one route to addressing the possibly serious consequences of

prioritising easy-to-research interventions.

B2378 - Do social cognitive deficits at an early age predict substance abuse problems at later ages - 22/01/2015

Aims

The aim of this project is to explore whether early deficits in social cognition are associated with later substance abuse problems. Previous studies have shown that impairments of social cognition are common amongst individuals who abuse substances. For example, alcohol (1), opiate (2), and tobacco (3) use have all been associated with impaired recognition of facial emotional expression. Additionally, these impairments persist when smokers become abstinent (4) and when alcoholics are detoxified (5), suggesting addicted individuals' may rely upon substances to aid their social cognitive abilities. Furthermore, these deficits are sustained up to ~2 months into sobriety (6). This raises the question of whether it is substance abuse itself that cause these deficits, or whether these deficits lead to substance use (for example, to enhance certain aspects of social cognition).

B2377 - Clarifying the SES-Health Gradient The Case for an Epigenetic Mechanism - 15/01/2015

Socioeconomic status (SES), an individual's position in society, is defined by a number of interrelated individual, structural, and environmental factors (e.g., income, education, neighborhood). We have known for some time that an SES-health gradient exists (i.e., low SES associated with poor health, high SES associated with good health) but exactly what it is about SES that gets into the body to shape health is still unclear. Yet, understanding these biological mechanisms will be critical for minimizing the costs of low SES for health as well as maximizing the benefits of high SES for health. This lack of clarity may reflect variations in the measurement of SES, a lack of recognition of factors that influence for whom the SES-health gradient will hold and, until recently, limited availability of epigenetic data. We contend that in order to clarify how SES might get into the body to influence health we should first, determine which indictor(s) of SES, and in which combinations, might work to influence biological mechanisms and second, we should consider whether there might be specific factors that influence for whom SES might get into the body to influence mental and physical health. We believe that psychological well-being is an excellent candidate. The key biological mechanism that we will focus on in these relationships is DNA methylation.

B2376 - Child PTSD and longitudinal adverse outcomes - 15/01/2015

The aim of the proposed study is to provide information regarding potential adverse outcomes associated with trauma exposure and posttraumatic stress symptoms (PTSS). Existing data suggest that youth trauma exposure and/or PTSS are associated with adverse outcomes in several domains including: substantially increased odds of objective physical disease states (Seng et al, 2004); poorer educational attainment (Hurt et al, 2000); engagement in substance use and other risky behaviours (Begle et al, 2011); and increased likelihood of antisocial behaviours/involvement in the youth juvenile justice system (Ford et al, 2010; Abram et al, 2004). However, existing studies are predominantly cross-sectional raising issues of cause versus consequence; or they have focused on specific populations or types of trauma, limiting the generalisability of the findings. The longitudinal data afforded by the ALSPAC cohort would allow for an analysis of whether youth trauma and PTSS contribute to later adverse outcomes, even once concurrent problem levels are taken account of.

B2375 - Genetic and environmental risk factors for the development and maintenance of PTSD with the ALSPAC cohort - 15/01/2015
B2373 - Dietary zinc intake in the ALSPAC cohortan investigation of dietary sources and growth outcomes - 08/01/2015

Aims and hypothesis

Preliminary investigations have shown that average dietary zinc intakes in the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort are below those recommended for children and this could be associated with deficits in long-term growth.

Exposure variables

The project will use the dietary data collected longitudinally from ALSPAC children from which nutrient intakes have been calculated. This will be combined with weight and height data collected at several time points throughout childhood. The project will investigate which foods and food groups contribute to zinc intakes in children age 1.5-13 years and whether this has an effect of height and body mass index at several time points throughout childhood.

B2372 - Intake of free sugars in the ALSPAC cohort an investigation of dietary sources and obesity outcomes - 08/01/2015

Aim and hypothesis:

Preliminary investigations have shown that free sugars intakes in the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort are above those recommended as a maximum for children and may be associated with fast early growth and obesity outcomes.

B2371 - Patterns predictors and neurobehavioral consequences of multiple metal exposure in pregnancy - 08/01/2015

Aims

Up to 25% of the global burden of disease is estimated to stem from preventable environmental exposures. Starting in utero, millions of children worldwide are exposed to toxic chemicals, including the metals lead, cadmium, and mercury, from natural and anthropogenic sources. Research clearly demonstrates that individually these toxic metals contribute to neurobehavioral deficits in children. It is also accepted that simultaneous exposure to multiple metals is the norm rather than an anomaly. Yet, surprisingly little is known about the combined effects of early exposure to multiple metals on child development and behaviour. Important research gaps, hinder our ability to set policies, create prevention or intervention measures, and care for affected individuals. First, except for select or specific population groups, the exposure to metals in the general population is likely to be of low magnitude. The patterns of exposure in the general population need to be established. Second, it is important to understand what sociodemographic factors are likely to predict exposures so that risk factors can be appropriately described and communicated. Most importantly, there is little understanding of the extent to which metals interact to produce deficits. Thus, the consequences, both in the short and the long-term, of multiple metal exposures need to be determined. The aim of this study is to 1) model the patterns of in utero exposure to three toxic metals (lead, cadmium and mercury), 2) compare sociodemographic factors/variables among groups of women with lowest and highest exposure patterns to identify salient predictors of exposure, and 3) examine the neurobehavioural consequences of exposure for the women's offspring using measures of early temperament and neurocognitive development.

Hypotheses

The central hypothesis is that women falling into the highest metal exposure pattern will have children with more difficult temperaments and lower developmental scores than women falling into the lowest exposure pattern.

B2370 - A multi-omics investigation into the metabolic and epigenetic effects of childhood glycemic profile - 08/01/2015

This study will employ a systematic approach to investigate the effects of childhood glycemic profile on the metabolome and the methylome. We propose that blood glucose level is linked to changes in the metabolome, which results in variation in DNA methylation between individuals. Using Mendelian randomization techniques it will possible to investigate the directionality of this relationship. It is possible that there is a causal relationship between blood glucose level as an environmental exposure due to diet and altered DNA methylation which may alter gene expression.

This systematic approach requires several steps. Firstly, using existing GWAS results, a genetic proxy for blood glucose levels will be used to perform a Mendelian randomisation analysis investigating the effect of blood glucose on the metabolome treating blood glucose as an exposure and metabolome as an outcome. GWAS results will then be used again to find a genetic proxy for the observed metabolome effects, thus obtaining a filtered list of SNPs that can be used in a second MR step to identify differentially methylated CpGs that are associated with changes in the metabolome. It would then be possible to investigate the transcriptional effects of these modifications, linking exposures to molecular mediators and phenotypic outcomes.

This systematic method has is advantageous over traditional EWAS due to the stepwise filtering of SNPs associated with the exposure of interest, and may be more likely to provide biologically interesting data relating to disease phenotypes. ALSPAC provides an ideal opportunity to test the utility of this approach, due to the availability of genotype, NMR metabolomics, DNA methylation and some transcriptional data from a large cohort.

B2369 - Nutrition DNA methylation and child conduct problems - 08/01/2015

Conduct problems (CP) in youth affect society in a wide and penetrating manner; the victimization and distress to individuals and impairment of life opportunities is substantial. The associated costs are thought to be especially severe for youth with an early onset (at or before the age of 10 years) of CP - these youth are often raised in high-risk environments (family, community); show abnormal neurocognitive development; and are at risk for a persistent pattern of offending (1-3).

Previous studies highlight that a poor diet (e.g., consumption of energy-dense foods that are high in saturated fat and low in unsaturated fat) in early life (i.e., in prenatal and early postnatal periods) can disturb child neurodevelopment and lead to cognitive, emotional and behavioural problems in later life (4-13). To date, however, no existing research has integrated - in a developmental context - nutrition (i.e., quantity and quality of dietary fat) and biological markers (genetic, epigenetic and metabolic) that can help to identify the mechanisms underlying the associations between poor nutrition from prenatal period through childhood and CP. For example, although epigenetic modifications have been associated with poor nutrition in general (14), further research is needed to examining the this is related to early onset of CP - and also the degree to which functional variation within genes that are involved in metabolism of the key macronutrients might moderate the associations between nutrition and DNA methylation in relation to CP (15, 16).

This application proposes a systematic examination of the impact of prenatal and postnatal nutrition and environmental risk exposure on CP in The Avon Longitudinal Study of Parents and Children (ALSPAC; UK). The developmental phenotype of CP trajectories between ages 4 and 13 years is available for the ALSPAC children (2). The sub-sample of ALSPAC children includes extensive measures of diet macronutrients using Food Frequency Questionnaire and dietary diary, and nutrition biomarkers available from a prenatal period through late-childhood; as well as whole-genome data for mothers and children; and DNA methylation status data available for children at birth, at ages 7 and 15-17 years.

The project aims to address the following research questions:

Aim 1: Does prenatal and/or early postnatal nutrition affect CP developmental trajectories?

Sub Aim 1a: Are these associations mediated by earlier neuro-cognitive development?

Sub Aim 1b: Are these associations affected by child stress exposures?

Aim 2: Are associations between nutrition and CP (partially) explained by DNA methylation?

Sub Aim 2: Are these associations moderated by child stress exposures?

Aim 3: Examine the role of SNPs involved in the metabolic pathways of key nutrients.

Aim 4: Examine causal associations using Mendelian Epigenetic Randomization.

B2368 - Genetic overlap between autoimmune diseases and allergic sensitization - 08/01/2015

This project will require no further data form ALSPAC. Data were provided as summary statistics for a meta-GWAS of allergic sensitization (Bonnelykke et al. Nat Gen 2013; 45(8):902-6) based on ALSPAC skin prick tests. The current proposal is to look up reported genes for other immune diseases in the meta-GWAS results, not limited to genome-wide significant loci, to study to which extent these are also associated with allergic sensitization

B2367 - Investigating the prevalence and predictors of e-cigarette use - 08/01/2015

Aims and hypotheses

Electronic-cigarettes (e-cigarettes) hold the potential to hugely reduce the harm caused by smoking, but it is important to determine the factors which lead to their use among young people. Previous cross-sectional research has investigated the prevalence of e-cigarette use among young people (1, 2), but to our knowledge, there have been no longitudinal studies investigating predictors of e-cigarette use.

ALSPAC has collected detailed information about substance use, in particular smoking behaviour. From these data, trajectories of smoking initiation during adolescence have been constructed (3). However, there is currently limited information regarding e-cigarette use. Identifying the pathways into e-cigarette use among young adults is key, given concerns regarding the potential of e-cigarettes to act as a 'gateway' to other, more harmful substances, such as conventional tobacco cigarettes (4). The ALSPAC young people are now between 22 and 23 years old. Therefore, this application is timely as data suggest that peak prevalence of e-cigarette use is in 16-24 and 25-34 year olds (5).

In this project, we aim to collect detailed information from the young people in ALSPAC regarding use of e-cigarettes; specifically frequency of use, demographics of users and dual use with tobacco cigarettes. Using this information, along with the rich data set already available within ALSPAC, we aim to answer the following questions:

1. What biological, social and environmental factors are associated with e-cigarette use in young people?

2. Are e-cigarettes likely to act as a 'gateway' to use of other, more harmful drugs among young people?

3. Is e-cigarette use an effective smoking cessation strategy among young people?

Study design

We will design questions on e-cigarette use to be included in the next annual questionnaire (2015/16) that will be sent to the ALSPAC young people. These data will be linked to previous ALSPAC data, allowing investigation of the biological, social and environmental factors associated with e-cigarette use. We are seeking funding for the data collection from Cancer Research UK (CRUK) have been asked to submit a full application by 22nd January 2015.

We will seek additional funding in the future to send follow up questionnaires, which will allow us to examine the long term implications of e-cigarette use. We would also like to extend this work to investigate e-cigarette use in the ALSPAC mothers and fathers.

B2366 - Exploring the relationship between antibiotic exposure in early life and psychological problems in preschool years - 08/01/2015

Research Question:

Are infants born to the ALSPAC cohort who received one or more courses of antibiotics during the fetal and early life more likely to develop psychological problems during their preschool years when compared to children who were not exposed to antibiotics?

Hypothesis:

It is hypothesized that antibiotic exposure during fatal and early life will disrupt the natural development of the human microbiome during a critical window of vulnerability. This will result in behavioural changes which will be observed as a higher prevalence of psychological problems in preschool years.

B2365 - Rare copy number variants and education achievement - 08/01/2015

Aims and hypothesis

The impact of rare copy number variants (CNVs) has almost exclusively been evaluated using clinical cohorts; it is thus unclear how these variants affect health in the general population. Our aim is to assess the genome-wide burden of rare CNVs on carriers' health and life quality in general population. We have conducted genotype and phenotype analyses of a random sample of 7877 adult individuals from the population biobank of Estonia (Estonian Genome Center, University of Tartu; Tartu, Estonia). Using this set we generated a genome-wide map of rare autosomal CNVs and identified 10.5% of the screened adult general population (n=831) as carriers of CNVs >=250kb with frequency <=0.05%. We found that when compared to the population, carriers of deletions >=250kb and duplications >=1Mb show lower education achievements (a proxy for intelligence) and a greater prevalence of intellectual disability. These effects are associated with the number and functions of contained genes, e.g. rare deletions are significantly enriched for genes with a role in neurogenesis, cognition, learning, memory and behavior. Interestingly, the effect on education attainment was more pronounced in female carriers of rare deletions in general population, who were also overrepresented amongst carriers.

Our results suggesting that rare CNVs contribute to a substantial portion of the population variance of educational attainment need to be replicated in a geographically independent cohort. The ALSPAC cohort of mothers and children would provide us, in collaboration with group of Dr. Nicholas Timpson, a valuable result as (i) ethnically unrelated to the discovery cohort; (ii) sufficient sample size of individuals with CNVs calls; (iii) the cognitive information of children is unbiased by preselection; (iii) large number of uniformly recruited females provides a possibility to validate the female effect of rare CNVs.

B2364 - Genetics and genomics of polycystic ovary syndrome and related sub-phenotypes - 08/01/2015

Polycystic ovary syndrome (PCOS) is a complex disorder causing metabolic disturbances and reduced fertility in women of reproductive age, the definition of which is an on-going debate among researchers in the field. PCOS is characterized by hyperandrogenism, chronic anovulation and glucose homeostasis. It is one of the most common endocrinopathies affecting 5-15% of women of reproductive age worldwide and causes more than 75% of cases of anovulatory infertility. The etiology of PCOS is largely unknown though contains a clear genetic component. However, to date, the only available PCOS genome-wide association data have reported 11 significant loci and come from a study of Han Chinese individuals. We, in the PCOS consortia, that consists of 15+ research teams, are gearing up to perform their first and second waves of genome-wide and also exome-wide association meta-analyses in up to 15,000 cases and 80,000 controls of European decent, as well as extensive pathway analysis and genomic follow-up. The overall aim is to identify genetic variation, transcripts and pathways that are associated with PCOS susceptibility (and related subphenotypes). We will perform case:control analysis for PCOS itself and for some of the related subphenotypes which present as dichotomous outcomes. We will in parallel perform quantitative analysis for subphenotypes that are quantitative traits. We will adjust for standard confounders like age and also investigate what effect related phenotypes like BMI have on the PCOS results by performing both adjusted and unadjusted analysis. The genetic and genomic discovery paired with biologic follow-up, holds the promise of bridging and linking knowledge from the metabolic and gynecologic disease fields and yield clinically useful information.

B2363 - Meta-analysis of the association of gestational weight gain with offspring outcomes - 08/01/2015

Background

Maternal early- / pre-pregnancy BMI and gestational weight gain have been shown to be positively associated with offspring greater adiposity in later life in numerous prospective cohort studies, including in previous publications from ALSPAC. However, the extent to which this association is causal or due to bias (including publication bias, where studies that show a positive association are more likely to be published) is unclear.

We want to explore this by undertaking an individual participant meta-analysis in all birth cohorts (globally) that we can identify and that have relevant data. Our aim is that this should allow us to obtain precise estimates that are less likely to be influenced by publication bias than undertaking a systematic reivew and meta-analysis of published studies.

Further we want to compare association of maternal exposures with offspring outcomes to the same associations in fathers in order to determine whether there is evidence of specific maternal associations, which would support a intrauterine causal effect.

Aims and objectives

1. To undertake an independent participant data meta-analysis of the association of maternal pre-pregnancy BMI and gestational weight gain with offspring adiposity and body composition.

2. To compare associations of maternal exposures with offspring outcomes to the same associations of paternal exposures to explore whether associations in mothers are likely to represent intrauterine causal mechanisms

3. To explore the extent to which any associations might be mediated by birth characterists and later offspring activity and energy intake

B2361 - Assessing the extent to which disclosurecontrol techniques impact on data utility - 18/12/2014

Cohort studies are required to comply with stringent ethico-legal safeguards when using individual level personal data; particularly when these data relate to sensitive topics. Many of the CLOSER cohort studies make assurances to study participants that participant identity will be known to core study staff, but hidden to the research end users of the data. Cohort data managers use a variety of processes to 'hide' participant identities, ranging from removing name and address information from data sets to complex statistical processes used to mask or block access to the underlying individual level data. In addition to any reassurances made to participants, cohort studies are required to comply with a range of legislation relating to participant confidentiality. The Data Protection Act 1998 makes a distinction between personal data and anonymous data; where personal data is information that relates to an identifiable individual.

This includes data which includes direct identifiers or where identity can be determined through linking to other readily available information. This classification is important as the safeguards required for the use of personal information are far more stringent than the safeguards required for the use of anonymous information. The Data Protection Act 1998 requires that individuals are informed of the use of their personal information, and in the case of sensitive personal information (such as information relating to health or criminality status) that consent is obtained. Furthermore, even when these safeguards are in place the Act requires that data are de-identified as soon in the research process as possible - ideally prior to point when data are provided to researchers. Achieving anonymity in a dataset is challenging and is complicated by the fact that detailed individual-level data is relatively easy to associate back to the individual who provided them.

In 2013 the Health and Social Care Information Centre (HSCIC) released the Anonymisation Standard for the Release of Health and Social Care Data . The HSCIC's chosen methodologies are seen as consistent with the Information Commissioner's Office (ICO) Anonymisation Code of Practice. The ICO have subsequently endorsed the standards anonymisation protocol. In this context, 'release' is taken to mean the distribution of cohort information from the central collecting organisation (e.g. ALSPAC) to research end users. The Anonymisation Standard adopted a statistical process known as K-anonymisation to control for disclosure risk through the suppression of unique patterns within individual-level data. The process works by transforming individual-level values to ensure that each individual record has k other records with identical values. Through suppressing uniqueness, K anonymisation reduces the potential for deductive disclosure. A concern, however is that the loss of information inevitably involved in this process (the scale of which increases as the K threshold is raised) may lead to a reduction in the epidemiological utility of the data.

This question can be addressed empirically. In ALSPAC we have linked study data to a number of

sources of health and social administrative data including the Hospital Episodes Statistics database.

Where linkage to HES is not undertaken within explicit individual consent but is permitted under

provision of Section 251 of the NHS Act 2006 different stipulations apply depending on the sensitivity of the data items linked. Information related to Sexual Health and Mental Health, for example is considered to be particularly sensitive and in this situation stipulations around "stronger" K anonymisation are likely to apply. Around 40% of our participants have explicitly consented to data linkage therefore considerations around K-anonymisation do not apply in the same way. We are therefore able to examine the influence, if any of different levels of k-anonymisation (and other privacy protection procedures) on effect estimates derived from a particular dataset. To do this we will apply a series of different anonymisation processes to a data set used in an existing, published, ALSPAC project on prevalence and risk factors for self-harm. Through undertaking equivalent analyses in the same dataset subject to different levels of disclosure control we will investigate the effect of the following common strategies:

1) no disclosure control beyond removing direct identifiers, 2) controlling for low cell counts in each

individual variable in isolation, 3) applying 'weak' k-anonymisation (at different k thresholds) to all

pseudo-identifiers in the data set in combination, 4) applying 'strong' k-anonymisation (at different k

thresholds) to all variables in the data set bar the outcome variable, 5) applying an alternative approach to anonymisation, which perturbs the data through adding a known level of 'noise' in order to mask ALSPAC Research Proposal Form page 8 of 10 December 2010the true underlying values, and, 6) using single-site DataSHIELD as a means of restricting access to the underlying individual-level data. Option 5 will render the data to a state where it is not real in any sense (i.e. the variable values will not relate to any individual as they have been statistically altered).

We will provide the research analyst with sufficient information to remove the noise from the data in their modelling (akin to the modelling undertaken to control for measurement error problems). As the artificial noise data is known, it will be possible to remove the effect of the transformations through the modelling and therefore allow the analyst to produce accurate results without ever being aware of the true underlying individual level data that relates to a study participant. In contrast, Option 6, will not attempt to alter the values of the underlying data. Instead, DataSHIELD will operate as a protective IT framework which will allow the analyst a means of extracting statistical information without having access to the underlying individual level data. This process is consistent with the principles of the ICOs anonymisation code of practice.

We will repeat this assessment, in a different exemplar setting, using self-reported information recording breast feeding and IQ, and linked educational assessment information from the National Pupil Database. The exposure variables, outcome variables and confounder variables are all pre-determined by the choices of the original investigators. This project is not designed as an investigation of these exemplar topics

B2360 - Aetiology of increased birthweight for gestation - 18/12/2014

Background: There is increasing evidence that childhood cancer is more likely to occur in children that were relatively large at birth, and unpublished information indicates that this is particularly true of non-leukaemic cancers occurring after 3 years of age [1]. The risk is lowest among children born small-for-dates and tends to increase linearly with increasing birth-weight. The evidence indicates that the birth-weight association with leukaemia relates to excessive growth in utero [2,3]. This raises the question as to whether there are features that increase the growth of the fetus that are responsible for increases in the risk of cancer. Although many high quality studies have focused on the aetiology of growth retardation, little attention has been paid to the high end of the birth-weight distribution.

Hypothesis and objectives: This study is designed to identify factors that influence fetal growth in order to develop coherent hypotheses as to ways in which the unexplained link with childhood cancer may be explained. We hypothesise that features of the environment including diet and lifestyle, genetics and epigenetics may play important parts. We have already shown an excess in birth-weight if the non-smoking mother was exposed in utero to her own grandmother's smoke [4], which indicates a possible epigenetic influence; additionally our unpublished data have shown an association with maternal prenatal intake of paracetamol (acetaminophen). Thus our hypotheses concern the likely complexity of factors that influence excessive fetal growth.

The objectives are to determine features of the life-course of each parent, and grandparent, to determine associations with increased fetal growth using an 'exposome' approach [as in B2190]. Where appropriate, linkage to genetic variants and methylation patterns will be used to determine biological pathways which may be associated with childhood cancer.

B2358 - Study of Emerging Adulthood and Cardiometabolic Health in ALSPAC the iNfluence of Growth and other Exposures-SEACHANGE - 18/12/2014

Hypothisis

1. Changes in exposures over the period 17-25y will be associated with change in cardiometabolic

phenotype over the period 17-25y.

2. These associations will be reflected in changes in intermediate molecular phenotypes (epigenetics and

metabolomic measures).

3. Changes in intermediate molecular phenotypes will act as markers of exposure, and, in some cases,

highlight possible causal pathways

4. Exposures over the entire life course to 25y will act via accumulative or sensitive period models to

determine outcomes at age 25y

Outline of the proposed study

ALSPAC commenced in 1990-92 and recruited children from 15 247 pregnancies.73 Follow-up data includes 59 questionnaires (4 weeks-18 years of age) and 9 clinical assessment visits (7-17 years of age). The resource comprises a wide range of phenotypic and environmental measures in addition to biological samples, genetic (DNA on 11,343 children, genome-wide data on 8,365 children, complete genome sequencing on 2000 children) and epigenetic (methylation sampling on 1000 children) information and linkage to health and administrative records.

Young adults participating in the ALSPAC study will be invited to re-attend clinic for detailed assessment of exposures, risk factors and phenotype. Based on previous experience and pilot studies, we anticipate approximately 4000-5000 young adults will attend the 25+ clinic. We will undertake a range of investigations including: cardiac structure and function by 3-dimensional (3D) echocardiography, including strain rate using a EPIQ 7 ultrasound (3D echo offers significant advantages over 2D/M-mode in the assessment of LV mass and remodelling[74]); carotid ultrasound for cIMT and carotid distensibility will be performed using a Panasonic CardioHealth station; carotid-femoral PWV will be measured using a Vicorder device; peripheral and central BP including waveform analysis (pressure separation75, reservoir/excess pressure) will be measured using a BP+ validated cuff-based device. BP and HR reactivity in response to a step exercise and handgrip will also be performed as done in ALSPAC 17+ clinic. Resting heart rate variability will be measured from a 5 minute resting ECG. Anthropometry, questionnaires (including dietary questionnaires), fasting bloods, urine, 3D body scans, metabolomics and DXA will be performed as part of the core clinic (supported by existing core-grant). Blood samples will also be collected for analysis of insulin (all participants), DNA methylation (in 1000 participants), chromatin preparation and storage. Urine will also be collected and stored.

B2357 - How early stress gets under the skin The role of DNA methylation in youth conduct problems and comorbid symptoms - 11/12/2014

Background:

Youth conduct problems (CP; fighting, stealing) are a major public health concern and a key target for prevention and intervention efforts. CP youth often experience high levels of environmental risk (e.g. harsh parenting, family conflict) and psychiatric comorbidity (e.g. depression, ADHD, substance use). Yet, little is known about biological factors that may explain the link between environmental risk, CP and comorbid symptoms.

Aims:

To investigate the role of DNA methylation - an epigenetic mechanism sensitive to environmental influences - in the development of CP and related comorbidities. Specific aims are to: (i) identify methylation markers that are associated with multiple symptoms vs symptom-specific markers; (ii) investigate whether methylation markers cluster to form biologically informative systems; (iii) examine methylation changes in relevant markers over time; (iv) establish whether markers are influenced by pre- and postnatal environmental risk exposure; and (v) test whether methylation mediates environmental effects on CP and comorbidities.

B2356 - 0 New b2356 - 11/12/2014

ALSPAC has the untapped resource of around 10,000 retinal photographs, which are currently being graded. This is an opportunity to analyse and interpret this data to determine what a child's optic disc looks like in the normal UK population. ALSPAC also has the unique benefit of parental data and child data going back to antenatally allowing analysis of factors that influence disk shape and size.

B2355 - Effects of early life residential mobility and key life events on mental health and risky behaviours - 11/12/2014

Project title

Effects of early life residential mobility on mental health and risky behaviours.

Aims

The research project will aim to address the following research questions:

i)Are cumulative residential moves throughout childhood associated with poorer mental health outcomes and increased risky behaviours in adolescence and early adulthood?

ii)Are there critical periods in which the effects of residential mobility on adverse outcomes are disproportionately stronger or weaker?

iii)Do physical characteristics of the move (distance, urban/rural, changing neighbourhood status) mediate effects?

iv)To what extent do background family characteristics and life events exacerbate or attenuate results?

v)Is residential turnover at the neighbourhood level associated with poorer health outcomes?

B2354 - Dietary patterns during pregnancy by cluster analysis and childhood neurodevelopment - 11/12/2014

Dietary patterns during pregnancy and childhood neurodevelopmental. This work is to be the international part of a PhD based in Brazil during this time experience will be gained working in Bristol.

The maternal diet can affect the infant neurodevelopmental (del Rio Garcia et al., 2009; Bernard et al., 2013). The ALSPAC study was explored and there are some studies that assessed the maternal dietary intake of fatty acids (Hibbeln et al., 2007; Hibbeln and Davis, 2009) and 'healthy' and 'unhealthy' food groups (Barker et al., 2013) with childhood neurodevelopmental deficiencies. Dietary patterns have been used in some studies to assess the relationship between diet and health outcomes, because they represent an overview of food and nutrient consumption (Slattery, 2010; Tucker, 2010).

Aim: To obtain clusters of dietary patterns during pregnancy and to examine the association between these dietary patterns and neurodevelopmental outcomes in childhood.

Hypotheses: The adherence to dietary patterns composed by healthy foods can reduce the risk of neurodevelopmental outcomes during the childhood, while the patterns composed by processed food can increase the risk of neurodevelopmental outcomes.

Exposure variable(s): Dietary patterns during pregnancy obtained by cluster analysis.

Outcome variable(s): Neurodevelopmental outcomes in child previously explored in Hibbeln et al. (2007) study. Including clinic measured IQ and parental questionnaire assessed Denver Developmental Screening Test and Strengths & Difficulties.

Confounding variable(s): Maternal education, social class, age at delivery, parity, energy intake, BMI. Child's date of birth, birth weight, sex, gestational age, breastfeeding, child diet at the time of assessment.

We plan to write at least 2 papers as a result of this work. We also have a comparable Brazilian cohort and aim to do some work comparing outcomes in Brazil with ALSPAC outcomes as appropriate.

B2353 - Gender biases in the identification of ADHD - 11/12/2014

Attention deficit hyperactivity disorder (ADHD) is defined by the presence of symptoms of inattention, hyperactivity and impulsivity. To receive a diagnosis of ADHD, six or more symptoms of inattention, hyperactivity and impulsivity must be present for at least 6 months and for children up to the age of 16. Symptoms include difficulties in sustaining attention, difficulties retaining information, difficulties in social etiquette and difficulties with impulse control.

Boys are more likely to present inattentive and hyperactive behaviours compared to girls therefore are more likely to receive a diagnosis of ADHD. Researchers have proposed the ratio of boys to girls with ADHD estimated at between 2:1 and 9:1.

In addition to 'real' differences in underlying symptoms of ADHD, skewed gender ratios could highlight a recognition issue whereby girls are less well-identified and boys are over-identified with ADHD. So the high boys/girl ratios in ADHD diagnosed children are due to a) real differences in symptomology and b) an additional referral or recognition bias. This could be due to girls potentially hiding a childhood history of hyperactivity/disruptive behaviours hence may have not been clinically spotted. Alternatively, it could be because boys typically present more disruptive behaviour therefore more easily spotted than girls, who are more likely to internalize distress.

Other than co-occuring symptoms on which boys and girls with diagnosis differ, differences in cognitive abilities could be potential triggers of referral bias. Higher scores on working memory and processing speed are more pronounced in boys with ADHD compared to girls. If girls with ADHD diagnosis have lower abilities than boys, it may be because they need more severe symptoms before they are referred.

This project highlights a public health concern as gender-sensitive diagnosis could lead to boys being over-diagnosed with ADHD therefore potentially damaging their life opportunities. Also the under-diagnosis of girls may mean they miss out on treatments that would benefit them. This project aims to investigate this gender bias in the identification of diagnosing ADHD.

B2352 - ICMR-MRC joint initiative aetiology and life-course of substance misuse and relationship with mental illness - 11/12/2014

The proposal is being developed. The main purpose is to develop cohorts in India and compare risks and exposures for developing substance use and mental health problems between India and UK - using ALSPAC and IMAGEN.

Background:-

In both, developed and emerging nations externalising behaviours are known to be risk factors for substance abuse and substance abuse is highly correlated with externalising disorders. Environmental risk factors for substance abuse, its relation to externalizing behaviour and its moderation by genetic and epigenetic factors have not been extensively investigated in emerging societies. Given that emerging societies show the biggest increase in alcohol and tobacco use, there is an urgent need to validate and adapt our understanding of etiology and determinants of substance abuse in these countries. Here we compare insights into etiology and trajectories into substance abuse gained from two major European and UK studies, IMAGEN and ALSPAC with Indian cohorts of different social and environmental backgrounds. We will also control for socio-cultural and environmental influences by investigating determinants of substance abuse in SCAMP, a UK cohort containing adolescents of both, European and South Asian descent.

Our project capitalizes on existing cohorts in India with over 18.000 participants, which it aims to enrich using the expertise and infrastructure created by the individual teams. The cohorts have been selected to allow an accelerated longitudinal design covering an age range of 0 to 25 years. These assets will be complemented by European and UK cohorts of approximately 20.000 participants, including IMAGEN (www.imagen-europe.com), ALSPAC and SCAMP, which have established the relevant neuroimaging, neuropsychological, behavioural and clinical assessments which will be applied in our project. As the ongoing SCAMP projects will recruit greater than 1000 13 year old adolescents of South Asian origin we will harmonize the assessment of our study and SCAMP. Together with data available in IMAGEN and ALSPAC this will allow the most comprehensive comparative analysis of brain development and behaviour in different social and cultural environments. In addition, we will use candidate gene sets identified in large GWAS meta-analysis consortia of over 300.000 participants, including ENIGMA, Alcogen and the Psychiatric Genetics Consortium, which are relevant for addictive behaviour and externalising symptoms. Using these assets we will test the following hypotheses:

a.)Exposure to environmental risk or resilience factors, which are pertinent to emerging societies both ante-natal as well as throughout childhood and adolescence are correlated with structural and functional impairments of reinforcement-related brain function, and externalizing behaviour including addictions. These risk factors include (but are not limited to) socio-cultural environment, psychosocial stress, malnutrition and exposure to neurotoxins,

b.)Environmental risk factors influence epigenetic methylation profiles and interact with candidate genotypes across the developmental span, altering development trajectories of growth and brain development, which give rise to variations in temperament and addictive behaviours. Relevant measures include birth weight, anthropometric -somatic and endocrinological measures, brain endophenotypes, cognitive abilities, temperament.

c.)Susceptibility to substance abuse and externalising disorders is dependent on ethnicity and/or socio-cultural influences in comparisons between UK and Indian cohorts

B2351 - Studies of telomere length and mitochondrial DNA copy number in association with age-related phenotypes within ALSPAC - 11/12/2014

Telomeres, the protective caps at the end of chromosomes, shorten with every cell division. Dysfunction of the maternally inherited mitochondrial genome leads to oxidative stress, and the genome is copy-number variable, with more copies in tissues with higher energy requirements. Damage to both telomeric and mitochondrial DNA contributes to cell signalling via p53-mediated pathways, leading to cellular senescence and apoptosis (programmed cell death). Telomere shortening, and mitochondrial dysfunction are therefore known mechanisms of cellular ageing, and recent studies have suggested that mtDNA copy number and leucocyte telomere length (LTL) may be related (Passos et al., Sahin et al.). Telomere length is related to diseases involving accelerated ageing, including those in which inflammation, oxidative stress and disordered cell turnover have been proposed as important: such diseases are cardiovascular disease (Haycock et al.), respiratory disease (Albrecht et al.), and putatively, psychosis (Nieratschker et al). Whilst classical risk factors related to these diseases may also associate with LTL/mtDNA copy number, inflammation may act as a global risk factor for them all, and LTL/mtDNA copy number may mediate these associations (Masi et al.).

We propose to measure average LTL in ALSPAC mothers and children using qPCR, and to perform downstream analyses on the dataset generated. By studying young people, we may analyse telomere length and mtDNA copy number as mediators of associations between early risk factors of chronic disease (e.g. growth trajectories (Barker, 2003), and inflammation) and outcomes, before a large burden of classical risk factors are accrued. Genomic control of these traits, including imprinting effects, will be assessed using mother-child pairs. As well as assessing prior hypotheses, we propose to perform phenome scans of LTL and mtDNA copy number. Ultimately, this proposal aims to understand the relationships between LTL and mtDNA copy number, and their contribution, individual or combined, to senescence.

Hypotheses:

1.Average telomere length will be shorter in ALSPAC mothers compared to offspring, and children's average telomere length will decrease with age.

2.SNPs that may be associated with telomere length may have small effect sizes. Controlling for parent-of-origin effects may unmask these effects.

3.LTL will correlate with phenotypes of accelerated ageing, inflammation or oxidative stress.

4.Telomere length will be related to foetal and childhood growth, biomarkers of growth (GHBP/IGF1) and pubertal stage (as measured by Tanner stage/testosterone).

5.Telomere length will correlate positively with mtDNA copy number.

6.Given the fundamental role of telomeric and mitochondrial dysfunction in senescence, as-of-yet unidentified phenotypes will be associated with these 'genetic phenotypes'.

Aims:

1.To assess average LTL in the Avon Longitudinal Study of Parents and Children.

2.To perform a genome-wide association study of LTL/mtDNA copy number in children, and to assess mother-offspring pairs for parent-of-origin effects.

3.To study telomere length and mtDNA copy number in relation to diseases involving accelerated ageing processes (cardiovascular disease, COPD/asthma, and putatively, psychosis/depression), risk factors for these diseases (e.g. classical CVD risk factors, smoking, inflammation), and intermediate disease phenotypes (e.g. spirometry, psychosis-like symptoms).

a.To refine these associations in individuals with extreme phenotypes.

4.To investigate LTL changes in relation to foetal and childhood growth and puberty.

5.To study the association between telomere length and mtDNA copy number.

6.To undertake phenome scans of LTL/mtDNA copy number (and genetic variants determining them) to determine novel associations.

B2349 - Identifying Parent -of -origin effects POE on birth weight - 04/12/2014

Aim: to replicate genetic associations showing parent-of-origin effects (POE) on birth weight, following initial analysis of UK Biobank data.

Proposal: Monogenic disorders of imprinted genes (e.g. IGF2/H19 disruption in Beckwith-Wiedemann syndrome or Silver-Russell syndrome) often show marked effects on birth weight. However, the role of imprinting (i.e. where the influence of an allele depends on whether it is maternally- or paternally- inherited) in common variation in birth weight is unknown. We hypothesise that there will be common variants at genetic loci which show POE on birth weight, and that known imprinted regions of the genome are enriched for these variants. Recently a method was published to investigate parent of origin effects (POE) in large genome-wide association study (GWAS) datasets of unrelated individuals (Hoggart et al 2014 PLoS Genetics).

We will be applying this method to the forthcoming GWAS data on birth weight in UK Biobank to identify POE across the genome, and to test whether POE on birth weight are more likely to occur in known imprinted regions.

Any loci showing evidence of association will require replication in independent studies. Ideally these studies would have mother, father and child genotype available, but there are few studies with these data. It is possible to gain a large amount of information, however, from the analysis of mother-child pairs. ALSPAC represents the best study in which to do this. We propose to replicate the identified loci from UK Biobank in ALSPAC and potentially other available studies including EFSOCH and HAPO. The replication sets will not have the statistical power comparable to Biobank but will have better quality phenotype data, the presence of maternal genotypes and will enable comparison of effect sizes of the associations observed in Biobank.

B2348 - Are Children with Impaired Vision or Hearing at Greater or Differential Risk of Unintentional Injury - 04/12/2014

The aim of my research is to investigate the extent to which visual impairment (VI) or hearing impairment (HI) affects a child's risk of unintentional injury (UI), and the association of that UI with a range of child, family and environmental factors. A systematic review I carried out demonstrated a paucity of studies, with the highest level of evidence found being case control studies. UI is a leading cause of morbidity and mortality for children, with the major global childhood UI killers being road traffic injury, drowning, fire related burns, falls and poisoning. Some of these areas of key interest to my research were not looked at by any studies, including drownings and fire-related injuries. Only one paper dealt with road traffic injuries, and only two case reports looked at poisonings. The severity of impairment, dental injuries, activity levels and effect of co-morbidity were described as needing higher level research.

No epidemiologically robust population-based cohort studies were found. The ALSPAC study has already collected detailed longitudinal data on sensory impairments and all the major childhood unintentional injuries, as well as a wide range of other relevant factors such as socioeconomic circumstances. The data is highly relevant to my area of research interest with detailed vision variables at age 7 and 11, detailed hearing variables at age 7, 9 and 11 and detailed unintentional injury variables at 5, 7, 11 and more specialised data at 13 and 16.

B2347 - Matching in the marriage market evidence from ALSPAC - 04/12/2014

Background:

In this study we will investigate how mothers' choose their partners. We will investigate this matching process using the exemplar of the relationship between parents' heights. Parents' heights are more associated than would be expected if individuals mated randomly within the population (Silventoinen et al. 2003). Height is a highly heritable phenotype. We do not know how much of the association of partners' heights is due to a genetic correlation, and how much is due to individuals from similar environmental backgrounds matching. For example, the associations of partners' heights could be because they chose to mate with individuals with similar backgrounds. We will extend the Mendelian randomisation framework to address these questions.

ALSPAC is an ideal dataset to investigate this hypothesis because it has detailed longitudinal data on both mother and fathers of the cohort children and genome-wide data on a large sample of the mothers.

Aims:

We will estimate the associations between mothers' height and height allele scores and their partners' height and observable characteristics using ALSPAC data.

Hypothesis: What are the associations between mothers' height and genotypic scores for scores for height and their partners' observed height and characteristics?

Exposure: The mothers' height at birth of their child and a weighted allele score of 697 recently reported height variants will be used as the exposure.

Outcomes: The outcomes will be the fathers' height, education, family income, paternal grand-parents education.

Confounding variables: first eight principal components of population stratification.

Outline:

People do not choose their partners at random: partners tend to be more similar than would be expected if partners were randomly chosen. We do not know if these associations are because people directly match on particular characteristics, height for example, or because partners match on a third confounding factor, such as their socio-economic background. We will investigate these associations in ALSPAC. There are now 697 genetic variants which are known to affect height (Wood et al. 2014). We will use these variants as instrumental variables for mothers' height in a Mendelian randomisation analysis.

In this study we will investigate the observed association between the mothers' height and their partners' phenotypes and compare the size of this association to the association implied by the genetic variants for height. If individuals actively match on height then we would expect similar associations between the observed height and the genetic variants for height. However, if the observed associations between mothers' height and their partners' phenotypes are the result of a third, confounding factor, then we would expect to find weaker evidence of associations between the genetic variants and the partners' characteristics. To maximise power we will construct weighted allele scores of the height genetic variants.

B2346 - Understanding variability in cardio-metabolic risk in the ALSPAC cohort - 27/11/2014

Objectives

Primary: 1) To investigate the association between birth order and measures of adiposity (BMI; waist circumference and fat mass, change in fat mass from 9 to 15 years), metabolic (fasting glucose, fasting insulin and lipid profile) and vascular (blood pressure) functions at 15 years old male and female adolescents enrolled in the ALSPAC cohort. 2) A diagnosis of metabolic syndrome will be performed based on measurement of waist circumference, fasting glucose, triglycerides, HDL, blood pressure and the relative risk for metabolic syndrome at age 15 associated with being first-born compared to later-born children will be assessed.

Secondary: We shall test for sex-differences in these associations.

B2345 - Association of atopic illness and raised inflammatory markers in childhood with manic symptoms in young adult life - 27/11/2014

Background:

Previous research using the ALSPAC cohort has found an association between childhood serum levels of interlukin 6 (Il-6) and C-Reactive Protein (CRP), and both depression and psychosis symptoms in young adult life (1). The association between childhood inflammatory markers and bipolar disorder has not been examined. There is some evidence that Il-6 is acutely raised during mood episodes in bipolar disorder but appears to return to control levels during euthymia (2). Also there are reports that inflammatory illnesses in childhood, such as asthma, are associated with both elevated Il-6 prior to the diagnosis (3) and with adult diagnoses of bipolar disorder (4).

Aim:

To examine the association between atopic illness (asthma and eczema) and inflammatory markers in childhood, and manic symptoms in young adult life.

Hypotheses:

1) That atopic illness in childhood is associated with increased risk of future manic symptoms

2) That higher serum levels of Il-6 and CRP in childhood increase the risk of future manic symptoms.

B2344 - Investigating the possible bidirectional association between smoking and caffeine using Mendelian randomization - 27/11/2014

Aims

To investigate the possible bidirectional association between smoking and caffeine consumption using Mendelian randomization.

Hypotheses

Coffee consumption and cigarette smoking are highly comorbid [1]. Observational studies suggest that coffee drinkers are more likely to be smokers than non-drinkers [1, 2], and also suggest a positive association between coffee consumption and cigarette consumption [3], and an inverse relationship between coffee consumption and smoking cessation [4].

However, the causal nature and direction of these effects are unknown and are difficult to infer from observational studies. Mendelian randomization methods minimise bias from confounding and remove the possibility of reverse causality [5].

Genetic variants for both smoking behaviour phenotypes and coffee consumption have been identified in genome-wide association studies [6, 7]. These can be used as instruments for measured coffee consumption and smoking behaviour in Mendelian randomization studies. Polygenic risk scores for these exposures can be generated from GWAS data to increase the power of Mendelian randomization analysis [8].

Polygenic risk scores for smoking behaviours and caffeine consumption will be generated from GWAS data for both the ALSPAC mothers and ALSPAC children. We will investigate the associations of genetic risk scores for smoking with caffeine consumption and the association of genetic risk scores for caffeine consumption with smoking. These analyses will be run in parallel with data from the Netherlands Twin Registry.

B2343 - The exploration of an association between previously reported orofacial cleft genes and lip trait phenotypes - 27/11/2014

The aim of this study it to explore a link between specific genes that have been reported to be associated with orofacial clefting and identified lip traits from 3D facial scans.

We hypothesise that SNP's associated with clefting, should have an effect on lip morphology. The exposure variable is the orofacial cleft gene carrier (see appendix for list of candidate genes) and the outcome variable is the characteristic lip trait (see categorisation table) - that may have increased/decreased occurrence of certain features. These features may in turn be considered risk factors in determining risk of orofacial clefting.

The GWAS for these lip traits has already been conducted (under B568) and so this proposal should just involve the look-up of the relevant variants in those results. Lavinia Paternoster (IEU) has access to these results. These look-ups and any subsequent analysis required will be carried out by Caryl Wilson-Nagrani as an IEU temporary visitor under the supervision of Lavinia Paternoster.

B2342 - Associations of Behaviour Disorders in Childhood and Psychotic-Like Symptoms in Adolescence - 27/11/2014

Associations of Behaviour Disorders in Childhood and Psychotic-Like Symptoms in Adolescence

The general aim of the project is to analyze the associations between childhood behaviour disorders and psychotic symptoms in adolescence. Many adults with psychotic symptoms and/or schizophreniform disorders received a psychiatric diagnosis in childhood. These diagnoses cover the full range of developmental, internalizing, externalizing, and behavioural disorders (Rubino et al., 2008). To date, it is not clear whether the presence of childhood mental symptoms and disorders as such represents a general risk factor for later psychopathology or whether there are specific associations indicated by stronger correlations for some disorders (research question 1) and how these associations are characterized (research question 2).

B2341 - Role of rare coding variants in speech and language disorder - 20/11/2014

AIM - to investigate the contribution of rare coding variants in selected candidate genes to speech and language disorders

BACKGROUND

Our lab investigates genetic contributions to speech and language disorders, primarily within a cohort of families in which at least one child is diagnosed with specific language impairment (The SLI Consortium (SLIC) cohort). Investigations in this cohort have highlighted specific genetic pathways and candidate genes that we believe might be linked to speech and language development. We would like to follow these genes up in more detail in a larger cohort. The effects we have identified are rare coding mutations. In order to follow these up, we therefore need access to a large cohort in which speech and language data and genetic sequencing are readily available.

B2339 - Investigation of the association between birth weight reproductive abnormalities and placental function - 20/11/2014

Background

Amongst disorders of sex development (DSD) cases, conditions associated with under virilisation of the presumed XY boys are the largest group of children. Our international group (I-DSD.org) recently reported in Pediatrics that this group of people will increase as more affected infants are raised as boys. XY DSD boys often have low birth wt and are also often small for gestational age (SGA), as confirmed by Hughes et al, Cambridge using the ALSPAC cohort. Altered exposure to androgens has been linked with DSDs, intra-uterine growth restriction (IUGR) and placental problems, possibly all involving the IGF signalling pathway. For example, exposure to exognous androgens in sheep advances placental differentiation and increases placental differentiation but this early compensation to maintain placental efficienc cannot be mainted long term leading to placental inefficiency and IUGR. Furthermore, altered steroid exposure in fetal rats through exposure to MPA, a synthetic progestogen, reduced external genitalia masculinisation in males and increased it in females, and reduced bodyweight and placental weight in both males and females.

Aims

We hypothesise that:

(1) Boys with DSDs (namely hypospadias and/or cryptorchidism) are more at risk of being SGA, possibly due to altered placental development and/or funtion.

(2) The SGA phenotype associated with DSDs, such as hypospadias, is different to the SGA phenotype without hypospadias.

(3) Boys with hypospadias may have been denied sufficient androgen exposure prenatally and/or experience an ongoing lack of androgens, which may have a negative impact on their future health and well being.

We therefore propose to analyse the ALSPAC data for variables such as birth weight, gestational age at birth, placenta weight, congenital abnormalities at birth such as hypospadias, anogenital distance in the child, any fertility treatment prior to pregnancy, as well as moderately long-term outcome that relates to height, cardiometabolic and body composition including skeletal health.

We wish to compare the following groups - hypospadias and SGA, SGA and no hypospadias, average GA and hypospadias and AGA and no hypospadias. We may also be interested in the same analysis for individuals with cryptorchidism

B2338 - Ascertaining direction of causality in associations between smoking cognition and schizophrenia - 20/11/2014

Aims:

Associations are consistently seen between cigarette use and psychosis, although direction of causation is not known. There is also a large body of literature showing cognitive impairment in patients with schizophrenia. There has been some suggestion that high rates of smoking in schizophrenia could be to alleviate cognitive impairment from both the disorder and anti-psychotic medication side-effects, as nicotine has been posited as a cognitive enhancer. We aim to investigate whether associations between cigarette use, cognition and psychotic experiences are causal, using Mendelian Randomisation.

Hypotheses:

As these are exploratory analyses, we do not have hypotheses as to what we will find in terms of causality.

Exposure variables:

Genetic instruments as proxy variables for cigarette use and for risk of schizophrenia.

Outcome variables:

Cognitive tasks at age 18, smoking at age 18, psychotic experiences at age 18 (all measured at clinic).

Confounding variables:

As this is a Mendelian randomisation design, the analyses should not be subject to the usual confounders that impact upon observational studies. However, gender and ethnicity will be accounted for in our analyses. Data on confounders has been requested to check for pleiotropy.

B2337 - The association between caffeine consumption during pregnancy and birth weight a Mendelian randomization study - 20/11/2014

Aim

To investigate if maternal caffeine intake during pregnancy causally influences offspring birth weight using a Mendelian randomization approach.

Hypotheses

A recent meta-analysis of observational studies found evidence that caffeine consumption during pregnancy is associated with increased risk of having a low birth weight baby [1]. However, it is not clear whether this association is causal or whether this may be due to confounding by other lifestyle factors. For example, coffee consumption is positively correlated with cigarette consumption, a known risk factor for low birth weight [2].

This problem of confounding can be minimised using Mendelian randomisation analyses, whereby genetic variants associated with caffeine are used as proxies for measured caffeine consumption. Genome-wide association studies have identified 8 independent genetic loci associated with coffee consumption [3, 4]. Some of these variants have been shown to associate specifically with caffeinated beverage intake in ALSPAC [5].

This project will investigate associations between maternal caffeine-related genetic variants and offspring birth weight using a Mendelian randomisation approach.

B2336 - Enhancing data collection in ALSPAC-G2 using novel methods A feasibility study - 20/11/2014

Background:

A high proportion of women start pregnancy overweight/obese. According to the developmental overnutrition hypothesis, this could cause offspring to be fatter throughout their lives, and therefore, this may perpetuate the obesity epidemic across generations.1, 2 Concerns about this hypothesis are influencing antenatal care. Two key changes to antentatal care which have occurred in relation to concerns about developmental overnutrition are:

1.Monitoring weight throughout pregnancy. This was previously done with the aim of identifying those at risk of SGA, but was stopped in the mid-1990s because of evidence of its poor predictive value.3 It is now being done with the intent of limiting gestational weight gain (GWG) in order to prevent women having infants who are LGA, since they may go on to be more adipose throughout their lives.4

2.The new International Association of Diabetes and Pregnancy Study Groups (IADPSG) criteria for defining gestational diabetes (GDM), which have been adopted by the WHO, aim to identify those at risk of LGA and greater offspring adiposity.5

However, whether the associations of maternal adiposity with offspring outcomes are causal is unknown, and if they are indeed causal, then the mechanisms are unclear.1, 2 Being able to accurately quantify maternal and fetal fat mass, glucose variability, diet, physical activity and a wide range of potential circulating nutrients in women during pregnancy could clarify the effects of maternal overweight/adiposity on her future health and that of her offspring. Having tools for obtaining these data that are acceptable, feasible, cost-effective and safe in pregnancy would support translation of research findings into clinical practice as appropriate.

B2335 - 10000 hours Children Childcare and Developmental Opportunity - 20/11/2014

Analysis of the ALSPAC data forms part of a larger grant application examining the genetic markers of phenotypic measures of emotional reactivity in early childcare settings. More specifically, the ALSPAC data will be used for the validation of a GWAS study examining associations with individual temprements and will form a cross-test of methodological reliability.

AIMS. The aims of the broader research program are to:

1.Characterise individual difference in child emotional reactivity through assessment of the the statistical association of genotype with physiological, observational, physiological, and report measures.

2.Examine the interaction of child emotional reactivity with qualities of the childcare environment to and assess impact on social-emotional regulation and behavioural development.

3.Identify the meaning of individual difference in children's reactivity for policy and practice in childcare settings.

The specific aims relevent to the use of the ALSPAC data will be to valiate genotypic markers identified within our target cohort, by examining the same geneotypes and their association with phenotypic variables of temprement, sleep, behaviour and behavioural diagnoses within the ALSPAC data set.

VARIABLES

Genotypes of interest will be ientified via an indepenent cohort study to be conducte as part of the grant application and are not known at this time. Phenotypic variables of interest will be temperament, behaviour, behavioural diagnoses and sleep characterisitcs. Socio-economic status and childcare charatersitics of the children are also requested.

B2334 - Effect of Socioeconomic Depreciation on Child Development A Longitudinal Study - 20/11/2014

Socioeconomic stability plays an important role in the normal development of a child. So, it is not surprising that adverse socioeconomic conditions arising from difficult financial circumstances have been associated with a number of mental health and cognitive problems. The motivation for the current line of thinking is a recent study published in JAMA: Psychiatry wherein we noted that macroeconomic shocks such as recessions can have long-term effects on the mental and emotional health of children between the ages of 0-18 months. Over the last two years, we have been expanding our work on the concept of socioeconomic depreciation (SED) or drop in family income. In this proposal, we will examine the mechanism behind the influence of SED on future behavior problems. Specifically, we are proposing that SED will affect attachment, which in turn will affect social development. Since attachment variables are not available in the ALSPAC data, ALSPAC will not be used to develop this particular hypothesis. However, ALSPAC will be used to explore the role of social development in future behavior problems. (Figure 1 available on request).

Secondly, we propose to explore the effects of prenatal exposure to SED. Borrowing from literature on fetal programming, we propose that prenatal exposure may lead to changes in temperament and increase vulnerability to behavior problems. Temperament has been described as a stable system of traits that moderates susceptibility to behavioral and emotional problems. In line with this argument, this study will examine if temperament moderates the link between SED and behavioral and emotional problems (Figure 2 available on request).

This proposal also extends our work into SED by testing for gene by environment interactions using the large public data sets from the Psychiatric Genomics Consortium (PGC). Because Dr. Faraone is on the PGC's Coordinating Committee, this aspect of the work will be straightforward. For each disorder, the PGC computed a SNP heritability, which indexes the amount of heritability due to common SNP variants. These SNP heritabilities were all much greater than zero and were statistically significant. These analyses also showed substantial and significant correlations between the heritabilities of some of these disorders. For example the correlation between schizophrenia and each of the mood disorders was greater than 0.4. This cross disorder polygenic overlap, along with prior evidence of overlap for single SNP variants and for CNVs, has confirmed prior work from genetic epidemiology indicating shared genetic risk factors among multiple psychiatric disorders. This work is relevant to genetic studies of SED because it allows us to create molecular polygenic scores for use in testing gene by environment interaction. These scores may explain, for example, whey two children raised in identical SED circumstances have different outcomes. When added to knowledge about SED, these genetic data could help allocate scarce resources where they are most urgently needed.

For this project, we propose to use ALSPAC. Details about our proposed work with ALSPAC are discussed below. ALSPAC data will be used to test the following hypotheses. The scientific outline (Section 8) provides a list of specific variables requested, and how those variables will be used in hypothesis testing. In that table, DV refers to Dependent (or Outcome) Variable, IV to Independent (or Exposure) Variable, MV to Moderating Variable, and CV to Confounding Variable.

B2333 - Association between asthma/allergies and depression/anxiety/self harm - 20/11/2014

Several reports indicate that asthma and depression co-occur(1). The association has been reported in countries with different social and cultural histories (2) suggesting a true association between these two conditions. In addition, some studies report a higher rate of suicide or suicide-related behaviours among asthma patients(3). Several pathways that include both directions of association (asthma leading to depression or depression leading to asthma) or common aetiological process that would increase the risk of both conditions have been proposed.

AIM. To determine whether there is an association between asthma/allergy and depression/anxiety/self-harm.

Specific objectives are:

1.Establish whether there is a cross-sectional association between asthma/atopy and depression/anxiety self-harm in children and adolescents.

2.Establish whether children with asthma/atopy have higher risk of developing depression/anxiety self-harm (prospective).

3.Establish whether cross-sectional and prospective associations between asthma and depression vary by gender.

4.Determine the pathways underpinning an association between asthma (and/or atopy) and depression (anxiety/self-harm).

B2332 - Autism sleep mental health parent distress and chronic pain in childhood - 20/11/2014

Aims:

To describe the prevalence of pain within those with diagnosed autistic spectrum disorder.

To describe the prevalence of pain within those with autistic like symptoms including social and communication difficulties, prematurity and delays reaching developmental milestones.

To explore if depression and anxiety are higher amongst those with autism and pain.

To explore if people with autism and pain suffer from sleep deprivation.

To explore how prevalent sleep deprivation is in people who present with persistant pain compared to those who present with autism and persistent pain.

To explore if sleep is dependant on anxiety scores in those with pain more than those without pain.

To explorwe if children with a diagnosed autistic spectrum disorder have other chronic sleep, pain or anxiety conditions.

B2331 - Translational Psychiatry - genetic variation and dysfunction of human ARC gene - 20/11/2014

The immediate early gene, ARC, is a key regulator of protein synthesis-dependent synaptic plasticity. Synaptic plasticity functions in memory as well as in adaptive changes related to fear, anxiety, and reward. Dysfunction of synaptic plasticity is increasingly implicated in neuropsychiatric conditions including depression, schizophrenia and autism spectrum disorders. Our recent work links several SNPs in Arc to cognitive function. We tested whether ARC variants are associated with six measures of cognitive functioning in two healthy samples-the Norwegian Cognitive NeuroGenetics (NCNG) sample and the Swedish Betula sample. Of a total 71 ARC variants, 21 were nominally associated with human cognitive functions involving semantic knowledge, visuospatial abilities, delayed episodic memory, and general cognitive abilities (IQ).

Preliminary meta-analysis of large-scale genome-wide association studies' (GWAS) results across two neuropsychiatric conditions showing the most genetic overlap - SCZ and BP (http://www.med.unc.edu/pgc) - reveals a synergetic effect of two SNPs located in the regulatory downstream 3' region of the ARC gene (rs7465272 and rs7835613, p = 2.31e-06 and 9.01e-06 respectively). Adding MDD to the joint meta-analysis further reinforces the involvement of one of those SNPs in the susceptibility to neuropsychiatric conditions (rs7835613, p = 7.90e-06). Taking these findings together with known neuronal functions of the ARC gene, we hypothesize that its genetic variants may accentuate such common genetic architecture of cognitive abilities in neuropsychiatric conditions.

Our planned analyses:

1. Genetic association of ARC gene complex with cognitive function (cross-sectional and longitudinal examination)

1.1 ARC gene and cognitive functioning

AIM AND HYPOTHESIS

Here we plan to perform regression analyses to investigate whether common ARC variants are associated with cognition or other aspects of brain plasticity. Since previous studies are suggestive to this association, we hypothesize that various aspects of cognition , plasticity, and/or neuropsychiatric disorders will be associated with ARC variants.

B2330 - An investigation of maternal risk factors for the development of paediatric obsessive-compulsive disorder - 13/11/2014

BACKGROUND:

Obsessive-compulsive disorder (OCD) commonly has its onset in childhood, affecting 1-4% of young people under the age of 18 (Douglass et al, 1995; Flament et al., 1988; Heyman et al, 2001) . The disorder is highly disabling across domains (Piacentini et al, 2003) and is predictive of a range of negative outcomes (Wewetzer et al., 2001; Micali et al, 2010). Furthermore, if left untreated the disorder typically follows a chronic course (Skoog & Skoog, 1999) and is major source of economic burden, ranking among the top 10 most disabling illnesses recognized by the World Health Organization (Murray & Lopez, 1996). There is a pressing need to further understand the mechanisms underlying the development and maintenance of pediatric OCD, in order to facilitate effective prevention and intervention.

OCD results from a complex interplay between genetic and environmental factors. Twin studies have shown that genetic factors explain 45-65% of the variance in OCD symptoms in children, with the remainder being accounted for by shared and non-shared environment (Pauls, 2008). The specific environmental risk factors remain unknown, but it has been proposed that aspects of family environment contribute to OCD (Van Noppen et al, 2009). Consistent with this, previous studies have demonstrated that parents of young people with OCD show elevated rates of critical and over-intrusive parenting styles (Barrett et al, 2002; Hibbs et al, 1991) and psychiatric disorders (Lenane et al, 1990). However, a major limitation of the research in this field to date is the reliance on cross-sectional designs, meaning that the direction of effects between childhood OCD and parenting style/parental psychopathology remain unclear. To date, no prospective studies have been conducted to test whether such family factors predict the onset of OCD in children.

AIMS:

This primary aim of this study is to test whether maternal parenting style and maternal psychopathology in early childhood predict the subsequent development of OCD symptoms in youth. A secondary aim is to test whether the persistence of OCD symptoms in young people is mediated by maternal parenting style and maternal pscyhopathology.

B2329 - Genic and intergenic heritability analysisof general cognitive ability - 13/11/2014

Aims

Genome Wide Complex Trait Analysis (GCTA) has been applied to Genome Wide Association Study (GWAS) data sets of cognitive ability to show that around half of the phenotypic variation is tagged by common variants (Davies et al., 2011). However, GCTA cannot provide information regarding which variants are more important. This study aims to find regions in the genome that make a significant contribution to the GCTA heritability estimate. Three groups of single nucleotide polymorphisms (SNPs) will be formed; the first group will consist of all SNPs available for use, the second set will consist of SNPs found in genes, whereas the third will be formed from SNPs that are found between genes. GCTA will be perfomed on each group allowing for both the genic and intergenic SNP-sets to be tested against 0 in order to determine if they each make a significant contribution toward intelligence differences. In addition the two groups will be compared against each other to show which regions matter most to human intelligence differences. Using GCTA in this way will help to show that variants within genes account for a significant proportion of the heritability of human intelligence. This will justify the use of gene and gene-set based analyses well as indicate which areas of the genome are of particular importance to cognitive ability.

Hypothesis

It is expected that for general cognitive ability both the geneic and the intergenic SNPs will make significant contributions to the total heritiability estimate. It is also expected that SNPs found within genes will also make a greater contribution toward the heritability estimates than SNPs found between genes as has been demonstrated for height (Yang et al., 2011) and indicated for schizophrenia (Schizophrenia Working Group of the Psychiatric Genomics Consortium, 2014).

Exposure variables

GCTA has been performed previously on general cognitive ability in The Avon Longitudinal Study of Parents and Children (ALSPAC) group (Benyamin et al., 2013) as it has a suitably large sample size (5517 at age 9) and an execellent test to derive an Intelligence Quotent (IQ) estimate, namely the Wecshler Intelligence Scale for Children-III (WISC-III). For the proposed analyses to take place, the genotype data along with Verbal (Information, similarities, arithmetic, vocabulary, and comprehenssion) and Performance (picture completion, coding, picture arrangement. Block design, and object assembly) subscales of the WISC-III will be used to form an IQ score. GCTA analysis will be performed on this IQ score using all SNPs available for analysis. Next, the total set of SNPs will be divided into genic and intergenic SNP-sets before GCTA is performed on both SNP-sets.

Outcome variables

The proportion of phenotypic varainace attributable to the genetic variation in each of the three groups will form the outcome variable.

Confounding variables

One potential source of confounding would be that the two SNP-sets could tag the same variants due to the existence of linkage disequilibrium.

B2327 - Vitamin D in Pregnancy and Perinatal Depression - 12/11/2014

Background:

Results from a recent meta-analysis suggest that low Vitamin D levels are associated with depression1. As pregnancy is a time for increased nutritional demands, precipitation of depression would be more likely during pregnancy if this hypothetical association were causal. Low vitamin D levels are common during pregnancy, particularly in high-risk groups.2,3,4 Some studies have reported an association between low vitamin D levels and depressive symptoms during pregnancy5,6 and in the postnatal period.7,8,9 However, other studies have not supported this hypothesis.10 Previous studies have been limited by sample size7,9, identification of depression10, or follow up time to development of symptoms.5,6,8

Aims:

*To determine the relationship between vitamin D (serum 25-hydroxyvitamin D3 and D2) and perinatal depression.

*To personally develop research skills in preparation for applying for research fellowships

B2326 - Recognising the hidden face of autismdefining the characteristics and needs of females with autistic difficulties - 23/10/2014

AIMS

We aim to discover:

1. The rates of ASD and of the broader autism phenotype in AT+ females, compared to AT+ males, AT- females and AT- males.

2. The rates of undiagnosed ASD in AT+ females, compared to AT+ males, and the characteristics across the lifespan that are associated with undiagnosed ASD.

3. The characteristics of the female autistic phenotype. To this end we will compare AT+ males and females on current and previous measures of social communication and inflexibility. We will also investigate whether the female autistic phenotpye reflects typical gender differences, by comparing gender differences for AT+ participants with gender differences for AT- participants.

4. The needs females with childhood autistic difficulties, by assessing mental health, well being and adaptive functioning of AT+ females across their childhood, adolescence and early adulthood.

5. Risk and protective factors in childhood that influence adult outcomes for women who have AT+ in childhood, by looking for associations between individual (e.g. childhood anxiety, IQ) and environmental (parenting, socio-economic status, educational provision) factors measured prospectively in ALSPAC.

B2318 - Prenatal and early childhood environmental risk factors for psychiatric outcomes using a novel exposure biomarker - 06/11/2014

There is substantial evidence that early environmental insults increase risk for psychiatric disorders,

especially those with strong neurodevelopmental origins. Thus, there is a need to reliably identify these

environmental factors, as well as whether higher exposure level during critical periods for

neurodevelopment are related to greater risk for psychiatric disorders. Moreover, while environmental

toxins have been reliably associated with early neurodevelopment, similar investigations into longer term

and psychiatric outcomes are scarce.

Current approaches use indirect measures of fetal exposure, such as chemical concentrations in maternal

blood and urine, which may not accurately reflect fetal uptake for many toxins due to variable partitioning

across the placenta (Smith et al., 2007). Thus, a direct marker of early exposure is needed to aid our

understanding of the etiology of psychiatric disorders, as well as to aid prevention.

The current study proposes to use a unique and well-characterized birth cohort: the Avon Longitudinal

Study of Parents and Children (ALSPAC) and applying an extensively developed and piloted method to

determine multi-toxin early exposure (Arora et al., 2006, 2011; 2012; 2013; Hare et al., 2011; Austin et

al., 2013). Human deciduous teeth undergo systematic mineralization commencing prenatally and are

composed of a collagen-based, lipid-containing, calcium-rich apatite matrix, which accumulates bone

seeking elements and organic compounds. The methodology combines detailed histological analysis and

associated analytical tools to establish a comprehensive record of weekly to monthly exposure history of

multiple chemicals and metals and history of infections from the second trimester through early

childhood.

Aims

The overall goal of this project is to determine the association of early life environmental metal and

chemical toxin and infection exposures with multiple psychiatric and neurological outcomes: psychotic

like experiences, depression, mild cognitive impairment and autstic-like traits. A detailed history of

exposure during prenatal and early childhood development will be established to distinguish between two

important aspects of the exposure profile:

1) Exposure timing: We will construct weekly to monthly exposure history over the prenatal and early

childhood periods in order to identify the developmental period(s) most strongly associated with risk for

poor psychiatric and neurological outcomes.

2) Exposure intensity: Cumulative exposure may be more important than exposure during any single

developmental window and our biomarker allows measurement of cumulative exposure from the prenatal

period to the time of tooth shedding, which occurs between ages 6 to 12 years.

B2316 - Examining the long-term outcome of early onset depression in 10-13 year olds - 31/10/2014

Aims

1. To investigate the long-term outcomes of early onset depression in children affected at the ages of 10 and 13 years.

2. To examine the potential moderating effect of factors that might predict long-term outcome, including comorbid psychiatric disorder and family history of depression.

3. To examine the course and correlates of depressive symptoms and disorder across adolescence in boys.

Background

Depression in pre-adolescence is a serious, neglected disorder. It is common, has poor outcomes, and has been the subject of very little research. This project will investigate the course of early onset depression in a large population cohort study

B2315 - Bayesian individual knot point models for modelling growth - 31/10/2014

This project is IEU research, linked with Laura Howe's MRC fellowship and the IEU stats theme. Analysis will be carried out by Sam Brilleman with supervision from Laura Howe and Kate Tilling.

Aim: to evaluate the use of Bayesian individual knot point models for modelling growth across childhood and adolescence and estimating age of puberty onset, and to compare these models with alternative approaches such as SITAR

Exposure: age

Outcome: height and weight

Confounding variables: gender

Project justification: Self-reported measures of pubertal status can be inaccurate and there is often lots of missing data due to participant embarrassment. Height-based indices of pubertal development offer an attractive alternative that may be both more accurate and result in less missing data. In this project, we will use all available height and weight data to estimate trajectories of growth across childhood and adolescence, using models that allow person-specific ages at which the rate of growth changes. The idea is that the timing of these knowpoints may be informative about pubertal growth spurts. The models will be compared with other approaches to identifying pubertal growth spurts from growth trajectories, e.g. superimposition by translation and rotation (SITAR), a method developed by Tim Cole.

B2314 - Handling multivariate missingness in health and behaviour data via multiple imputation under MNAR Issues in Practice - 31/10/2014

BACKGROUND:

Data collected by ALSPAC to explore potential predictors of adolscent alcohol, tobacco and cannabis consumption exhibit substantial levels of missingness in both outcomes and covariates and are plausibly missing not at random (MNAR). This is also the case for data collected by ALSPAC to explore potential correlates of adolescent mental health. Standard maximum likelihood and Bayesian full probability modelling procedures can quickly become computationally infeasible in the presence of multivariate MNAR missingness. We propose to tackle this difficulty by extending a popular procedure for performing multiple imputation under MAR, Fully Conditional Specification, to handle MNAR missingness mechanisms. Our method will be broadly applicable to future analyses of the ALSPAC data and to both cross-sectional and longitudinal data.

AIMS:

1. To develop a new statistical method for handling datasets with multivariate MNAR missingness.

2. To use this new method to further explore the missing data mechanism for

a. key variables on alcohol, tobacco and cannabis use in teenagers.

b. key variables on mental health outcomes in teenagers.

B2313 - Participant views on research ethics in Children of the 90s supporting participant-aligned policy development - 23/10/2014

Introduction

The social context in which biomedical research occurs is constantly changing, eg. social media is reshaping views and expectations about individual privacy; understandings of health are constantly evolving. At the same time, new research technologies are becoming available with increasing rapidity, eg. new 'omics tools for analysis. Any change in society or technology may raise new ethical questions for studies such as ALSPAC and may have implications for the policies used to govern these studies.

New policy issues emerge relatively frequently but not necessarily in predictable patterns. Recently emerging issues of concern to cohort studies and biobanks internationally have included: return of incidental findings, recall by genotype, commercial funding in research and data sharing. Legislation proscribes some actions related to these emerging issues, (eg. EU Directive 95/46/EC: 'Protection of personal data', 2012), funder policy provides broad guidelines for policy (eg. MRC/Wellcome Trust 'Framework on the feedback of health-related findings in research', 2014), and individual studies produce in house policy (ALSPAC 'Disclosure of biomedical information to participants', 2011).

Transparency of study policies and practice, especially as new issues emerge, is axiomatic to building and maintaining trust. For longitudinal studies maintaining trust with their participants is crucial to the establishment and maintenance of the long term relationships that characterise these studies; relationships that are realised in participant retention. But extant trust is not enough. Policies must also continue to be sensitive to and aligned with participant (social) values and norms. One way to achieve this is to ensure meaningful engagement of participants in the issues that impact them. Children of the 90s has always been keen to involve participants in the research and ethical decisions made about the study. As part of that commitment the Data to Knowledge Research Group, University of Bristol, will undertake a series of qualitative studies to explore, in depth, the views and perspectives of participants on key emerging research/ethical issues. Drawing from the findings of these qualitative studies ALSPAC will then invite the wider cohort to become involved in engagement activities to assess the views of the broader constituency.

This programme of work will address key issues as they arise over the duration of the current strategic award funding (2014-2019). In the first instance these will include return of incidental findings, recall by genotype, commercial funding in research. In each case the aims and objectives of the research will take the form:

Aim

To gain a better understanding of Children of the 90s participants' perspectives on the issue under study.

Objectives

1. To assess the attitudes of participants to the issue and to understand whether these attitudes may change over time.

2. To understand the potential impact of the issue on Children of the 90s participants.

3. To help inform the policy on the issue in Children of the 90s.

Proposed methods

B2312 - Whole genome sequence based analysis of liver function within the UK10K project - 23/10/2014

The UK10K project represents one of the first large scale applications of next generation sequencing to population based epidemiological samples and the examination of complex phenotypes. The objectives of this work are to record whole genome sequence variation at and below 1% minor allele frequency, to provide an imputation reference and to use this, not only to provide a resource for the scientific community (both genotypes and phenotypes), but also to examine genetic associations across a spectrum of genetic variation.

The study is composed of two samples drawn from European population based epidemiological studies (The Avon Longitudinal Study of Parents and children and Twins UK) and forms a collection of nearly 4000 participants now with whole genome sequence data and phenotypes (along with complementary imputed internal replication data sets). A total of 1,990 individuals from TwinsUK and 2,040 individuals from ALSPAC were consented for sequencing. Variant sites and genotype likelihoods were called using samtools and genotypes were refined and phased using BEAGLE, with similar procedures to the 1000 Genomes Project.

In addition, both ALSPAC and TwinsUK consented to release phenotype data related to cardiovascular disease as a public resource for the association analyses. For TwinsUK, liver phenotypes including bilirubin, alkaline phosphatase, GGT and albumin were released. The association analyses for the liver phenotypes are currently reaching a critical phase for the singlepoint associations, and also for those more rare variants with analyses being undertaken using variant aggregation techniques such as SKAT. Consequently, we are following up possible avenues for increasing our sample sizes, in particular data sets with existing whole genome sequence data such as ALSPAC. To this end, we are writing to seek a collaborative arrangement efforts to continue our analysis of both single point and rare variant associations. These phenotypes would not be part of the UK10K public release.

B2310 - Formulating Identifying and Estimating the Genomic Architecture of Non-cognitive Skill Formation - 23/10/2014

Background:

Economists and psychologists have established that non-cognitive traits, such as persistence and motivation, are more strongly associated with educational, labour market and risky behaviour outcomes than cognitive measures such as IQ (1-3). This observation has been used to motivate substantial government investments in early years interventions, such as Head Start in the US and Sure Start in the UK. These programs are partly designed to develop children's non-cognitive skills and ultimately improve their outcomes as adults (4). Yet, despite the increasing enthusiasm for these initiatives amongst policy makers, there are still major unresolved questions about whether the associations of non-cognitive skills and later outcomes are due to underlying causal relationships.

The evidence about the importance of non-cognitive skills is largely based on observational studies, both cross sectional and longitudinal. It is very difficult to infer causation in these studies, because of the challenge in sufficiently accounting for all the potential differences between individuals. This may be one reason why, in practice, experimental and quasi-experimental studies have found that the success of early interventions has been mixed (5). Additionally, we do not know the extent to which the associations between non-cognitive skills and educational and labour market outcomes are driven by common genetic and environment factors. The progress in genome-wide data and statistical tools such as GCTA mean it is now possible to estimate both the contribution of common genetic variation to these traits and the proportions of the associations of non-cognitive skills and outcomes which are due to a shared genetic aetiology. Finally, we can use these methods to show how common genetic variation influences these traits across the life course (6).

Aims:

We will use Genome-wide Complex Trait Analysis to investigate the genetic architecture underlying cognitive and non-cognitive skills.

B2309 - Genomewide association study for BMI in infants and children the Early Growth Genetics consortium - 23/10/2014

The analyses to be undertaken for this project at simple and require only a number of basic procedures. These will all be run by local ALSPAC analysts (Timpson or Stergiakouli) and only results provided for the work of the consortium. Analyses follow:

(i) GWAS for BMI (see attached protocol (based on the 1000g analysis, though this is the same for the HAPMAP imputation based analyses) for this procedure)

(ii) Sensitivity analyses (slight alterations to models run for GWAS, but no substantive changes)

(iii) For top SNP variants, expression data available on ALSPAC LCLs will be assessed in efforts to chart cis eQTLs relevant to implicated genetic signals.

B2308 - Exploring the genetic and epigenetic mechanisms of early human language development - 23/10/2014

Aims and objectives

Within this project, we aim to enhance the understanding of genetic and epigenetic factors driving the development of human language, and how these factors impact on later child development. We will 1) investigate the genetic architecture of early linguistic abilities, especially expressive language, with respect to common and moderately rare genetic variation, exploiting detailed information from UK10K(http://www.uk10k.org/) and 1000Genomes(http://www.1000genomes.org/)1.

Aim I: Search for single variant genetic effects through a genome-wide meta-analysis of early linguistic skills

Aim II: DNA-based heritability estimations for early language skills using genome-wide data

Aim III: Identification of pleiotropic effects between early linguistic skills and intellectual and developmental outcomes in middle/late childhood

Furthermore, epigenomic variation at birth is likely to harbour a large proportion of cumulative environmental changes during early prenatal development2.

Aim IV: Search for links between epigenetic changes in newborns and early linguistic skills

B2307 - Association between arterial stiffness of ALSPAC fathers mothers and blood pressure trajectories of their offspring - 23/10/2014

Hypertension represents a major cause of cardiovascular morbidity and mortality, affecting one in three adults worldwide[1]. Intergenerational transmission of blood pressure characteristics has long been demonstrated[2, 3] and may be attributed to a variable combination of genetic and environmental factors[4-8].

Despite some studies demonstrating age-specific effects[9], tracking of cardiovascular traits, including blood pressure, has been shown to persist into adulthood[10]. There has been a suggestion that a stronger maternal-offspring association exists for some cardiovascular risk factors, including hypertension[11-13], although this has not been replicated in other studies[14-16], which has led to speculation that intrauterine influences may contribute to development of risk factors for adult diseases in the offspring[17].

Adolescent blood pressure increases with ageing and the rate of change has been shown to track into later adult life, being associated with higher systolic pressures and thus a greater risk of cardiovascular events[18, 19]. It has been postulated that adolescence provides a critical window for mediating the transition to adult hypertension[20], with the familial aggregation potentially increasing throughout this time[21]. However, there has been limited evidence to support screening and interventions in childhood to prevent later cardiovascular disease[22, 23]. Recent analysis of serial measurements in longitudinal studies have allowed calculation of adolescent blood pressure trajectories, which may facilitate a more accurate depiction of the associations between childhood blood pressure changes and later cardiovascular disease[24], allowing for better stratification of cardiovascular risk and interventions that are targeted[25] rather than population-based[26].

Arterial stiffness, measured non-invasively through pulse wave velocity[27] is independently associated with several cardiovascular risk factors in adults, including systolic hypertension[28, 29]. The main contributors to arterial stiffness are known to be time (age), heart rate and blood pressure[30] - pulse pressure is correlated with arterial stiffness and reflects age-related changes in systolic (increase) and diastolic (decrease) that occur with ageing. Such changes result from the reduced ability to repair damage to collagen and elastin fibres caused by constant expansion and relaxation and may be a reflection of age repair mechanisms more generally[31]. Arterial stiffness is related to ageing in other domains including cognition[32, 33] and thus parental vascular ageing may provide an indicator of an individual offspring's propensity to age across more than just cardiovascular traits, allowing for early interventions that minimise these effects.

The ALSPAC study provides an excellent resource to explore these issues further. In addition to investigating the relationships between blood pressure trajectories and vascular ageing in this study, the project will enable us to clean the existing PWV data. Due to occasional field worker errors and a software upgrade that changed the output fields, it will be first necessary to produce a clean research ready dataset with the arterial stiffness exposures that can subsequently be used by others.

B2304 - Costs and Gains to Postponement How Changes in the Age of Parenthood Influence the Health and Well-being of Children - 16/10/2014

The overarching aim of the COSTPOST project (more detailed summary reported below), which will last for a total of four years, is to investigate the consequences of fertility postponement on a range of outcomes for children and their parents. In particular, the COSTPOST project has been inspired by the fact that since many industrialized countries have experienced a remarkable postponement of first births to older maternal ages, we should know more about its consequences for the well-being of children and their parents.

B2303 - Parental separation and later life cardiometabolic health a cross cohort comparison - 16/10/2014

Background:

There is a growing recognition that adverse experiences such as abuse, neglect and domestic violence in early life may have implications for cardiometabolic health later in life. But whilst a substantial body of evidence has examined the long term consequences of parental divorce on mental health, the potential implications for physical health including cardiometabolic health have received far less attention. Limited evidence suggests that children who experience parent divorce are at increased risk of obesity, poor self-rated health, asthma, cancer[1], and more recently, CVD mortality[2] and stroke[3]. Early life socio economic position is probably a main confounder of the association of interest. Cross cohort comparisons (here between ALSPAC, Pelotas and APCAPS) allow us to examine an association of interest in different settings, with differing confounding structures (e.g. in high and low income countries). The assumption is that if an association is consistent in both settings, it is less likely to be driven by residual confounding[4]. In addition, the role of age at parental divorce and the degree of conflict in the household prior to the parental separation as potential effect modifiers of the association between parental divorce and cardiometabolic health will be explored. Finally, a range of social, behavioural, and biosychosocial factors are likely to mediate associations between parent divorce and cardiometabolic health in later life. These will be identified and examined here.

Aims: Using detailed data from the Avon Longitudinal Study of Parents and Children (ALSPAC), the 1993 Pelotas birth cohort from Brazil and the APCAPS cohort from India, we will examine the association of parental divorce with adiposity (BMI, DXA-determined total body fat mass) and cardiovascular risk factors (blood pressure, lipids, glucose and insulin) measured at 15-18 years.

B2302 - Childhood Sexual Behaviour and Adolescent Sexual Orientation - 16/10/2014

To explore the relation between childhood sexual behaviour and adolescent sexual behaviour, and possible mechanism underlying this relationship (e.g., the roles of childhood gender-typed behaviour, childhood victimisation, childhood and adolescent intimate friendships, and pubertal development).

Middle childhood--conventionally defined as between 6 to 11 years of age--provides rich contexts in which sexual orientation might develop. It nurtures intimate same-sex friendships [1], and coincides with adrenarche--a potential biological catalyst for the emergence of sexual attraction [2]. Sexual behaviour (e.g., masturbation) in middle childhood may be related to adolescent sexual orientation in at least 2 ways: The pleasure resulting from genital stimulation during adrenarche may involve same-sex friends in intimate interactions, which may lead to adolescent same-sex sexual attraction and activities.

Also, childhood gender atypicality may be involved in the link between childhood sexual behaviour and adolesent sexual orientation: for example, gender atypicality in middle childhood may increase victimization, which could be associated with increased childhood sexual behaviour, perhaps to offset negative emotions [3]; in addition, childhood gender atypicality is directly linked to same-sex sexual orientation [4].

B2301 - Genome-wide study of genetic variants associated with recognition of negative non-verbal emotions - 25/09/2014

Aims:

To identify individual genetic variants (specifically single nucleotide polymorphisms, SNPs) that are associated with the ability to identify non-happy emotions in the DANVA facial emotion recognition test, controlling for performance on the equivalent test of happy face recognition. Secondarily, to attempt to stratify this analysis by the type of non-happy emotion (angry, fearful, and sad). Thirdly, to test whether variants associated with sensitivity to non-happy emotion in faces are enriched for association with response to cognitive behavioural therapy for anxiety disorders in a separate cohort. Finally, to explore whether the ability to identify non-happy emotion can be predicted by the genetic risk for psychiatric disorders.

B2299 - Investigation of cell mixture adjustments in analysis of DNA methylation in cord blood and childrens blood - 25/09/2014

Aims: To compare performance of existing methods for cell mixture adjustments in analysis of DNA methylation in cord blood and children's blood

Hypothesis: When the reference samples do not match with study samples, reference free methods are more robust than reference based methods.

Variables:

Total cholesterol

HDL-cholesterol

LCL-cholesterol

Triglycerides

Methylations measured on Illumina 450k methylation array (under ARIES project) as well as covariates including Age, Sex, BMI, Smoking, SEP measures

B2297 - Prenatal alcohol exposure and cordblood DNA methylation - identifying latent structure in high dimensional data - 18/09/2014

Aims

To employ techniques for identifying latent structure in genome-wide DNA methylation data, characterised by high dimensionality, in order to increase statistical power to detect effects due to prenatal alcohol exposure (both maternal and paternal).

Objectives:

1. To identify latent structures in genome-wide cord-blood DNA methylation

2. To correlate these with maternal and paternal alcohol use before and during pregnancy (in search for both maternal-intrauterine and paternal-line effects)

3. To investigate to what extent confounding could explain these associations

4. To investigate the persistence of the latent structures into childhood and adolescence

5. To investigate whether the relationship between exposures and latent structure persist in later childhood and adolescence

Hypothesis

DNA methylation is thought to be one possible mediator of the feto-toxic effects of alcohol use in pregnancy, given the remarkable correspondence between the most alcohol-sensitive gestational periods and the occurrence of major epigenetic events (including erasure of methylation marks around gastrulation). This is further supported by various animal experiments. Further evidence also points at the role of paternal alcohol use around conception on offspring DNA methylation marks, in particular affecting (paternally) imprinted genes.

B2296 - Does Mhc-linked mate choice affect child health - 11/09/2014

The main aim of this study is to test the hypothesis that females gain genetic benefits for their offspring through mate choice. Whilst it is known from work on non-human animals that mate choice can result in improved growth and survival of offspring (e.g. Petrie 1994) the possibility that human mate choice can affect subsequent fitness-related traits of children has not been investigated. We aim to specifically test this possibility using data collected for the ALSPAC study.

If females are gaining genetic benefits for their offspring from mate choice we can predict that disruption of the mate choice process will result in a lack of genetic benefits and thus poorer offspring growth and health. It is known that from the laboratory that use of the contraceptive pill at the time of mate choice can result in the alteration of female mate preferences such that females are more likely to prefer individuals that are more Mhc similar to themselves (Roberts et al 2008; Alvergne & Lummaa 2010). Mhc similarity between biological parents can lower the degree of heterozygosity at the Mhc in children such that they are less able to combat disease. We would like to test whether such mate choice disruption has any real world consequences. We aim to do this by:-

1) comparing health of children for a sample of women who chose their biological fathers whilst taking the pill with that of a sample of women who intitiated oral contraceptive use after meeting the biological fathers of their children.

2) comparing the degree of MhC similarity between mothers and fathers in a group of women who met their partners whilst using oral contraceptives with another group of women who started using oral contraception after making their mate choice.

3) comparing the degree of heterozygosity at the Mhc in the children of mothers who chose their partners whilst on the pill with those from mothers who did not.

B2295 - Identification of epigenetic and genetic associations with leukocyte telomere length - 11/09/2014

Aims:

The overall goal of our planned project is to identify and characterise DNA methylation changes associated with telomere shortening, a biomarker for healthy ageing, and interrogate the potential causal role of these epigenetic variants in disease risk. Within this, the specific Aims for the proposal to work with samples and data from the ARIES collection of ALSPAC participants are as follows:

i) To carry out a pilot investigation of a subset of ARIES DNA samples, to assess the suitability of the MM-qPCR method for measuring mean relative leukocyte telomere length (LTL) in this cohort.

ii) To identify novel epigenetic variants (DNA methylation of CpG sites) associated with LTL.

iii) To identify genetic variants that influence methylation levels at CpG sites associated with LTL

B2294 - Parent-of-origin specific genome- and epigenome-wide analyses on fetal growth and postnatal outcome - 11/09/2014

Identifying genetic and epigenetic markers for fetal growth variation is important for both perinatal and adult health. Imprinted genes, which show parent-of-origin, specific, monoallelic expression, play key roles in fetal growth. There have been several genome-wide association studies to link genetic variants with birth weight, although none of them assumed parent-of-origin inheritance pattern, mainly because it requires large family cohorts to impute parental origin of the variants. As a recent collaborative project with the ALSPAC, we have shown that the maternal inheritance of a single copy number variant (repeat sequence 1: RS1) in the promoter of imprinted PHLDA2 gene to be significantly associated with increased birth weight and head circumference1. We hypothesise that there will be more genetic variants associated with fetal growth to be identified if parental origin of the allele is taken into account. Therefore, we would like to carry out a genome-wide search for genetic variants in assocition with fetal growth considering parental origin effects. Importantly, monoallelic expression of imprinted genes is controlled by differential DNA methylation established during gametogenesis. We propose to carry out a study using existing genomic, epigenomic, expression and phenotypic data at the ALSPAC to find genes important in fetal growth using a parent-of-origin model.

B2293 - Cardiometabolic consequences of genetic inhibition of interleukin-1/ - 11/09/2014

As part of the UK10K consortium (B916 and amendments), ALSPAC undertook association studies which included core inflammatory phenotypes (in this case CRP & IL6). In accordance with the replication amendment for these analyses (performed internally and on ALSPAC imputed GWSA data), results were shared with UK10K analysts for the followup of de novo signals. In the absence of novel research findings, it is proposed that these results (aggregated with 9 other study estimates and in this case only based on two SNPs (rs6743376 and rs1542176 ) which followup IL1 work from the Cambridge led initiative on IL1a/b) are shared with an ongoingand phenotypically linked data set.

ALSPAC is one of the only data sets available with GWAS imputed data of this nature and which has fed into UK10K analyses already formulated which can swiftly feed into this research effort on IL1. As such we are requesting that these two loci and their meta-analysis results (of which ALSPAC GWAS replication results (i.e. that applied for here) only play a small part) are fed into the existing meta-analysis.

B2292 - Mediation analysis in life courseepidemiology methodological innovation and application to studies of obesity and card - 10/09/2014

Aim:Life course epidemiology is the study of how exposures during gestation, childhood, adolescence and adulthood influence later health and wellbeing. Analysis of data from across the life course enables us to examine the dynamic ways in which variables of interest change and interact across a person's life span, determinants of these changes, and how the pattern of change relates to later health. A key focus within life course studies is analysis of mediation, i.e. the chain of intermediate processes that links an exposure to an outcome. Well-executed mediation studies are a crucial next step for the field of life course epidemiology. They represent an opportunity to increase understanding of pathways and mechanisms by studying the causal chains that explain exposure-outcome associations. Mediation analysis can therefore provide aetiological insight and identify potential intervention targets. In recent years, the epidemiological literature has given much more consideration to some of the statistical issues in mediation analysis than was the case previously; epidemiologists are now much more likely to give careful thought to mediator-outcome confounding and the potential resultant collider bias, and methods are now available that allow for exposure-mediator interactions or for situations where a confounder of the mediation-outcome association is caused by the exposure. Counterfactual theory has been used to show that the 'total' effect of an exposure on an outcome can be decomposed into the 'natural' direct and indirect effects, and methods for identifying these effects have been developed. However, several challenges remain. In this proposal, I will address 2 key issues in mediation analysis: 1) mediation analysis with repeated measures data, and 2) causal mediation analysis using Mendelian Randomization (MR), and will apply appropriate methods to address the following 2 questions of public health importance in the field of adiposity and cardiometabolic health:i) Whether the trajectory of growth and development affects cardiometabolic health independently of final attained adiposity.

B2291 - Modelling strategies in epidemiology - colinearity and bias - 05/09/2014

Profs Pearce & Greenland have been working on a paper concerned with modelling strategies in epidmiology. This includes exploring issues of whether or not to adjust for covariables that are strongly correlated with the main exposure. They would like to include real life examples in this paper and have therefore asked colleagues if they could provide any. Debbie Lawlor provided an example of a published paper where the strong correlation between dietary sodium and potassium intake was an issue in exploring the relationship of infant sodium intake with subsequent offspring blood pressure. We would like to include reference to this in our modelling paper, including some additional analyses that were not in the original paper. DA Lawlor has agreed to complete these analyses for us, and she and ALSPAC will be acknowledged. We do not, therefore, require any data to be provided to us.

B2290 - Identifying genetic variants influencing maternal health morning sickness and breastfeeding - 28/08/2014

Aims

The general aim of the project is to contribute to the characterization of the genetic risk factors for NVP and BF through genome wide association meta-analyses, in order identify genetic variants influencing these traits and to develop predictive models of which women are more prone to develop NVP and to breastfeed. The results of these studies will help inform the design and translation of more individualized reproductive health interventions.

B2289 - Vitamin D genetics and the risk of schizophrenia - 28/08/2014

We have recently replicated an association between low neonatal 25 hydroxyvitamin D (25OHD) and risk of schizophrenia (n = 2600, Danish case control sample). While exploring gene-environment interplay, we identified a gene-environment correlation (rGE) linking high scores on a schizophrenia-based Polygene Risk Score (PRS-Sz) with low neonatal 25 hydroxyvitamin D3 (25OHD3). This associated was present in the control sample (thus the association was not driven by the putative link between vitamin D and schizophrenia). We speculate that the PRS-Sz contains variants that are associated with 25OHD3 concentration - for example, several of the strongest GWAS hits for schizophrenia involve calcium channels, which could influence vitamin D half-life. Thus, we hypothesize that the PRS-Sz may contain (nested) sub-PRS that are related to vitamin D concentration.

B2288 - Beyond health care Improving social economic and health outcomes for young people with anxiety - 28/08/2014

The aims of the analyses of ALSPAC data are:-

(1) To determine the incidence of anxiety (clinical levels and any anxiety symptoms) in this cohort

(2) To determine the incidence of anxiety (clinical levels and any anxiety symptoms) in this cohort

(3) To determine the course of anxiety symptoms over time

(4) To estimate and quantify the impact of early-onset anxiety on current and later social, health and economic outcomes, adjusting for confounders.

-

B2287 - Identification and evaluation of obesity subtypes in youth - 28/08/2014

AIMS & HYPOTHESES

Aim 1: To use latent class analysis to empirically derive obesity subtypes

Hypothesis 1: Distinct subtypes of obesity exist that can be characterized by a combination of behavioral, physiologic, environmental, genetic and other familial factors.

Aim 2: To examine whether the following groups are distinct obesity phenotypes: onset of obesity before 5 years of age; obesity onset before age 18 and at least one obese parent; obesity with loss of control eating; obesity with emotional eating

Hypothesis 1: There will be overlap between the empirically derived subtypes in aim 1 and the proposed subgroups in aim 2.

Hypothesis 2: Risk factors (birthweight, maternal weight status, high sugar-sweetened soda or fast food intake, low physical activity, depressive symptoms, internalizing and externalizing symptoms, experiencing trauma, early puberty, screen time) for and cognitive (low inhibition, high impulsivity) and biological correlates (high systolic blood pressure, low leptin, low HDL levels, poor sense of smell) of obesity may vary by subtype.

Aim 3: To examine the patterns of association between the obesity subtypes derived in aim 1 and the obesity SNPs identified or confirmed in previous large genetic epidemiology consortia7,9

Hypothesis 3: FTO and MC4R will be more strongly associated with subtypes focused on unhealthy eating behaviors (i.e., loss of control eating and emotional eating).

As secondary aims we will explore whether the empirically derived classifications vary by developmental stage (childhood vs. adolescence) or gender. In other secondary aims we will investigate if fMRI results among girls show differences in selective attention and working memory across the obesity phenotypes identified.

B2286 - Replication of genetic findings for VPS4A and THRB genes in ALSPAC sample - 28/08/2014

In the IMAGEN sample of 2000 adolescent sample from the European cohort, we have detected a strong association between SNP rs16958736 (of VPS4A gene) and the activation of striatum (i.e. caudate, putamen and nucleus accumbens) in 'large win' vs 'no win' contrast of Monetary Incentive Delay (MID) task with P=1.30E-7. A following haplotype analysis then found that the same haplotype that was associated with the activation of striatum was also in association with the hyperactivity (ADHD) assessment from SDQ questionnaire. Meanwhile, in Drosophila, we found that both over-expression and knock-out of VPS4A could alter the frequency of locomotion activity of flies. By searching in the literatures, we then found that VPS4A encodes an ATPase which is involved in trafficking of G protein coupled receptors (GPCRs), including dopamine and noradrenaline. We therefore hypothesize that VPS4A may influence synaptic plasticity through regulating signalling at the dopaminergic and noradrenergic synapse.

In another paper, we have detected the SNP rs2067499 from THRB (Thyroid Hormone Receptor B) in strong association with ACC (anterior cingular cortex) and INS (insula) with P=1.19E-7, the same SNP was then found with significant association with ADHD assessment from SDQ with P=0.014. We propose that a mild resistance to TH (Thyroid Hormone) is associated with increased ACC-INS connectivity and results in ADHD-symptoms by enhancing sensitivity to external and internal stimuli.

B2285 - The Influence of Childhood Motor Ability on Adolescent Physical Activity and Bone Strength - 14/08/2014

Aims:

The overall aim of this project is to investigate the longitudinal relationships between early motor milestones, motor skills in childhood and physical activity and bone strength in adolescence

B2284 - Early Life Influences on Irreversible Obstructive Airway Disease in Adolescence - 14/08/2014

Aims and Hypotheses

The project therefore plans to investigate whether low birth weight, and rapid early growth (0-2 years), in addition to asthma, early transient wheeze and maternal smoking, are associated with the development of specific obstructive pulmonary function abnormalities in adolescence.

We have hypothesised that there is an association with low birth weight/IUGR and the development of reduced pulmonary function; that there is also an association between rapid growth during 0-2 years and reduced pulmonary function; and that asthma may mediate this. In addition, the project plans to look at whether low birth weight explains the association between maternal smoking and reduced function.

B2282 - Early life/adolescent influences on STI outcomes - 07/08/2014

Aim/Objectives:

The major aim of the present study would be to examine how early life (i.e. parenting practices and genetic parental proxies as well as psychopathology problems during childhood) and early adolescent variables (i.e. adolescent risky sexual and substance use behaviours as well as adolescent psychopathology problems) jointly influence later ("distal") disease outcome such as Chlamydia infection during middle and late adolescence (i.e. 17-22 years old) or/and teenage pregancies. We would test hypotheses about the mechanisms by which contextual factors or developmental processes affect developmental change and ultimately chlamydia infection at the age-range of 17-22 years old and teenage pregnancies. We will be considering methods that not only consider the longitudinal nature of the data, but also maintain the distinction between intra-and inter-individual change. Careful consideration would be given to aspects such as measurement error, the theory of change for the variables in the model, the critical role of time in interpreting results, and the variety of possible indirect effects that will be a part of each considered model. Different approaches of causal mediation modelling would be considered while a range of sensitivity analyses would be performed in order to estimate and evaluate the assumptions for causal interpretation. Although ALSPAC contains a wealth of data at different ages that enables assessment of these pathways, it also introduces a number of additional methodological challenges such as missing data problems or low power for some socio-economic or/and geographically variable exposures. For instance, children from lower socioeconomic groups were more likely to drop out of ALSPAC over time and for those who remained in the study a very low prevalence of C. trachomatis are currently found.

B2281 - Bullying and cardiovascular and respiratory diseases - 07/08/2014

AIMS

The epidemic of non-communicable diseases is challenging the health care system, has advanced into the focus of major medical journals and public health authorities worldwide, and The World Health Organization (WHO) has recently claimed to raise the priority accorded to non-communicable diseases. For example, it is cardiovascular diseases that are one of the leading non-communicable disease causes of premature morbidity and mortality worldwide and that will even remain among the three leading causes of burden of disease according to projections of mortality and burden of disease to 2030.

Likewise, respiratory diseases represent a major challenge for public health, as they have a huge economic impact and are highly prevalent both in developed and developing countries; it has been estimated that by 2025, an additional 100 million people will be suffering from asthma. Therefore, to improve urgently needed preventive approaches, the study of risk factors, including early-life influences, using prospective cohort studies has been identified as a grand challenge in chronic non-communicable diseases.

It has long been known that psychological factors have the potential to cause, influence, or exacerbate physical disease processes via their impact on biological function Among such psychological factors, the concept of school bullying has received growing attention as health risk factor in recent years. School bullying has been associated with an increased risk of psychological symptoms and psychopathologies, medication use, suicide and self-harm 17 18, and psychosomatic and physical complaints. Moreover, first evidence indicates that school bullying is associated with alterations in stress reactivity, and workplace-bullying victims may also have a higher risk of cardiovascular diseases.

However, the role of school bullying within the aetiology of chronic physical diseases has hardly been addressed to date. The World Health Organization has claimed to promote the understanding of the morbidity and mortality associated with bullying in order to give this psychosocial hazard a stronger level of worldwide public health attention and to improve action towards it. Therefore, in line with current strategic research goals targeting amongst others etiological factors of widespread diseases, the aim of the proposed study is to improve our understanding of the role of school bullying especially with regard to non-communicable physical diseases in childhood and adolescence, using well-established indicators of (i.e. peripheral biomarkers and data from clinical examinations) and questionnaire/interview information on physical diseases, with a special focus on cardiovascular and respiratory health. The major advantage of using data from the ALSPAC study is the opportunity to use longitudinal data based on a large sample of adolescents, including well-established biomarkers of and clinical information on cardiovascular and respiratory health, together with self-reports and external reports on physical health.

B2280 - Non-patient recruitment into research studies by genotype A new ethical challenge or same-old story - 07/08/2014

AIMS

  1. Investigating how participants interviewed draw upon different influences, perceptions and ethical reasoning in discussing issues regarding recruitment to RBG studies.

  1. Exploring the degree which participants suggest increased or decreased disclosure of individual genetic information, including anticipated and incidental findings, would affect their views on these studies and willingness to participate/work in these areas.

  1. Using specific case studies of current or planned ALSPAC RBG studies to aid participants in clarifying and challenging their own views on RBG.

  1. Outlining the identified issues and opinions on best practice in the form of a written set of principles, with the aim to inform future work in this area.
B2279 - Factors affecting response rates to ALSPAC questionnaires - 24/07/2014

AIMS

The aim is to analyse response rates over time to all ALSPAC questionnaires, to investigate predictors and modifiable organisational factors associated with improving response rates.

B2278 - Does body mass index influence smoking behaviour A Mendelian Randomisation study - 24/07/2014

Aim

To investigate if body mass index causally influences smoking behaviour using a Mendelian randomization approach.

B2277 - Early pathways to borderline personality symptoms at age 11 the role of temperament and maladaptive parenting - 24/07/2014

AIMS:

We aim to use the ALSPAC data to study the relationships between child temperament, maladaptive parenting and adolescent BPD. More specifically, this study is aimed at disentangling the nauture of associations by testing direct, moderation and mediation effects.

B2276 - Bivariate genome-wide association study of birth weight and endophenotypes related to five diseases in later life - 24/07/2014

AIMS:

Aim 1: Genome-wide bivariate association analysis of birth weight and key quantitative phenotypes from the 20 year follow-up studies within Raine and ALSPAC.

To date, two genome-wide association studies (GWAS) have been conducted for birth weight (involving the investigators of this proposal), which identified seven single nucleotide polymorphisms (SNPs) that effect birth weight (14, 15). Two of these SNPs are in genes previously associated with type 2 diabetes, ADCY5 and CDKAL1, highlighting the genetic links between fetal growth and postnatal metabolism. At both of these loci, the birth weight lowering allele was associated with increased risk of type 2 diabetes. In addition, the authors investigated a further 47 type 2 diabetes associated variants and found the type 2 diabetes risk alleles at GCK and MTNR2B were associated with higher birth weight. These results indicate that there may be multiple genetic pathways which link birth weight to adult disease. A further link with the DOHAD hypothesis was through the ADRB1 gene, a locus which was associated with birth weight and adult blood pressure. Of the final four SNPs, two were in height associated genes, indicating a continued link with growth over the postnatal period. Although these SNPs found to date for effecting birth weight have pleiotropic effects with risk of disease in adults, the percentage of variance explained by these confirmed loci (0.76%) is lower than many other complex phenotypes (for example, 1.45% for BMI (16), 5.8% for BMD at the femoral neck (17)). Given twin and family studies estimated heritability of birth weight from the fetal genome to be between 10 and 30% (18, 19), there is still a substantial genetic component to be described.

Bivariate genetic association analysis has been shown to have increased statistical power over univariate analysis to detect genetic variants that contribute pleiotropically to the two phenotypes in the opposite direction to the prevailing phenotypic correlation (20-22). This approach is ideal for detecting variants that underlie DOHAD. We will conduct a bivariate genome-wide analysis of birth weight and each of our key phenotypes, with the hypothesis of increasing the statistical power to identify novel genetic variants that have pleiotropic effects.

Aim 2: Gene-based bivariate analysis of birth weight and key quantitative phenotypes from the 20 year follow-up studies within Raine and ALSPAC.

There has recently been a lot of debate regarding the 'missing heritability', or the amount of heritability of common traits that is not accounted for by the known genetic variants (23). As with many common traits, this is seen with birth weight (as outlined above) and each of our key phenotypes. Statistical methods have been developed to estimate the proportion of variability explained by common genetic variants on genome-wide SNP chips (24). By partitioning the genome into smaller chunks of SNPs, these methods can be applied to estimate and test the heritability of a particular genomic region (25, 26). This novel statistical approach efficiently and effectively combines genetic variants across a region to assess whether regions of the genome influence trait values. Utilizing this novel approach and the bivariate structure of the data, we will conduct a bivariate analysis of birth weight and the key quantitative phenotypes by partitioning the genome-wide chip data into groups of SNPs that belong to genes.

B2275 - RCT of opt-in v opt-out home visits for Tracking Tracing - 24/07/2014

AIMS

The aim is to compare an opt-in approach with an opt-out approach to tracking and tracing 'disengaged' participants for whom ALSPAC does not have a current address in terms of effectiveness, cost-effectiveness and acceptability.

B2274 - RCT of choice online or paper v online only completion for YP23 questionnaire - 24/07/2014

AIMS

The aim is to compare online only completion with a choice of online or paper completion in terms of response rates and costs for the YP questionnaire.

B2273 - Psychological influences on educational outcomes and childhood predictors of later psychiatric disorder - 17/07/2014

Aims

To understand the impact of differential patterns of depressed mood in adolescence on educational outcomes

To describe the epidemiology and life course of somatic symptoms in childhood and how they might be associated with psychiatric disorder in adulthood.

B2272 - Valorisation of birth cohorts to prevent obesity neurodevelopmental and mental health disorders - 17/07/2014

Objective 1: To generate and supplement existing genetic, epigenomic and metabolomic data across five large European cohort studies to provide an unparalleled resource for investigating associations between early life factors and subsequent obesity, neurodevelopmental and mental health outcomes.

Objective 2: To integrate inter-generational phenotypic, genetic, epigenomic and metabolomic data across the five cohort studies through harmonization of data and meta-analysis.

Objective 3: To identify causal relationships between prenatal exposures and metabolic and neurodevelopmental outcomes using a variety of state-of-the-art causal analytic methods including Mendelian randomization, maternal-paternal, between-sibling and cross-cohort comparisons.

Objective 4: To synthesise information to inform and prioritise future interventions and public health policy that will have a meaningful and lasting impact upon the incidence of these health challenges.

B2271 - Neuro-developmental trajectories and adult mental disorder - 17/07/2014

Aims:

(I) We will test the hypothesis that young adults who fulfil our operational criteria for 'psychotic disorder' will show significant changes (anomalous developmental trajectories) between age 20 and 24 in: (a) fronto-temporal white matter tracts; and (b) medial temporal grey matter, and (c) dorsolateral pre-frontal activation during a working memory task. These abnormalities will be qualitatively similar to but less severe than those established in psychotic disorders.

(II) We will also test the prediction that connectivity parameters namely efficiency and density, which were found to be abnormal (reduced) in participants at age 20 with psychotic experiences will have normalised or progressed according to recovery/persistence of psychotic experiences (PEs) at age 24, respectively.

(III) Finally we will take the opportunity to carry out a resting state fMRI series in order to enhance our structural graph theoretical analyses with functional connectivity analyses which may then be related to prior psychopathology, that at age 24 and subsequently.

B2270 - Genomic Framework for OSteoporosis SEQuencing studies GEFOS-SEQ - 10/07/2014

The FP7 funded GEFOS consortium identified a range of BMD-related loci by GWAS (1). This Horizon 2020 application (PI Fernando Rivadeneira, Erasmum Medical Centre, Netherlands) represents an extension of this program, intended to identify further BMD related loci by harnessing whole gemome sequencing technology. It is intended that ALSPAC will contribute to work package (WP) 2, 3 and 6.

In WP2, a musculoskeletal (MSK) chip with GWAS and customized content, which after genotyping ~60,000 young and elderly individuals from 36 studies previously involved in GEFOS (mostly European), will allow the discovery of common, less frequent and rare variants; together with fine mapping of gene regions associated with traits and pathological conditions of the MSK system including BMD, fracture risk, sarcopenia and frailty. ALSPAC mothers will form part of a replication cohort for novel genotype-BMD associations arising from this MSK chip.

In WP3, BMD associated variants will be analysed in relation to different endophenotypes, based on our previous studies suggesting different genetic influences on trabecular and cortical bone (2-4). Associations will be analysed between genetic markers of interest and cortical bone phenotypes obtained in ALSPAC off spring as measured by tibial pQCT, and trabecular bone phenotypes as obtained in ALSPAC mothers by radial pQCT.

In WP6, genetic influences on BMD identified in WP2 will be examined using a lifecourse approach, by comparing the strength of associations (as reflected by beta coefficients) across different times of life. Results from ALSPAC offspring (total body DXA at age 9 and 17, hip DXA at 13 and 17), and ALSPAC mothers (pre versus postmenopausal hip BMD) will contribute to these analyses.

It is envisaged that ALSPAC genetic data will be in the form of genome wide data imputed to 1000 genomes, as previously obtained. In the case of rare variants of interest which are not covered by imputation, there may be a need for custom genotyping. Bone outcomes will comprise DXA and pQCT measures as previously obtained in ALSPAC off spring and mothers.

B2269 - Relationship between breastfeeding and autism - 10/07/2014

AIMS:

The aim of this study is to examine whether children with higher autistic trait scores are more likely to experience reduced breastfeeding exposure, and the direction of this possible relationship. We will look at two opposing hypotheses; that reduced breastfeeding duration may be an aetiological risk factor for the subsequent development of autism spectrum disorders, or that an early manifestation of autistic traits is a decrease in the duration of breastfeeding relative to the mother's intended duration.

B2268 - Runs of homozygoisty and human quantitative traits ROHGen - 11/07/2014

The primary intent of ROHgen is to investigate the influence of ROH on complex traits; to show for which traits and end points there is evidence of recessive effects, how strong they are and eventually potentially to count and map these effects. This will be done by conducting the same analyses across many cohorts and then sharing various statistics relating to ROH or trait associations for central meta-analysis.

Hypothesis: ROHs are associated with health-related outcomes and quantitative traits of interest.

B2267 - Is oculomotor control a potentially useful biomarker of neurocognitive function in young adults - 10/07/2014

Our proposed study of pursuit and saccade eye movemets in the ALSPAC cohort will allow many hypotheses to be tested but initially we will concentrate on:

Variation in anti-saccade task accuracy with IQ (as per Evdokimifdis et al)

Variation in smooth pursuit and saccade function with PLIKS score (as part of Zammit et al's programme)

Variation in sacccade fuction as a measure of executive control, according to previous exposure to potential neurotoxins such as tobacco, alocohol, cannabis, other drugs

Variation in oculomotor parameters according to previous stressful experiences - this is relevant to the current popularity of eye-movemet based thereapy for post-traumatic stress disorder.

Variations in oculomotor control according to genotype for specific candidate genes and as the phenotype for GWAS studies of genetic predictors of oculomotor control

Further researc questions will be developed in line with current literature and withstrategic funding calls.

B2266 - The role of metabolomics and gut microbiome in modifying arterial disease progression in relation to adiposity - 10/07/2014

AIMS

1. To assess whether change in dietary habits from adolescence to young adulthood can modify the gut flora, increase the production of noxious metabolites (TMAO) and accelerate arterial disease progression.

2. To assess whether dietary supplementation of probiotics can modify the gut flora and can benefit the lipid profile and vascular risk of overweight and obese individuals

B2265 - Measuring emotional recognition in ALSPAC - 10/07/2014

Emotion recognition deficits and biases are a ubiquitous feature of mental health problems, including anxiety and depression, conduct disorder, psychosis, autism-spectrum disorder, and addiction. However, it remains unclear what the direction of causality is between these deficits and biases, and these mental health problems.

Given the rich lifecourse data and detailed psychiatric information available within ALSPAC, as well as existing measures of emotion recognition in childhood (DANVA), the collection of emotion recognition data in early adulthood in ALSPAC would enable these relationships to be comprehensively investigated.

We have developed a computer-based six-alternative forced choice task that is highly-sensitive to individual differences in emotion recognition. The Emotion Recognition Task is available commercially through Cambridge Cognition, as part of the Cantab Research Suite. It is used in the Cantab Schizophrenia battery and the Cantab Depression battery.

http://www.cambridgecognition.com/tests/emotion-recognition-task-ert

Other variants of the task, such as a two-alternative forced choice Task (which uses ambiguous stimuli tanging from one exemplar emotion to another, rather than from a an ambiguous-neutral expression exemplar emotions), are not currently available through Cambridge Cognition. We retain the right to use the task for research purposes, and have developed an online version for remote delivery.

We therefore propose to collect data on emotion recognition, using the online Emotion Recognition Task, in the ALSPAC cohort. We envisage that this would be completed in parallel with a future questionnaire sweep (possibly December 2015). The task itself takes approximately 15 minutes to complete.

B2264 - The Combined Impact of Genetic Variants on DNA Methylation - 26/06/2014

Although the combined impact of genetic variants on phenotypic traits has become of increased interest over the last few years, there has so far been little research undertaken to understand the combined impact of variants on DNA methylation. We intend to apply collapsing approaches to collapsed methylation scores to investigate this. This could be an attractive approach in contrast to individual CpG site analyses for many reasons, such as computional efficiency, reducing the burden of multiple testing, smoothing out artefacts and representing the underlying biology in a different form by collapsing across functional units (e.g. CpG islands, including/excluding shores, entire promoter regions). Furthermore, the manner in which methylation data is collapsed is an aspect of this work which will need to be evaluated. There are currently some methods out there which could be used for this purpose, although so far they have mainly been used to investigate the relationship between methylation and phenotypic traits.

As pairwise association analyses for individual CpG sites is currently being undertaken using the 450K methylation data in ALSPAC, this should provide a useful comparison for this proposed approach.

B2263 - Factors Associated with Dental Health in a Population Cohort - 26/06/2014

Caries is one of the most common childhood disease processes, with over 50% of children in the western world having at least one cavity or filling, and the number rising to 78% by the time the child reaches adulthood. Caries has a prevalence rate five times higher than asthma (Peterson et al., 2011) and is a common cause of tooth loss in adults (Phipps and Stevens, 1995). It is a dynamic process beginning with tooth surface loss that eventually leads to cavities. Untreated caries can lead to pain, swelling, abscesses and in extreme cases, systemic blood infection (Monse et al., 2009). In western developed countries, the diet of adolescent populations is very rich in carbonated drinks and high-carbohydrate snack foods, also associated with a higher caries risk (Majewski, 2001). Although caries is a physical condition many psychosocial factors are involved, such as attitudes and behaviour re: oral hygiene, education level and access to dental care. Over and above other physical causes of adolescent caries (poor oral health, poor diet and subsequent chemical processes) maternal psychosocial factors are also an indicator of subsequent caries experience in their adolescent children (Nelson et al, 2012).

B2262 - A Mendelian Randomisation Study of the effect of dietary milk intake calcium on BMD and metabolomic variables - 26/06/2014

There is an observational relationship between dietary intake of dairy/calcium and subsequent risk of osteoporosis/BMI. However, many of these studies are observational in nature and thus subject to confounding. We would like to investigate this relationship using Mendelian Randomization in ALSPAC and in other cohorts that contain these data. Our intention is to use variants related to (i) dairy intake, and (ii) calcium intake/levels (as identified through previous GWAS or through GWAS in ALSPAC) to investigate the relationship between these exposures and (i) bone related phenotypes, height, weight and BMI and (ii) metabolomic measures in ALSPAC.

B2261 - Exploring distinctive facial features and their association with known candidate genes - 03/07/2014

The aim of the study is to explore the association of distinctive facial features with candidate genes reported to be associated with facial development.

We intend to replicate the findings reported by Claes et al 2014 where the authors found an association of 20 genes with distinctive facial features. This study uses a novel technique bootstrapped response-based imputation modelling to explore the relationships of sex, genomic ancestry and a set of craniofacial candidate genes. The procedure will be replicated on 4747 3D 15 year old facial shells. In addition an additional 30 genes which did not show any association in Claes' sample of 592 will be explored using the ALSPAC cohort.

Essentially the proposed method uses dense spatially dense quasi-landmarks on 3D images (greater than 7,000), principal component analyses and a new partial least squares regression (bootstrapped response-based imputation modelling (BRIM) to measure and model facial variation.

By simultaneously modeling facial shape variation as a function of sex and genomic ancestry along with genetic markers in craniofacial candidate genes, the effects of sex and ancestry can be removed from the model thereby providing the ability to extract the effects of individual genes.

B2260 - Genome wide association of sitting height ratio in ALSPAC adults - 03/07/2014

Aims:

To identify genetic causes of variability in body proportions using sitting height ratio in adults, and to test for whether height-associated loci increase or decrease sitting height ratio. We propose to do this by performing a standard genome-wide association study between imputed genotypes and sitting height ratio, adjusted for confounders and covariates. We will meta-analyze the results from ALSPAC with those we have already obtained from other cohorts.

B2259 - Deciphering Developmental Disorders Analysis using quantitative phenotypic information - 19/06/2014

Aims:

Our aim is to develop a method which can identify highly unusual patterns of pre- and postnatal growth within the individuals recruited to the DDD (Deciphering Developmental Disorders) study.

B2257 - Connecting early language and literacy skills to later reading and writing abilities and disabilities - 19/06/2014

AIMS

There are two main aims of the proposed study. The first aim is to examine the longitudinal predictors of later reading and writing levels in unselected populations. More specifically the longitudinal predictive role of early oral language and literacy skills assessed at different developmental points will be examined. In this way, it will be possible to use the smaller cohorts, from such as the clinics 25 months and 49 months to examine the prospective longitudinal relations between early oral language and later literacy skills as well as educational and vocational outcomes. The second aim of the study is to conduct a retrospective analysis of the data and examine the early markers of two main subtypes of reading difficulties, namely dyslexia (specific reading impairment) and specific reading comprehension impairment. The early markers of later writing difficulties will also be examined. Prior research on the relationship between reading comprehension and text writing reported only moderate relations suggesting that the comprehension and production of written text call upon similar as well as distinct cognitive-linguistic skills. There is currently very limited understanding of the early markers of text writing difficulties.

B2256 - Long term follow up of speech and language skills in the ALSPAC cohort - 19/06/2014

AIMS

The aim of this study will be to collect speech and language data from the young adults in the ALSPAC cohort. This will enable a comparison with their performance at previous timepoints (for example, 8 years, 5 years, or in preschool) and with their social functioning in adulthood. Little is known about long term outcomes for individuals with persistent speech and language impairment with regard to whether or not their problems resolve as they get older. It is known however that when problems persist, individuals are at greater risk for low academic outcome, decreased employment opportunities, increased involvement in criminal activity and increased mental health problems. It is not clear whether these increased risks are due to poor communication skills per se, or whether impaired speech and language in the early years affects other skills, such as social and academic progress, which in turn reduces the individuals' opportunities.

B2255 - Long Term Educational Impacts of Preterm Birth - 12/06/2014

AIMS:

The aim of the project is to investigate the relationship between the infants born preterm, and in particular those born 'near term' (32-36 weeks gestation) and their long term educational outcomes.

B2254 - Incidence co-occurrence course and outcomes of childhood problems - 12/06/2014

AIMS:

The aims of the analysis of ALSPAC data are

- To determine the incidence of risk factors for various childhood problems in this cohort

- To determine the incidence of childhood problems in this cohort

- Where data availability allows, to determine the course of these problems (persistence over time)

- To investigate clustering of multiple problems within children

- To estimate the impact of childhood problems on later outcomes, adjusting for confounders

B2253 - Maternal risk factors in infancy for offspring depression in adolescence - 12/06/2014

BACKGROUND/ AIMS:

Early identification of depression is critical to enable preventative interventions to take place in the early years, where they are most effective. Depression is the leading contributor to the global burden of disease among young people.

In infancy the child's environment is usually determined by their mother because children spend most of their time with and are dependent on mothers for care. Many early risk factors for depression centre on the mother: maternal depression, low maternal education, multi-parity and young maternal age.

Mothers deemed at risk are increasingly being targeted in interventions globally. However, rather than reflecting causal effects, observed associations between each maternal factor and offspring depression could be confounded. This makes it unclear which mother-infant dyads to prioritise for interventions. It is also unclear how to intervene because most of these maternal risk factors are very difficult to change. Therefore, in order to identify opportunities for intervention, it is also important to identify modifiable indirect pathways which mediate associations.

B2252 - Effect of deviations from expected birth weight on later life cognitive performance and cardiovascular disease - 12/06/2014

Research Objectives:

The purpose of this project is to determine the effect of deviations from expected birth weight on later life outcomes within the ALSPAC cohort. The study will have the following two specific aims:

1. To develop and validate a method of determining expected birth weight9, 10 through the use of a prediction equation to be developed based on the relationship between gestational age, parity, gender, and other maternal characteristics (age, height, weight, smoking status, mother's own birth weight) and birth weight of offspring in the ALSPAC cohort.

2. To relate deviations from expected birth weight to a set of later life outcomes in the ALSPAC cohort including markers of cognitive development and function and cardiovascular disease outcomes.

B2251 - Are the age pattern of BMI development overweight and obesity different in different settings - 12/06/2014

AIMS

The aim of this study is to compare BMI development in the Northern Finland Birth Cohorts born in 1966 and 1986 from the same geographical area but at different stages of the obesity epidemic, the Danish Aarhus Birth Cohort from 1990-92, and ALSPAC, of similar birth year but from a different geographical area.

B2250 - Illustration of analytical power with proxy versus distal measurement - for nature reviews neuroscience review - 05/06/2014

AIMS:

We aim to show the analytical gains from increased sample size, but also that relatively low numbers of samples can be used to locate strong genetic signals in the presence of perfect intermediate measurements (here response to taste test challenge). We also which to use a dietary measure from Food Frequency Questionnaire data (likely the consumption of cruciferous vegetables) to illustrate the systematically poor power (at even relatively large sample sizes) when using a poor or distal phenotypic measure.

B2249 - Identifying the impact of mental disorder risk alleles on childhood neurodevelopment - 05/06/2014

Aims

1)We will test the hypotheses that risk alleles in the general population impact on pre-pubertal neurodevelopmental domains involving 1) emotion/mood regulation 2) cognition/learning 3) social cognition/communication and 4) behaviour regulation.

2) Test the hypothesis that mental disorder RP scores that we find to contribute to domains of neurodevelopment at age 7/8 years have longitudinal effects.

3) Test that bullying/victimisation at 7/8 years further predicts longitudinal change in RP score-associated neurodevelopmental domains.

B2248 - Forms of body-modification as an indicator of self-image and risk-taking - 05/06/2014

AIMS

The purpose of this proposal is merely to obtain approval to ask the accompanying questions. We will submit further proposals for any analysis we wish to carry out.

B2246 - Genetic determinants of liver function and their relationship to cardiometabolic health - 29/05/2014

The broad aims of our study are as follows;

1.Examine the association of metabochip variants with ALP, ALT, AST, GGT, Bilirubin and Albumin to determine whether (i) these replicate published GWAS findings and (ii) identify new variants

2.Undertake Mendelian randomization study of the causal effect of ALP, ALT, AST, GGT, Bilirubin and Albumin (markers of liver damage) with CHD, stroke, type 2 diabetes events and with risk factors for these outcomes (i.e: fasting glucose, fasting insulin, LDL, HDL, Triglycerides, total cholesterol, SBP and DBP)

B2245 - Precursors and Outcomes of Sibling Bullying A Longitudinal Study - 29/05/2014

Aim

The overall aim of the study is to investigate how sibling bullying relates to peer bullying in order to find the embryonic origins of bullying.It is planned to go about this by longitudinally studying sibling bullying. The overall study is broken down into two parts: The first part will examine the precursors of sibling bullying, the second part will examine the outcomes of sibling bullying, inclusive of examining how sibling bullying relates to peer bullying.This break down is done in order to answer the following questions: (1) what factors influence sibling bullying (as a bully, victim, and bully-victim)? (2) What are the specific outcomes of sibling bullying (as a bully, victims and bully-victim)? (3) Are there cross-over effects from a sibling bullying dynamic to a peer bullying dynamic? (4) Should there be cross-over effects, how strong are they? Do bullies, victims and bully-victims at home, remain in their respective roles in a peer bullying dynamic?

B2244 - Affective cognitive control and depression creating a new evidence base for prevention - 29/05/2014

AIMS

The aim of the proposed project is to investigate a specific cognitive process that has been hypothesized by several neuropsychological models to play a causal role in depression; affective cognitive control. The study aims to address the lack of population based studies using computer based behavioural measures of affective cognitive control to investigate a) cross-sectional and longitudinal associations with depression and b) associations between potentially preventable environmental risk factors and affective cognitive control in adolescence. Findings of the research are intended to contribute to an evidence base for new prevention strategies for depression that target affective cognitive control.

B2243 - Understanding gender differences in cardio-metabolic risk across the life-course - 22/05/2014

AIMS

The aim of the project is to investigate whether known gender differences in cardio metabolic risk in mid-life are already present in childhood, whether they change across childhood and adolescence, and what biological and behavioral factors may underlie the gender differences.

B2242 - Risk and resilience in the context of interparental violence - 22/05/2014

AIMS:

The aims of this research are therefore to examine the impact of domestic violence as measured in the ALSPAC cohort on the behavioural and emotional development of children up to age 8 years, and examine factors that may increase the likelihood of resilience. In particular, both physical and non-physical forms of domestic violence, and the parental role in the impact of violence on child outcomes will be explicitly examined. The research questions to be addressed are:

1. There will be variation in the behavioural and emotional development of children exposed to domestic violence;

2. The variation in behavioural and emotional development of children exposed to domestic violence will vary depending on which parent used violence and which parent was victimised;

3. The variation in behavioural and emotional development of children exposed to domestic violence will vary depending on the type of domestic violence to which they were exposed (physical, emotional, combined);

4. Children who are identified as resilient in the context of physical domestic violence will be identified as resilient in the context of non-physical domestic violence;

5. The relationship between exposure to domestic violence and child development will be mediated or moderated by: maternal depression; parenting quality; child's cognitive ability and child's temperament.

B2241 - Emotional sexual and physical abuse in early life - 12/06/2014

Here I propose to include questions on emotional, physical and sexual abuse to the next ALSPAC YPs questionnaire. This proposal is directly linked to approved project B2134. As noted above, there is an inceasing interest in abuse as a novel cardiometabolic risk factor. As part of project B2134 I propose to study this association in ALSPAC mothers and fathers. Collecting these data in the YPs will allow to do so in this cohort as well and will enhance ALSPAC as a resource to study intergenarational, familial patterns of abuse.

B2239 - Investigating associations between obesity memory and hippocamapl volume using a Mendelian randomisation approach - 15/05/2014

Aim:

To investigate associations between obesity, memory and hippocampal volume using a Mendelian randomisation approach

B2238 - Modelling within-individual variation - 15/05/2014

Aim:

To develop statistical methods to model the variability of clinically-relevant measures within an individual, and relate this variability to both exposures and outcomes. We will develop methods for nominal and continuous exposures and outcomes, and both intensively and sparsely collected data. We will then apply these methods to simulated data,and to the ALSPAC example.

B2237 - Improved detection of allergic disease risk loci by combining information from genetically correlated traits - 15/05/2014

Aims:

We propose to search for genetic risk factors shared between asthma (A), hayfever (H) and eczema (E) by performing a GWAS with cases defined by the presence of at least one of these three diseases (A+ or H+ or E+). Controls will be defined as individuals who are free of any allergic disease (A-H-E-). To compare the effect of individual variants on each disease per se, we will perform a secondary set of analyses, contrasting allele frequencies between the three mutually exclusive phenotypes A+H-E- (asthma only), A-H+E- (hayfever only) and A-H-E+ (eczema only).

B2235 - Telomere Dynamics and Cardiometabolic Disease in the First Two Decades of Life - 15/05/2014

Aim 1:Telomere dynamics from birth to adulthood. We propose to characterize telomere length and its rate of erosion across various developmental periods between birth and 25 years of age.

Aim 2: Pre-natal health of mothers and early-life telomere dynamics. We propose to assess the longitudinal association between maternal body mass index, HDL/LDL ratio, cholesterol and triglyceride levels during the first trimester, and gestational diabetes as reflected by blood glucose levels in the mothers, and the rate of telomere erosion from birth to 25 (?) years of age in their children.

Aim 3: Early-life telomere dynamics and cardiovascular / metabolic outcomes in early adulthood. We propose to assess the longitudinal association between the rate of telomere erosion in children from birth to 15 years of age, and cardiovascular / metabolic health outcomes 5 - 10 years later including arterial stiffness, blood pressure, intima-media thickness, HDL/LDL ratio, triglyceride levels, flow-mediated dilation, adiposity, and fasting blood glucose.

B2234 - Lifecourse epidemiology of womens reproductive health and its relation to chronic disease - 08/05/2014

Aim 1: To study the life course epidemiology of female reproductive health and potential in early adulthood. I will use data on foetal exposures, growth, adiposity, diet, physical activity, smoking and stressful life events assessed repeatedly throughout childhood, adolescence and early adulthood to estimate the contribution of these and to identify critical and/or sensitive periods to female reproductive health and potential.

Common pregnancy complications (gestational diabetes, hypertensive disorders, preterm delivery, large- and small-for-gestational-age babies) affect some 30% of pregnant women. It is not known if these complications simply unmask an underlying propensity for cardiovascular disease (CVD), or contribute to it.

Aim 2:To investigate the role of pregnancy complications in shaping cardiovascular risk. If pregnancy complications per se increase CVD risk, causal mechanisms should be identified as these may provide treatment targets in women who experienced pregnancy complications to mitigate these effects. Even if the pregnancy complications only unmask women at increased risk of CVD, greater post-natal monitoring to identify if and when women cross established treatment thresholds is likely to be warranted.

Research into the female reproductive health and chronic disease has generally focussed on a single indicator of female reproductive health, whilst it is likely that information on multiple indicators such as menstrual cycle length and pregnancy complications; behaviours such as hormonal contraception use; and gynaecological disorders and their treatment can better characterise women's reproductive health and improve understanding of both its causes and consequences. Moreover, it is still unclear whether associations between indicators of reproductive health and chronic diseases are causal and if so via what causal pathways, or whether both female reproductive health and chronic disease are driven by common antecedents.

Aim 3: To study the relationship between female reproductive health and chronic disease. I will study the separate and joint associations of multiple indicators of female reproductive health with major disease outcomes (breast cancer, CVD, diabetes, osteoporotic fractures, depression, dementia, lung disease) and examine whether associations are independent of established disease specific risk factors.

Regardless of whether indicators of reproductive health are causally related to chronic disease outcomes, it is possible that readily available information on indicators of female reproductive health can improve risk stratification in women.

Aim 4:To determine whether information on female reproductive health can improve the performance of existing risk scores for the prediction of diabetes, CVD, osteoporotic fractures and dementia, or simplify them without loss of accuracy.

B2233 - The temporal ordering of global dimensions of psychopathology - 01/05/2014

Aims:

To examine whether temporal orderings exists between the three higher order factors of psychopathology; internalizing, externalizing and psychosis.

B2232 - Associations between antenatal domestic violence and cord blood DNA methylation - 01/05/2014

Aim:

To determine whether there are associations between antenatal domestic violence and DNA methylation.

B2231 - Do Psychological Health Issues in Early Childhood Precede Pubertal Maturation - 01/05/2014

Aims

Early puberty is associated with poor mental health outcomes in adolescence, from diminished mental wellbeing to psychopathology, especially amongst females. Explanations for this observed association predominantly centre on developmental mismatching of cognitive and emotional capacities and social engagement with older rather than same age peers. Research in this area has, however, largely neglected to examine the extent to which mental health issues precede premature pubertal development.

Life history theory considers early pubertal development to be an adaptive response to early environmental adversity, including factors such as familial discordance, hostile or neglectful parenting and low resource stability including family economic hardship. These social determinants of early puberty are also known to be related to behavioural problems and psychosocial difficulties (e.g., Boe et al., 2012). The inter-related nature of these outcomes and their timing require further exploration. Relevant longitudinal research in this context (Mensah et al., 2013) has recently revealed psychosocial and behavioural adjustment issues among four year-olds that go on to experience premature puberty. Utilisation of ALSPAC data will enable further generalisation of this research. We aim to follow up and extend research in this area by examining the extent to which psychological health, health-related behaviour, neurodevelopmental disorders and cognitive abilities in early childhood vary according to subsequent pubertal timing.

Pubertal timing is strongly controlled by genetic factors (heritability of menarcheal timing is estimated to be as high as 74%; He & Murabito, 2014). Both genome-wide association studies and candidate approaches have identified these factors which are among the most robust findings in the field of complex trait genetics. We would like to include genetic variants in our analysis to control for genetic influences and also test whether genes associated with pubertal timing in boys and girls could be directly implicated in related psychological and behavioural phenotypes. Interestingly one of the genes identified, CYP19A1, has also been implicated in dyslexia, a common neurodevelopmental phenotype. For this reason, we would like to include reading-related measures in our dataset. Also pertinent to this context are findings of sex differences in neurodevelopmental disorders (e.g., Willcutt & Pennington, 2000). We aim to examine potential environmental and genetic factors which may contribute to gender differences in prevalence rates.

This project builds on a collaboration between research groups in the School of Medicine, University of St Andrews, which is focusing on a wider project on the determinants and consequences of early pubertal timing. Professor Candace Currie currently acts as International Coordinator of the 43-country Health Behaviour in School-aged Children (HBSC) study and directs the Child and Adolescent Health Research Unit (CAHRU) in St Andrews. Professor Currie has a strong track record in fields of puberty and adolescent health and has been an active researcher in these areas for over 20 years. Dr Silvia Paracchini is a Royal Society University Research Fellow and an active researcher in the field of neurodevelopmental genetics. She has extensive experience in working with cognitive measures from the ALSPAC dataset. Dr Ross Whitehead is a Research Fellow with the Scottish HBSC team and has backgrounds in cognitive neuroscience and the evolution of human behaviour. As part of our collaborative project, we will extend our analysis to other relevant existing cohorts such as the 'Generation Scotland' study, which allows retrospective investigation into some of the above research questions

B2230 - DNA methylation patterns in genes controlling vitamin D metabolism a lifespan approach - 01/05/2014

Aims:

1 Assess the changes that occur in DNA methylation status over the life span for vitamin D relevant genes. Including, how does early life methylation status vary from that of later life?

2.What are the implications of these changes for vitamin D status and health outcomes over the lifespan?

3.Do any of these methylation changes correlate with traditional risk factors for vitamin D deficiency (e.g. ethnicity, age, obesity) and if so how?

4.How do people who respond well to vitamin D supplements differ in methylation status (for vitamin D related genes) from those who do not respond well?

B2229 - Lifecourse determinants of diet in a contemporary population of young adults - 01/05/2014

We plan to collect dietary data as part of the clinic being planned in the ALSPAC participants.They will be asked to complete three 24-hour dietary recalls, using a newly developed online system (exact tool to be determined - we are currently negotiating with two research groups over their tools: Jane Cade's MyFood24 (Leeds University) and Emma Foster's INTAKE24 (University of Newcastle)) at around the age of 24. YPs will be requested to complete a recall prior to coming to a clinic planned to start in June 2015. There will then be opportunity for the YP during the clinic visit to ask any questions about their dietary recall. The tool we use will automatically provide us with all the data necessary (food groups and nutrient intakes as derived using standard food tables). The tool will be both smart phone and tablet compatible. This means at least one recall could be collected during the clinic visit if time is available between sessions (we anticipate it will take 10-15 minutes to complete one recall) if we were to purchase a number of tablets. Reminders will then be sent out via email/text after the clinic visit to complete futher 24-hour recalls.

We also propose the collection of new questionnaire data in the YPs, to include questions such as current living arrangements (who, what, where), what the YP is currently doing (work, study etc), who normally prepares food etc and other eating behaviours. Such questions will be included in either the 2014 or 2015 Q as appropriate (but ideally 2014 from a temporal point of view, though we acknowledge funding may not be in place in time).

In addition to examining food groups and nutrient intakes, we will use three methods: cluster analysis, principal components analysis and reduced rank regression to obtain dietary patterns: All these methods reduce the complex nature of many inter-correlated dietary variables into a smaller number of variables which best describe the overall patterns of diet in the population but result in different outcome variables providing slightly different ways of assessing overall diet. These methods have been used extensively by the applicants to determine dietary patterns throughout childhood and into adolescence and will be used to see whether dietary patterns track into adulthood.

The ALSPAC resource provides the perfect opportunity to develop causal models that will explore which of the following are most important in determining 'healthy' dietary intake in early adulthood:

* Individual factors such as previous diet (including breastfeeding and weaning and dietary intake throughout childhood and in early adolescence), eating behaviours (such as skipping breakfast) physical activity, body composition, life events and other health behaviours;

* Familial factors such as parental diet, eating attitudes and behaviours, lifestyle and health factors

* Social and environmental factors such as housing, education of both the individual and their parents.

B2228 - Exploration of possible link between blood selenium and risk of pre-eclampsia pregnancy-induced hypertension - 24/04/2014

Aims:

To analyse the mothers' total blood selenium in regard to the subsequent development of the hypertensive disorders of pregnancy, particularly of pre-eclampsia.

B2227 - The evolution of behavioural development in social animals - 17/04/2014

AIMS

I will use evolutionary theory, underpinned by mathematical and computational modelling, to understand how natural selection has influenced patterns of development and how these interact with early life conditions to shape behaviour. The underlying assumption of the proposed project is that children gradually develop social competence through interactions with their peers. Using the ALSPAC data I will test some general predictions derived from evolutionary models of social behaviour, in which individuals are uncertain of their own qualities but can learn about this through their social experiences (see e.g. Fawcett & Bleay 2009, Behav. Ecol. 20, 68-78; Fawcett & Johnstone 2010, Proc. R. Soc. B 277, 1427-1434). The project has two main components:

(1) To refine the models and generate more specific predictions, I will incorporate data on patterns of physical development (growth in body size, strength, pubertal development etc.), changing social situations (age-structuring of interactions, number and age of siblings, moving to a new school, etc.) and early-life stress (low SES, stressful events, etc.) in an attempt to explain age-dependent patterns of play-fighting, aggressive behaviour and reproductive strategies. To assess causal relationships, I will use Mendelian randomisation (MR) techniques based on SNPs robustly associated with patterns of development (body size and reproductive maturity).

(2) I will then conduct a targeted recall study to measure the perception of social emotions (facial image recognition task; see e.g. Penton-Voak et al. 2013, Psych. Sci. 24, 688-697) and responsiveness to social experiences (winner vs. losing a competitive task; see e.g. Pound et al. 2009, Proc. R. Soc. B 276, 153-159; van der Meij et al. 2012, Proc. R. Soc. B 279, 202-208), using a subsample of ALSPAC participants who have followed diverging trajectories of physical development and experienced different social environments early in life. This will shed light on the psychological mechanisms associated with different developmental patterns of social behaviour.

B2226 - Birth weight and metabolomics profiles through the lift-course Meta-analysis of 20000 people - 10/04/2014

Aims:

Low birth weight is linked with an adverse metabolic profile in adulthood and increased risk for cardiometabolic diseases. We aim to elucidate this relationship by examining associations of birthweight with a comprehensive metabolite profiled quantified by high-throughput serum NMR spectroscopy. We will assess associations of birthweight (as continuous measure) with uniform data on serum metabolites in greater than 20,000 individuals from several population-based cohorts from Finland, and would like to include ALSPAC in the analyses. ALSPAC has recently completed high-throughput metabolite profiling by NMR for multiple time-points in both the children and the mothers. The multiple time-points metabolite data in ALSPAC will be examined for effect modulation by age, ie. if effects of birthweight are fixed during adolescence and early adulthood. Similar multiple time-points is available for 2 Finnish cohorts.

B2225 - Patterns in the size timing and frequency of food and drink consumption and diabetes risk in young adults - 10/04/2014

Aim:

To systematically assess variation in the size, timing and frequency of consumption within a day, from day-to-day and across the lifecourse and how it relates to diabetes risk at 25 years of age and change in diabetes risk from 15 to 25 years of age.

B2223 - Chronic irritability in ADHD Examining clinical and genetic links with depression - 10/04/2014

Aims:

The proposed project aims to use data from the ASLPAC study to test whether:

1. In children with ADHD, symptoms of irritability are associated with an increased risk of depressive symptoms in adolescence.

2. In children with neurodevelopmental disorders (including ADHD, Intellectual Disability (ID), Autistic Spectrum Disorder (ASD), Communication Disorders, Motor Disorders), symptoms of irritability are associated with an increased risk of depressive symptoms in adolescence.

3. In children with ADHD and other neurodevelopmental disorders, symptoms of irritability index higher rates of family history of depression and increased genetic risk for depression.

B2222 - Does body dissatisfaction cluster in schools - 10/04/2014

Aims and Objectives

The aim of my project is to increase understanding of eating disorders (ED) and body dissatisfaction (BD) in adolescent girls from the perspective of population-level pathways.

Understanding whether ED and BD cluster in schools would inform the development of school-level interventions to reduce incidence of ED. No studies have investigated whether ED and BD cluster, despite the clinical observation that it appears to be the case, although disordered weight control behaviours do vary between schools. Preliminary results from the Swedish cohort described below suggest around 9% of variance in rates of ED is at school level.

B2221 - Maternal function folate status and risk of ASDs in the ALSPAC birth cohort - 10/04/2014

Aims

In our proposed work, we aim to investigate relationships between ASD and related traits, and key determinants of functional folate-status in a large, well-characterized birth cohort with prospectively collected data. Determinants of folate-status to be investigated include self-report of maternal folate supplementation at 16 and 32 weeks gestation, dietary folate intake at 32 weeks gestation, child folate intake reported at 1 year of age, as well as maternal and child genetic variants involved in one-carbon metabolism and epigenetic regulation. These determinants are to be investigated both individually, and jointly to assess potential interactions.

B2220 - Does early frequency and form of stools predict later bowel and bladder dysfunction and their consequences - 10/04/2014

To establish if early questionnaire data on frequency and form of stooling predicts future bowel and bladder dysfunction in children. This data will be ised to model the costs and benefits of treating infants and children for long periods with stool softeners to reduce the incidence of constipation, soiling and daytime wetting.

B2219 - The role of DNA methylation in the aetiology of type 2 diabetes - 10/04/2014

AIMS

The proposed project aims to investigate the relationship between increased risk of type 2 diabetes and methylation profile. Specifically:

1. Is variation in DNA methylation associated with risk of type 2 diabetes?

In ALSPAC mothers, individuals will be selected based on high and low risk of developing type 2 diabetes (using measures of glucose and insulin, metabolomics data, diagnoses of gestational diabetes or repeated measures of glycosuria during pregnancy). We will then look for associated patterns of DNA methylation.

2. Can DNA methylation signatures predict who progresses to type 2 diabetes and/or other co-morbidities (cardiovascular disease) from those who will not?

Using follow-up data from ALSPAC mothers (FOM) we will investigate if methylation status at baseline has any predictive influence on which individuals developed adverse health outcomes (type 2 diabetes or worsened metabolic profile). DNA methylation measures at follow-up will identify methylation differences over time and may also identify loci associated with later health adversity.

3. How do genetic variation influence methylation patterns?

At methylation loci of interest (following discovery in aims 1&2) we will identify any relationship between methylation and measured genetic variants. This will help us to understand by how much methylation patterns are determined by the underlying genetic sequence.

4. To utilise genetic sequence-methylation associations in order to distinguish between non-causal biomarkers and causal pathways

The causal/non-causal relationships between genotype, DNA methylation and metabolic measures will be investigated using Mendelian randomisation. Using genotype information from objective 3, SNPs that correlate highly with methylation at CpG sites of interest will be utilised as 'proxy' measures of DNA methylation. This permits the use of genotype data and therefore the relationship between (proxy) methylation and outcome of interest can be evaluated.

B2218 - Pathways to positive and negative sexual health outcomes in young adulthood ALSPAC at 24 - 03/04/2014

Sexual behaviour is a normal part of human development, and sexual health is a central component of physical and mental health. However, sexual activity can also lead to adverse health consequences including sexually transmitted infections (STI) and unintended pregnancies, whose impact may be profound and long lasting. Intimate relations may also be the setting for violence between partners with wider health consequences for families. In the UK and elsewhere the above adverse outcomes are common and may be increasing, in part reflecting deficiencies in intervention policies. The UK Government has specified improving sexual health as an overarching priority. Sexual behaviour associated with increased risk of adverse sexual health outcomes may be influenced by the dynamic interplay of biological, individual, social, cultural, environmental and political processes across the life course. In particular, sexual development takes place in the context of developing social, peer and romantic relationships. It follows that an understanding of the development of young adult sexuality and other risk-taking behaviours and the association between these behaviours and outcomes such as STI requires longitudinal data about early and middle childhood experiences, as well as accurate data about the onset of romantic, sexual, and risk-taking behaviour from late childhood onwards. Such understanding is key to the design of appropriate public health interventions to improve sexual health. If the causal roots of risky sexual behaviour and its adverse sexual health consequences lie early in the life course then this is where effective intervention should be targeted. However, it may be that risk of adverse sexual health outcomes is substantially determined by proximal factors essentially independent of the pathways that precede them. This possibility has different implications for prevention. It may also be the case that most risk of adverse sexual health outcomes is not primarily attributable to a definable syndrome of risky sexual behaviour. Finally it is important to investigate the predictors of positive sexual health outcomes as these may also have implications for effective health promotion.

Investigation of these hypotheses, and their different implications for prevention, calls for general population based studies of adolescents at an age where a sufficient proportion is sexually active with prospective data both on sexual behaviour, its correlates and antecedents and on sexual health outcomes. ALSPAC is one of the few studies internationally, and the only study in the UK, currently able to support such investigation

Objective 1: To measure patterns and prevalence of sexual behaviour and related risk behaviours at age 24

Participants attending the clinic will be invited to complete a validated computer assisted self-interview (CASI), covering sexual behaviour, attitudes and lifestyle (including age at coitarche in non-virgins, circumstances of first intercourse, whether activity was regretted, condom and other contraceptive use, pregnancy and parenthood, use of pornography, other 'romantic relations', intimate partner violence, and positive sexual experiences. Questions used will be the same as in previous assessments to maintain consistency and allow estimation of incidence with more detailed questions on current sexual lifestyle appropriate for young adults also included.

Objective 2:To estimate the age-specific prevalence and incidence of genital Chlamydia, Mycoplasma, and Gonorrhoea in a birth cohort of UK adolescents.

ALSPAC participants attending the age 24 clinic assessments will be invited to submit a first catch urine specimen, which will be tested for the presence of the above infections, and a blood sample, which will be tested for the presence of chlamydia antibodies. Permission will also be sought to test stored blood and urine samples collected at previous clinic assessments between the ages of 11 and 15.

Objective 3: To investigate pathways to both positive sexual health outcomes and risky sexual behaviour and adverse sexual health outcomes from early life to adolescence in a birth cohort of UK adolescents

Objective 4: To investigate life course influences on use of sexual health services and participation in Chlamydia screening

Objective 5: To investigate the validity of serological testing as a measure of lifecourse exposure to genital Chlamydia trachomatis

Objectives 4 & 5 will use data obtained from linkage between ALSPAC and the PHE CTAD database.

Objective 6: to collect information on sexual networks to inform modelling of the transmission dynamics of common STI.

We will examine four broad hypotheses

a.) Risky sexual behaviour is an important independent risk factor for adverse sexual health outcomes.

b.) Other problem behaviours and outcomes (substance use, antisocial behaviour, low educational attainment) are important independent risk factors for risky sexual behaviour.

c.) There is a causal pathway from early life adversity and childhood problems to risky sexual behaviours, mediated through other problem behaviours in adolescence (substance use and/or antisocial behaviour and/or low educational attainment).

d.) Early life adversity, childhood problems, and other problem behaviours in adolescence are associated with STI infection.

A key issue in making inference about causal relations between variables such as those in the above diagram is clarification of the extent of socio-economic confounding. Many associations between different adverse health and social outcomes are likely to reflect their covariance with social disadvantage, rather than a distinct causal pathway. Some of these relations, however, may mediate the association between social disadvantage and poorer health. We will add, in turn, potential confounding variables related to (1) early life adversity and childhood socioeconomic circumstances; (2) childhood psychosocial problems; (3) other variables relating to problem behaviours in early adolescence; and finally (4) behavioural variables measured concurrently with sexual behaviour and sexual health outcomes. In considering the choice of possible confounding variables we will follow the approach of Hernan and colleagues who point out that strategies based on knowledge of the causal structure are more appropriate than those based on statistical strength in choice of confounding variables. We will use multilevel models as appropriate, to include repeated measures on each individual (for example to reflect changing socio-economic circumstances).

B2217 - Do parental child and home environment factors mediate the association between socioeconomic status and injury - 03/04/2014

AIMS:

Research has consistently shown that children of low socioeconomic status (SES) are at an increased risk for injury. However, the mechanisms of this association are not fully understood.

Factors such as poor parental supervision, behavioral problems in children, and unsafe housing have been associated with increased risk of injury. Prior studies using the ALSPAC data have found that various social and environmental characteristics such as living in a single parent home, parental depression, living in an unsafe neighborhood, and presence of safety hazards in home can contribute to injury in children four years of age and younger (1-3). Findings from Reading et al. indicate that individual characteristics of children and parents explain neighborhood clustering of injury rates (2), however, the degree to which these factors explain socioeconomic variation in injury is not fully understood.

The aim of the current study is to examine whether parental, child, and home environmental factors mediate the association between family socioeconomic status and injury in young and school aged children.

HYPOTHESIS:

It is hypothesized that child characteristics, parental characteristics, and quality of the home environment will mediate the association between socioeconomic status and injury.

EXPOSURE/MEDIATING VARIABLES:

Family income, housing characteristics (e.g., type of home, age of housing, home hazards, number of times the family has moved, neighborhood safety), parental/supervision factors (parental education level, general physical health, depression, alcohol use, exposure to traumatic events, size of family, marital status of parents), and child characteristics (age, gender, race/ethnicity, behavior/temperament).

OUTCOME VARIABLES:

Child accidents and injuries (types of injury, how/where occurred, severity of injury)

B2216 - Pregnancy complications menopausal transition and metabolomics - 03/04/2014

BACKGROUND

1. Pregnancy complications and subsequent metabolic profiles in mid-life.

Pregnancy complications, including hypertensive disorders of pregnancy (HDP), gestational diabetes (GDM), preterm birth, small for gestational age (SGA) and large for gestational age (LGA) are associated with subsequent increased cardiovascular and diabetes risk in the mother, though the precise mechanims underlying these associations are unclear.[1] In ALSPAC we have previously shown that HDP is associated with a wide range of cardiometabolic risk factors (greater body mass index, fat mass, waist circumference, blood pressure and fasting lipid levels and adverse fasting lipids) approximately 18 years postnatal, whereas GDM was associated only with greater fasting glucose and insulin. However, both were associated with the same increased risk (~30%) of predicted CVD based on the Frammingham equation.[2] Preterm birth and SGA were associated with higher blood pressure 18 years later and LGA with higher waist circumference and fasting glucose.[2]

A number of small studies (commongly fewer than 100 participants) have shown that blood based metabolites (either maternal gestational or fetal assessed in cord blood), including amino acids, fatty acids, lipids and phospholipids, are associated with pre-eclampsia.[3-8] One study found differences in sphingolipids, phospholipids, carnitines and fatty acids in early pregnancy maternal serum comparing those who had a SGA infant to those with a normal for gestational infant,[9] and one differences in cord-blood glucose, several amino acids, lipids and lipoproteins between infants of mothers who did, and those who did not, have GDM.[10] To our knowledge no study to date has examined the relationship of pregnancy complications with future metabolic profiles in the mother some years after delivery and the extent to which these might explain any association of these complications with atherosclerosis.

2. Menopausal transition and metabolic profiles

There is increasing interest in the role of the menopausal transition and health ageing in women.[11,12] Endogenous oestrogen levels are cardioprotective and a large number of cross sectional studies have shown that cardiovascular events and risk factors are higher in women who are post- compared to pre-menopausal.[13] From the small number of relatively small (N ~ 50 to 1000) studies with repeat measurements of cardiovascular risk factors there is evidence that as women go through the perimenopausal transition adiposity, fasting glucose, insulin, LDLc and triglycerides increase and HDLc decreases independently of age-related changes, whereas blood pressure changes at this time appear to reflect age effects.[13] Recently a meta-analysis of cross sectional associations in greater than 10,000 participants

found metabolic profile differences between women and men, with a sex*age interaction that supported adverse (in relation to atherosclerosis) changes in women around the time of the menopausal transition. In cross-sectional analyses in a subgroup of the women they showed adverse levels of lipids, lipoproteins, fatty acids and amino acids in between age matched women who were pre-, peri- and postmenopausal.[14] To our knowledge no one to date has examined prospective associations of menopausal status and change in this with change in metabolic profiles.

OBJECTIVES

1. Pregnancy complications and subsequent metabolic profiles

1. To determine the associations of HDP, GDM, preterm birth, SGA and LGA with subsequent (~18 years later) metabolomic profiles, including identifying the extent to which the different pregnancy complications overlap with each other in terms of relating to similar future metabolic disruptions.

2. To determine the cross-sectional association of metabolic profiles with atherosclerosis, as measured by cIMT, in middle-aged women.

3. To determine the extent to which metabolic profiles mediate any associations of complications of pregnancy with future cIMT

2. Menopausal transition and metabolomic profiles

1. To determine the cross-sectional associations of menopausal status and hormone use (women will be categorised into mutually exclusive categories of: hysterectomy/oophorectomy; using HRT; using hormonal contraception; pre-menopausal; in menopausal transition; early post-menopause; late post-menopause, according to STRAW criteria for menopausal/reproductive status) with metabolic profiles.

2. To determine the prospective change in menopausal status with change in metabolomic profiles.

METHODS

1. Pregnancy complications and metabolomic profiles

For this paper obstetric and early pregnancy questionnaire data will be combined with data from FoM1

Analyses will be done by Qin Wang with supervision from Mika Ala-Korpella and Debbie Lawlor

2. Menopausal status and metabolomic profiles

For this paper data from FoM1 and FoM2 will be primarily used

Analyses will be done by Qin Wang (as above)

Data preparation

Debbie Lawlor will work with Kate Northstone to put some of the non-metabolomic data together, Kate / someone from her team will link these data to the metabolomic data and add a research collaborator number before they are transferred to Mika Ala-Korpella at the University of Oulu.

REFERENCES

1. Rich-Edwards JW, Fraser A, Lawlor DA, Catov JM. Pregnancy Characteristics and Women's Future Cardiovascular Health: An Underused Opportunity to Improve Women's Health? Epidemiol Rev 2014; 36: 57-70

2. Fraser A,

3. Kenny LC, et al. Novel biomarkers for pre-eclampsia detected using metabolomics and machine learning. Metabolomics 2005; 1: 277-

4. Kenny LC, et al. Robust early pregnancy predictors of later pre-eclampsia using metabolomic biomarkers. Hypertension 2010; 56: 741-49.

5. Aitkinson KR, et al. An altered pattern of circulating apolipoprotein E3 isoforms is implicated in pre-eclampsia. J Lipid Research 2009; 50:71-80.

6. Turner E, et al. Plasma from women with pre-eclampsia has a low lipid and high ketone body content - A nuclear magnetic resonance study. Hypertension in Pregnancy 2007; 26:329-42.

7. Odibo AO, et al. First-trimester prediction of pre-eclampsia using metabolomics: a discovery phase study. Prenatal Diagnosis 2011; 31:990-94.

8. Bahado-Singh RO, et al. Metabolomics and first-trimester prediction of early-onset pre-eclampsia. Journal of Maternal-Fetal and Neonatal Medicine 2012;25:1840-47.

9. Horgan RP, et al. Metabolic profiling uncovers a phenotypic signature of small for gestational age in early pregnancy. Journal of Proteome Research 2011; 3660-73.

10. Dani C, et al. Metabolic profile of term infants of gestational diabetic mothers. Journal of Maternal-Fetal and Neonatal Medicine 2013 doi: 10.3109/1476058.2013.823941.

11. Bittner V. Menopause and cardiovascular risk cause or consequence? J Am Coll Cardiol 2006;47:1984-86.

12. Report of the WHO Scientific Group. Research on the menopause in the 1990s. Geneva: World Health Organisation; 1996. Report No.: 886

13. Lawlor DA, Hardy R. A life course approach to metabolic and vascular function. Kuh D, Cooper R, Hardy R, Richards M, Ben-Shlomo Y, eds. A life course approach to healthy ageing. OUP; 2013.

14. Finish menopausal metabolomics study

B2215 - Understanding participation and non-participation in HE for white working class and minority ethnic groups BIS - 27/03/2014

The principal aims of this project are:

1) To examine potential gaps in in the current understanding of why these groups are less likely to progress to HE and to test hypotheses using the ALSPAC dataset linked to NPD and HESA.

2) Undertake qualitative interviews with the groups of interest, in particular to establish what individuals felt were the barriers to higher education for them personally. For those who made the successful transition, we would like to understand the factors that contributed to their HE participation.

B2214 - Early life predictors of visual and refraction-related phenotypes in early adulthood - 27/03/2014

Aims

Our interest is in how early childhood exposures/behaviours influence the development of the visual system, its peak performance and markers of later sight-threatening disorders (such as glaucoma) and how these interact with genetic factors. Within this broad theme, we aim to address research questions framed by the following hypotheses.

B2213 - Parent-of-origin specific genome- and epigenome-wide analyses on fetal growth and postnatal outcome - 27/03/2014

Aim:

To identify genes important in fetal growth and postnatal outcome, using a parent-of-origin analysis model.

B2212 - Genetic variation and smoking - contribution to GSCAN GWAS Sequencing Consortium of Alcohol and Nicotine use - 27/03/2014

We will analyse the association between various smoking phenotypes in YPs and mothers and common genetic variation (GWAS, available for most YPs and mothers) and more rare genetic variation (based on GWAS data imputed to a novel imputation panel based on sequencing data, therefore available for most YPs and mothers, as well as on a subsample of the cohort with UK10K sequencing data).

YPs Analyses

Phenotypes to be analysed will include initiation, age at initiation, first response to tobacco, tobacco intake (as indexed by daily cigarette consumption), and level of nicotine dependence (based on the FTND questionnaire). Both cross-sectional measures and derived life-time consumption measures will be used. Where possible and appropriate, trajectories of use will be defined as part of an ongoing collaboration with Prof Matt Hickman and Dr Jon Heron.

Mothers Analyses

Phenotypes to be analysed will include initiation, age of initiation, tobacco intake (as indexed by daily cigarette consumption), level of nicotine dependence, and smoking cessation. Both cross-sectional measures and derived life-time consumption measures will be used.

A detailed analysis plan for the GWAS of individual studies to be included in the GSCAN collaboration is available online (http://gscan.sph.umich.edu/gwas/analysis_plan).

B2211 - Genetic variation and alcohol use - contribution to GSCAN GWAS Sequencing Consortium of Alcohol and Nicotine use - 27/03/2014

AIMS:

We will analyse the association between various dimensions of alcohol use in YPs and mothers and common genetic variation (GWAS, available for most YPs and mothers) and more rare genetic variation (based on GWAS data imputed to a novel imputation panel based on sequencing data, therefore available for most YPs and mothers, as well as on a subsample of the cohort with UK10K sequencing data).

B2209 - Maternal smoking in pregnancy in relation to offspring methylation and asthma - 27/03/2014

Aims:

We (Joubert et al. Environ Health Perspect. 2012;120:1425-31) and subsequently others have identified replicable methylation differences at birth in relation to maternal smoking using the Illumina 450K platform. Some of the same changes have been seen in adult smokers. It is not known whether these differences persist to later childhood, whether the persistence may differ across loci, or whether postnatal exposure might contribute to the persistence of these methylation changes. We propose to analyze ALSPAC data in the setting of meta-analysis across cohorts with data on maternal smoking during pregnancy and offspring Illumina 450K methylation and asthma phenotypes to address the following specific aims:

1. Do methylation differences at specific loci related to maternal smoking detected at birth persist to later childhood, taking into account postnatal exposure to smoking.

2. To examine the association between maternal smoking during pregnancy, assessed by plasma cotinine, and the development of asthma phenotypes in the child.

3. Investigate whether methylation differences at birth related to maternal smoking may be a biomarker of the risk of developing asthma phenotypes from exposure to maternal smoking during pregnancy.

B2208 - Biobehavioural pathways to adolescent substance use - investigations using genetically-informed data from ALSPAC - 20/03/2014

Aim 1: Biobehavioral pathways of development: Test biological-environmental pathways for adolescent substance use. Hypotheses are that (1) increased prenatal risk and earlier pubertal timing will partially mediate genetic influences on internalizing and externalizing problems and subsequent substance use, and (2) earlier pubertal timing will partially mediate parenting influences on internalizing and externalizing problems and subsequent substance use.

Aim 2: Biological-Environmental Interactions: Test biological (genetic, endocrine) X environmental (prenatal, parenting) interactions for adolescent substance use. Hypotheses include that (1) genetic influences, as measured by polygenic scores, will moderate associations between prenatal risk exposure and adolescent substance use, (2) genetic influences, as measured by polygenic scores, will moderate associations between parenting and adolescent substance use, (3) prenatal risk will moderate associations between pubertal timing and adolescent substance use, and (4) parenting will moderate associations between pubertal timing and adolescent substance use.

B2207 - Characterising the genetic and dietary predictors of the size frequency and timing of consumption and its health impact - 20/02/2014

Aims: to explore the feasibility of calculating data on the size, timing and frequency of consumption by extracting exact time data from original diet diaries completed at ages 7, 10 and 13 years.

B2206 - Exploring the association between Attention Deficit/Hyperactivity Disorder ADHD and socioeconomic disadvantage - 20/03/2014

Using the ALSPAC dataset, this study will address the following questions:

Study 1

* Aim: Are there individual-level associations between parental income, occupation, education and single-parent status and risk of ADHD in the child? Hypothesis: all the above factors will be independently negatively associated with an outcome of ADHD. Exposure variables: parental income, occupation, education and marital status near birth-age 3 of child. Outcome: ADHD by DAWBA at age 7 1/2 (no confounding variables in this study).

* Aim: Which socioeconomic association is strongest, and what are the potential mechanisms for this effect? For example, if single parenthood is the most salient factor, is this due to mediation by poor diet, mothers' smoking during pregnancy, or other factors? Hypothesis: using the strongest predictor above, this association will be mediated by parenting/diet/smoking. Exposure variables: SES variable. Confounding/moderating/mediating variables: diet at age 3, caffeine intake at 6/7 years old, parent involvement, parent mental health. Outcome variable: ADHD by DAWBA at age 7.

Study 2

* Aim: Does this association vary by ADHD at developmental stage or by change in family SES? Hypothesis: SES variables measured at birth/infancy will be the strongest predictors of ADHD at age 7 or 15. Change in family SES will be associated with a change in ADHD symptoms as measured by the SDQ.

Exposure variables: SES variables at several timepoints. Confounding variables: Significant confounders from study 1 part 2. Outcome variables: ADHD by DAWBA and attention symptoms on SDQ at age 7, 9, 11, 15.

Study 3

* Aim: What is/are the most salient measure/s SES when evaluating risk of ADHD in children? (parent SES factor vs school-level factors added to model) This study has implications for policy with regards to early intervention to reduce prevalence of ADHD, as well as contributing to health inequalities literature and also moving toward suggesting a standardised or single SES measure to be used in future research, reducing heterogeneity within the research community. Hypothesis: single parent status, income and school-level deprivation will be the strongest predictors of ADHD outcome. Exposure variables: Parental income/education/occupation/single parenthood, school-level deprivation (free school meal status or IMD), and class-level deprivation (number of free school meals in class). Outcome variables: ADHD by DAWBA at age 7 and 15.

B2205 - Peak lung function and its associations with longitudinal wheezing phenotypes - 20/03/2014

The project aims to identify genetic and environmental factors associated with failure to acquire expected peakk lung function in early adulthood as a prequel to chronic obstructive pulmonary disease, to specify functional and inflammatory outcomes of well-characterised asthma and wheezing phenotypes through chidhood and adolescence, and to test a novel device for measuring lung function using a mobile phone app in a the context of population-based data collection.

The project aims are three-fold:

1. To extend measurement of lung function in the original ALSAC cohort to its physiological peak in early adultood; completing the trajectory of lung function accural during childhood

2. To conduct a detailed assessment of the outcomes adn endotypes of longitudinal chidhood wheezing phenotypes by recruiting a sub-sample for:

(a) Detailed lung function measurements in a respiratory laboratory

(b) Standardised exercise challenge and cardiorespiratory perfomance (VO2max)

(c) Detailed measures of airway inflammation (Exhaled NO, induced sputum collection)

3. To conduct a feasibility and validation study of the use or a novel mobile-phone based lung function app (SpiroSmart) for near-subject testing in a smapel of participants that have had laboratory measurements as part of Aim (1).

B2204 - Early life stress age of puberty and reproductive behaviour - 20/03/2014

Objectives:

1. To provide a multi-faceted understanding of the causal variables underlying behaviour and the psychological correlates that form and mediate individual life history strategies, allowing a strong test of hypotheses of psychosocial acceleration in response to early adversity.

B2203 - Foetal testosterone 2D4D digit ratio and social cognition - 20/03/2014

Foetal testosterone plays a significant role in a wide range of sex-differences. In animal studies it has been found that foetal testosterone influences the development of the of the brain; the hypothalamus, limbic system, and neocortex (Arnold & Gorski, 1984; Breedlove, 1994; MacLusky & Naftolin, 1981). It has also been found to influence behaviours (Goy & McEwen, 1980) and cognitive abilities (Williams & Meck, 1991). Sex differences in behaviour and cognition are also apparent in humans (Baron-Cohen, 2003). Traditionally research in this area has focused on abilities of logic; spatial, mathematical, and verbal ability (Kimura, 1999). More recently investigations have looked at potential social sex differences. Geary (1998), suggested that women exceed men in particular aspects of socio-cognitive ability; non-verbal communication, language and theory of mind. Baron-Cohen (2002) proposed that women have a better ability to identify and understand another's state of mind, emotional state (empathy), and to respond appropriately.

Lower 2D:4D digit span ratio is a sexually dimorphic trait, thought to be indicative of higher testosterone exposure. On average males have a lower digit span ratio than females (Maning, 2002). Growth of the 4th digit, as promoted by testosterone, is thought to occur in a 'respective window' in utero and therefore 2D:4D ratio remains constant through out postnatal development. Subsequently 2D:4D has been deemed a useful biomarker for extent of prenatal testosterone exposure (Maning, 2002). There is an abundance of evidence in support of this view. For example, it has been found that women with congenital adrenal hyperplasia have more masculine span and males with the condition have smaller digit ratios than control males (Okten, Kalyoncu, & Yari?, 2002 ).

Whereas digit span ratio has been associated with numerous mental health disorders- Depression, Psychopathology, ADHD (Bailey & Hurd, 2005; Blanchard & Lyons, 2010; McFadden, Westhafer, Pasanen, Carlson, & Tucker, 2005), most frequently the literature has investigated links with social cognition and autism. Individuals with autism are thought to be subject to a hypermasculined brain, characterised by low empathising and high systemising traits. At the other end of the continuum the so-called feminised brain is characterised by high empathising and low systemising (Baron-Cohen, 2002). Deficits in social cognition and autistic traits have been found to be indirectly associated (via digit span ratio) with prenatal testosterone exposure (e.g. Honekopp, 2012). In support of these findings, more males have autism than females.

However, conclusions made by papers investigating digit pan ratio and social cognition are often based on small sample sizes (around 50 participants). Furthermore, a study by Voracek and Dressler (2006) which used a relatively large number of participants (N= 423), found a lack of correlation between 2D:4D and empathising, systemising and autistics traits, using measures developed by Baron-Cohen (2002). The purpose of this research is to better investigate whether a link between foetal testosterone and social cognition exists, specifically the ability to empathise. The aim of the study is, by using such a large data set, to overcome the experimental limitations to which previous studies may have succumb.

The exposure variable will be 2D:4D and outcomes variables will be social communication, non verbal information, theory of mind, friendships, and gender behaviour. If 2D:4D is indicative of in utero testosterone exposure, and this has organisational effects on brain development that are reflected in lateroutcomes, it is predicted that lower digit span ratio will be associated with poorer social communication, non- verbal information, theory of mind scores and friendships scores and more male typed gender behaviours.This hypotheses will be assessed using appropriate regression techniques.

B2202 - DNA methlyation and processing of facial emotion during 75 carbon dioxide anxiety challenge - 20/03/2014

Aims:

To investigate sources for individual variation in emotional face processing during state anxiety.

The majority of research has examined the association between trait anxiety and emotional processing. In contrast, the effects of state anxiety have been understudied. Our laboratory is experienced in the use of anxiogenic challenges that safely and transiently increase anxiety. This involves short (up to 20 minutes) inhalation of air that has higher levels of CO2 than normal air (7.5%). There is substantial individual variation in anxiety sensitivity and emotional processing, and in this study we would investigate whether effects differ on the basis of DNA methlyation patterns, which have recently been identifed as biological markers of early life stress. DNA methylation profiles have already been generated from the peripheral blood of approximately 1000 ALSPAC mothers and children as part of the Accessible Resource for Integrated Epigenomics Studies (ARIES).

B2200 - Replication of DNA methylation and gender association study - 13/03/2014

Aims: To replicate genome-wide sex-specific CpG sites.

B2199 - Metabolomics workpackage of LIFECOURSE Longitidunal Investigation of biological Factors Explaining age-related Cognitive and Cardiometabolic Outcomes Relationship to Survival and effect of Environment Horizon 2020 bid - 13/03/2014

OBJECTIVES (note these will be achieved within the collaboration of greater than 50 studies and greater than 500,000 participants; ALSPAC will contribute to some but not all and for each objective more than one study will always contribute)

1a. To determine how metabolomic profiles change with age from birth through to old age.

1b. To explore the extent to which risk factors from across the life course (diet, physical activity, alcohol, adiposity) alter general age related trajectories

2. To determine the extent to which blood-based metabolic profiles (assessed at different ages), in addition to clinical characteristics, improve stratification of adults into different levels of risk for cardiovascular disease, type 2 diabetes and dementia

3a. To determine the effect of risk factors, such as greater adiposity, low levels of physical activity, poor diet and excessive alcohol consumption, on metabolic profiles at different ages.

3b. To determine the effect of different blood-based metabolic profiles (assessed at different ages) on subsequent risk of adverse cardiometabolic risk factors, CHD, stroke, type 2 diabetes, lower cognitive function and dementia.

3c. To determine the role of blood-based metabolic profiles (assessed at different ages) in the causal pathway between upstream risk factors (such as greater adiposity, low levels of physical activity, poor diet and excessive alcohol consumption) and subsequent cardiometabolic, cognitive and ageing outcomes

B2198 - Exploration of maternal alcohol consumption nutrient intake dietary patterns and infant outcomes - 13/03/2014

Aims:

To explore associations between alcohol consumption levels and patterns, and intake of methyl donor nutrients and dietary antioxidants during pregnancy.

To derive maternal dietary patterns associated with alcohol consumption levels, drink preference and drinking patterns prior to and during pregnancy.

To explore associations between maternal nutrient intake, maternal alcohol consumption, birth outcomes and cognitive development in offspring.

B2197 - The association between stressful life events during pregnancy and offspring mental health - 13/03/2014

Aims&Hypotheses

Theprimaryaimoftheprojectistoexaminethelong-termassociationbetweenmothers'exposuretostressfullifeeventsduringpregnancyandindicesofinternalizing(i.e.,symptomsofdepressionandanxiety)intheoffspring'schildhoodandadolescence. Ourprimaryhypothesisisthatin-uteroexposuretomajor stressfuleventswillbeassociatedwithincreasedriskofdepressive symptomatologyinchildhoodandadolescence,andthatthisassociationwillpersistafteradjustingfortheeffectsofchronicstressorssuchaspoverty,maternalpostnataldepression,andrecurrentstressfuleventsinthepostnatalperiod. Oursecondaryaimwillbetoexaminethelong-termassociationbetweenmothers'exposuretostressfullifeeventsduringpregnancyandindicesofexternalizing(i.e.,behaviouraldisorderssuchasconductproblems)intheoffspring'schildhoodandadolescence.

B2196 - Association of maternal and pre-pubertal 25-Hydroxyvitamin D with post-pubertal Anti-Mllerian Hormone in off-springs - 13/03/2014

Aims

The aims of the study are:

(1) to investigate the prospective association between 25(OH)D concentrations at the mean age of 9.9 years and serum AMH at the mean age of 15 years in a large cohort (N=5,080 with levels of 25(OH)D at age of 7,9, or 11 and N = 3,474 with measured levels AMH at the age of 15 years, once data available we will estimate the exact number of eligible pairs for this analysis).

(2) to investigate the prospective association between maternal pregnancy 25(OH)D concentrations and offspring AMH at a mean age of 15 years in a large cohort (N =7,714 mothers with pregnancy 25(OH)D results and N = 3,474 with measured levels AMH at the age of 15 years).

Depending on the results relating to these two primary aims we will further examine whether any association of maternal pregnancy 25(OH)D with offspring AMH at mean age 15 years is mediated by offspring's own pre-pubertal 25(OH)D.

B2195 - Comparison of a developmental time series of expression against the expression individuals with autism spectrum disorder - 06/03/2014

This is a very simple and brief study that is a follow-on to a study that we published previously on gene

expression in individuals with autism spectrum disorder (Kong SW, Collins CD, Shimizu-Motohashi Y,

Holm IA, Campbell MG, Lee I-H, et al. (2012): Characteristics and predictive value of blood

transcriptome signature in males with autism spectrum disorders. PLoS ONE. 7:e49475.) that we have

appended to this application. The aim of this study is to identify the developmental location of every one

of our subjects with Autism Spectrum Disorder (ASD) in gene transcriptome space. We hypothesize that

individuals with more severe autistic features will be more delayed (in their transcriptomic age relative to

their chronological age) than those who have less severe features (against the ADI/ADOS metrics that we

have for each subject). We will proceed with creating a principal component analysis of the ALSPAC

individuals based on the rank normalized expression data. This will provide a multidimensional map of

development of expression for these individuals. The expression data of the ASD individuals will be also

rank normalized and then these individuals will be projected into the ALSPAC expression space for those

genes present on both platforms used (for the ASD study and the ALSPAC study). Prior studies we have

conducted suggest that the effect of age on transcription will be located in the first two principal

components which will allow us to measure the developmental displacement of each ASD individual

relative to the ALSPAC group. We will have to examine gender as a confounding variable as well as the

scores of the SCDC questionnaire for ALSPAC subjects.

B2194 - Ageing lungs in European cohorts ALEC - HORIZON 2020 - 06/03/2014

The overall objective of the proposal is to exploit information held within existing cohorts and their population-based biobanks to improve understanding of the determinants of and risk factors for low lung function , respiratory disability and the development of a major cause of disease, disability and death in European adults, namely chronic obstructive lung disease (COPD). Lung function in adult life is a critical objective marker of good lung health, strongly associated with other major chronic diseases (for example cardiovascular disease) and is a major independent determinant of overall health status (physical and mental health, quality of life, exercise capacity, independent living).

We will

1. identify determinants and risk factors (behavioural, environmental, occupational, nutritional, other modifiable lifestyle, genetic) of poor lung growth, excess lung function decline and occurrence of low lung function, respiratory disability and COPD within existing child and adult cohorts

2. validate the role of risk factors for poor lung growth, excess lung function decline and occurrence of low lung function, respiratory disability and COPD through a) integration of data from relevant disciplines (clinical, epidemiological, molecular, genetics, epigenetics) and b) valorisation of knowledge gained from the cohort-related population-based biobanks

3. generate and integrate information on change in DNA methylation patterns with ageing to identify risk factors and validate the role of these risk factors

4. generate a predictive risk score that takes account of the combined effects of factors that cause poor lung growth and lung function decline and lead to low lung function, respiratory disability, and COPD in older adults

This work will provide an evidence base for risk identification that can underpin future preventive and therapeutic strategies and policies.

B2193 - IQ and A-level achievement do children with the highest IQs obtain the best A-levels - 27/02/2014

Aim:

The aim of this project is to examine the variance in A-level grade outcomes that is attributable to child IQ, and to what extent this is modified by parental characteristics.

B2192 - Development of health risk in childhood and adolescence Gene-environment interactions and its underlying mechanisms - 27/02/2014

AIMS:

Health risk behaviors related to substance (ab)use and externalizing problem behavior threaten the healthy development of children and adolescents. Specifically, early onset substance use and conduct problems are key predictors of later addiction and clinical-level antisocial personality disorder. These are greatly debilitating conditions for any individual, but also the societal costs associated with these conditions are enormous. Harsh or inconsequent discipline, lack of warmth and sensitivity, abuse by parents, and parents' dependence on substance use are among the strongest predictors of substance (ab)use and conduct problems in childhood and adolescence.

Previous research over the past decade has indicated that family risks may have a particularly detrimental effect in children carrying specific genotypes, that regulate the activity within dopaminergic, serotonergic, GABAergic, and cholinergic pathways. In our proposal, we aim to identify gene-environment interactions that predict health risk behaviors in childhood and adolescence - focusing on genetic risk on the one hand, and on specific family and parenting risks on the other hand. Although the field of GxE research holds great promise, until now it has proven difficult to replicate GxE findings. This has two main causes: first of all, a lack of statistical power in most correlational studies focusing on GxE (e.g., Duncan & Keller, 2011) and secondly, a lacking specification of possible explanatory mechanisms underlying GxE (Dodge, 2010; Weeland, Overbeek, Orobio de Castro, & Matthys, 2014).

Thus, our overall aim is to 1) conduct cross-validated tests of gene-environment interactions related to the development of common addictive behaviors (smoking, alcohol, marijuana) and conduct problems or antisocial behavior in childhood and adolescence, and 2) to test possible mechanisms underlying this gene-environment interplay. With regard to this latter aim, we aim to examine specficially whether children's temperamental traits, such as for instance (but not limited to) levels of (dis)inhibiton and reward and punishment sensitivity, can be identified as explanatory factors underlying the gene-environment interactions that lead up to the development of health risk behaviors.

B2191 - The exploration of environmental and genetic contributions to facial shape - 27/02/2014

Aim:

To employ novel techniques to explore the environmental and genetic contributions to facial shape at 25 years of age and change in face shape from 15 to 25 years of age.

B2190 - Identification of avoidable environmental factors that increase the risk of preterm delivery an exposome approach - 27/02/2014

Hypotheses

The major hypothesis is that there are environmental factors, hitherto unsuspected, that have an effect on the risk of preterm delivery. It is anticipated that such environmental effects may interact with the genetic markers of mother and/or fetus, or work through DNA methylation.

Specific aims will determine, using a hypothesis free approach, whether any of the following are associated independently with preterm delivery: lifestyle of parents and grandparents (including smoking, alcohol, drug abuse, caffeine and activity levels); other physical exposures (medications, diet, work-based chemicals, noise, radiation); psychosocial features of parents and grandparents (including stressors based on life events, social circumstances, financial difficulties, domestic abuse, abuse of the parents in childhood); and mental and physical health of parents and grandparents. For all relationships identified, assessments will be made concerning relevant genetic and epigenetic associations, and their interaction with the exposures.

B2189 - Association between infant sleep position and gross motor skills and intelligence in childhood - 27/02/2014

Aim:

To determine if child sleeping position in infancy is associated with gross motor or mental development in childhood.

B2188 - The role of metabolomics in reproductive and perinatal epidemiology - 27/02/2014

OBJECTIVES (note these will be achieved within the collaboration; ALSPAC will contribute to some but not all and for each objective more than one study will always contribute)

1a. To determine how metabolomic profiles change with age from birth through to old age.

1b. To explore the extent to which markers of reproductive health (age at menarche, age at first birth, parity, age at menopause, transition through menopausal transition) alter general age related trajectories

1c. To explore the associations of adiposity and change in adiposity with change in metabolomic profiles with increasing age.

1d. To explore the associaitons of reproductive hormones and change in reproductive hormones with change in metabolomic profiles with increasing age.

2a. To determine the extent to which blood-based metabolic profiles (assessed at different ages), in addition to clinical characteristics, improve stratification of women into different levels of risk for infertility

2b. To determine the extent to which blood-based metabolic profiles improve risk prediction of live birth obtained from IVFpredict.

2c.To determine the extent to which blood-based metabolic profiles (assessed at different pre-pregnancy and gestational ages), in addition to clinical characteristics, improve stratification of women who become pregnant into different levels of risk for hypertensive disorder of pregnancy, gestational diabetes, preterm birth, large for gestational age and small for gestational age.

2d. To develop the best prediction tools for single and combined adverse pregnancy/perinatal outcomes

3a. To determine the role of blood-based metabolic profiles (assessed at different ages) in the causal pathway between greater adiposity and subsequent reproductive and perinatal outcomes

3b. To determine the role of maternal gestational and fetal (assessed in cord-blood) blood-based metabolomics in the causal pathway between maternal gestational adiposity and weight gain and subsequent offspring (and the next generation - grandchildren) adiposity and cardiometabolic health

4a. To determine the extent to which metabolic profiles change as women go throug the menopausal transition and determine whether any change is independent of age related change

4b. To determine the extent to which reproductive hormone changes as women go through the perimenopausal transition are related to menopausal transition changes in metabolic profiles

4c. To determine the extent to which any menopausal transition changes in metabolic profiles result in future cardiometabolic diseases.

B2187 - Changes in oral health behaviour between childhood and adolescence- analysis of data from ALSPAC - 27/02/2014

Aim:

The aim of this data analysis project is to describe the changes in oral health behaviours between childhood and adolescence using data from the Avon Longitudinal Study Of Parents And Children (ALSPAC) survey, by performing a statistical analysis.

B2186 - Genome-wide association study of body perception - 27/02/2014

We have investigated BMI in childhood using different time points in genome-wide association settings. Our results suggest that the genomic profile differs according to the nature of the phenotype being investigated; optimising BMI appropriattely for each age group, so that the correlation of BMI with height is removed, resulted in SNPs in ADCY3 being genome-wide significant while this was not the case when BMI was used without this adjustment (Stergiakouli et al under review).

As an extension of this project we would like to perform a genome-wide association study of body shape perceptions using data from the "Growing up" questionnaire. This questionnaire was completed by the children when they were ~ 77 months and asked them to choose one from a series of pictures which best reflected how they thought their body looked.

We are interested in comparing the results from our previous GWAS of BMI in childhood with a GWAS of body perception. We would also test if top hits from published GWAS on BMI in childhood and adulthood can be replicated using body perception data.

B2185 - The role of Y chromosome in sexually dimorphic psychiatric disorders - 27/02/2014

Psychiatric disorders show sex differences and early-onset neurodevelopmental disorders, such as ADHD, conduct disorder and autism are more common in males (Ober et al, 2008). In other disorders, such as schizophrenia, there is an earlier age of onset and worse prognosis for men (Ober et al, 2008). The Y chromosome is potentially an important influence on male susceptibility to neuropsychiatric disorders. Animal models have indicated a role for Y chromosome in aggression and impaired parental behaviour (Gatewood et al, 2006). However, due to difficulties arising from the lack of recombination, the Y chromosome has been largely excluded from genetic studies of neuropsychiatric disorders. Although the Y chromosome has been investigated in relation to autistic traits (Jamain et al, 2002) and aggression (Shah et al, 2009) in humans, these studies have not used Y chromosome haplogroups appropriately. Even though Y chromosome markers are now present on most genome-wide association chips, Y chromosome haplogroup analysis is not routinely included in genome-wide association reports of sexually dimorphic disorders.

For my PhD research I had derived Y chromosome haplogroups in children with ADHD from Cardiff University and controls. Although, there were no haplogroups overepresented in children with ADHD, there was a difference in IQ scores across haplogroups only within cases with ADHD. However, this study was based on small number of individuals and since then more Y chromosome markers for deriving haplogroups have become available.

Y chromosome haplogroups have been derived for all male participants with GWAS data in ALSPAC.

We are planning to test if Y chromosome haplogroups, that have already been derived in children from the ALSPAC study, are associated with number of ADHD symptoms, number of autistic symptoms, number of conduct disorder symptoms and number of psychotic symptoms.

We are also planning to test if this association is mediated though IQ or educational attainment.

ANOVA will be used to perform association testing between Y chromosome haplogroups and number of psychiatric disorder symptoms. ANOVA will be also used to test if Y chromosome haplogroups are associated with IQ or educational attainment as measured by GCSE and A levels results. Social class will be included as a covariate in analyses.

B2184 - EUthyroid - 27/02/2014

Aims

To extend the investigation of the relationship of maternal iodine status in pregnancy with child neurocognitive outcomes. To explore the relationship between repeated iodine measures during pregnancy and child neurocognitive outcomes.

B2183 - Characterisation of the microbial flora in children with cleft lip and/or palate - 27/02/2014

Study aim: Our study aims for a comprehensive investigation of the bacteria colonising the inside of the mouth (oral flora) within children with CL/P at the age of three months (i.e. before the cleft lip surgery), in comparison to healthy children in the same age range.

B2182 - Detecting serum metabolite-associated gene sets within ALSPAC - 27/02/2014

Aims:

1. Assess elastic nets, random forests and support vector machine regression models for their applicability to the outlined problem.

2. Identify sets of genes that contribute to each metabolic phenotype.

3. Carry out functional analyses on identified gene sets.

4. Compare gene sets between time points and between similar metabolite measures.

B2181 - Predictors and correlates of eating disorders over the lifetime investigating trajectory recovery and relapse - 27/02/2014

Aims

1. To investigate predictors, and correlates of diagnostic cross-over (i.e. Anorexia Nervosa to Bulimia Nervosa) over the lifetime and recovery/relapse from an eating disorder.

2. To investigate outcomes of lifetime eating disorders: weight status, body composition and bone density.

B2180 - Novel ways of utilizing genome-wide DNA methylation data from peripheral blood samples in genetic epidemiology - 27/02/2014

The overall aim of this proposal is to develop statistical methods and paradigms to better leverage the considerable amount of peripheral blood DNA methylation data that has been (and will be) collected from large scale epidemiological studies. In particular, our focus is on developing and optimizing statistical methods of using DNA methylation profiles to "tag" environmental exposures, so that this information can be better utilized to investigate the genetic and environmental basis of complex traits and diseases.

The specific aims of the proposal are:

Aim 1: To assess the degree to which medically relevant environmental exposures can be tagged by DNA methylation profiles from peripheral blood and to investigate the ability of different statistical approaches to tag these exposures.

Aim 2: To investigate the degree to which "DeMendelization" of methylation profiles (i.e removing the effect of genetic variants) can improve tagging of environmental exposures.

Aim 3: To investigate whether genome-wide association meta-analyses of methylation profiles that index environmental exposures could be used to identify genetic variants underlying medically relevant exposures known to have a heritable component.

B2179 - Psychological vulnerability for depression in young adulthood - 27/02/2014

Aims and Hypotheses

The proposal will investigate the nature of the psychological vulnerability for depression. We will test the hypothesis that the existing measures of psychological vulnerability in ALSPAC - the dysfunctional attitudes scale and cognitive styles questionnaire will be associated with the later development of depression. We will also investigate novel psychological tests of operant and instrumental conditioning and their relationship with prior measures of psychological vulnerability and the cross sectional association with depression. Finally we will investigate the influence of early adversity on the measures of psychological vulnerability.

B2178 - School exclusion in ALSPAC early markers concurrent needs later outcomes - 27/02/2014

Aims

To explore the distribution and correlations of school exclusion in children and young people in ALSPAC, with particular focus on early risk markers, concurrent needs, developmental trajectories and later outcomes.

B2177 - Identification of novel early life environmental exposures that increase the risk of childhood asthma - 20/02/2014

The aim of the proposed project is to relate specific IgE sensitisation to flour allergens in children and parental occupational exposure to flour.

B2176 - Characterisation of transgenerational determinants of disease risk induced by ancestral or early-life parental exposures - 20/02/2014

This is part of an EU proposal which will be led by Olle Bygren at the Karolinska Institute in Stockholm. The over-arching aim of the study is to determine transgenerational effects of smoking, stress and famine on subsequent generations. We propose to undertake the following two work-packages using ALSPAC:

1. Transgenerational smoking studies:

Detailed information was collected from the parents during pregnancy concerning their own backgrounds, including their childhood. The details included the age at which the parents started to smoke, the maximum amount they had smoked in their lifetime, the duration in years that they had smoked,and the amounts they were smoking at three stages of the study pregnancy. There was also information on the preceding generation [including whether the parents' own parents were smokers, and whether the grandmother smoked when expecting the study parent]. Information on the study 'child' is now available concerning the age at which he/she started smoking, and the amount smoked in adolescence and will be available for the early 20s.

The data currently available allow detailed time-related data on active and passive smoke exposure of the grandparents, the parents and the child. Although we have carried out research projects on: (a) the association between paternal onset of regular smoking in the pre-puberty [slow growth] period, and (b) exploration of the effects of parental prenatal smoke exposure on the anthropometry of the study children, there is much still to be done.

The long-term effects across the generations of active and passive smoke exposure will be assessed for the first time in a human population. This work-package will determine whether there are other outcomes [we have already shown associations with height, fat and lean mass in the next generation to age 17; these observations will be extended in this work-package to age 24]. Candidate outcomes will include factors that have been linked with smoking in a single generation or with prenatal exposure, but not across generations. Possibilities include: markers of the metabolic syndrome such as insulin resistance, reproductive outcomes such as miscarriage and subfertility; myopia; hyperactivity; conduct disorder and criminal behaviour; neurocognitive and motor development.

2. Transgenerational stress studies:

Detailed information was collected from the parents during pregnancy concerning their own backgrounds, including their childhood. Information included traumatic events, such as separation, divorce or death of a parent, physical or emotional abuse and neglect, with a childhood traumatic life event scale of over 40 items. The parents also completed life event scales to cover the first half of pregnancy, and subsequent approximately annual periods for the first 10 years after delivery. In parallel a series of similar questions elicited traumatic events experienced by the study child at approximately annual periods.

The data currently available allow detailed time-related data on traumatic events to the parents and to the child. Ideally, the study would benefit from knowledge of traumas to the generation before. This work package will be used to make detailed enquiries of the parents in regard to the childhood of their own parents. This would particularly enquire about their experience of World War II - where were they, were they evacuated, were they bombed, did they lose family members as a consequence, etc.

Outcome variables that will be considered include neurocognitive development and motor abilities [we have already shown a strong association between maternal stress in mid-childhood and developmental coordination disorder in the child], as well as growth. We will look in particular at differences between the study offspring according to whether the maternal or paternal parents experienced the trauma, the ages at which it occurred, and the sex of the offspring.

B2175 - AN EXPLORATION OF EXPERIENCE AND ENGAGEMENT IN A BIRTH COHORT/ BIOBANK A QUALITATIVE STUDY - 20/02/2014

AIM:

This study aims to investigate the experiences of participation and engagement of current participants in a longitudinal birth cohort/biobank.

B2174 - Assessing disease by self-report in the 2014 ALSPAC children questionnaire mailout - 20/02/2014

Questions to include:

Have you ever been diagnosed with any of the following?

YES BY A DOCTOR YES BY SELF NO NOT SURE

Asthma

Eczema

Psoriasis

Hypertension (high blood pressure)

Heart Attack/Myocardial Infarction

Stroke

Polycystic Ovary Syndrome

Endometriosis

Crohn's Disease

Ulcerative Colitis

Ankylosing Spondylitis

Psoriatic arthritis

Spondyloarthropathy

Rheumatoid Arthritis

Sjogren's Syndrome

Lupus

Grave's Disease

Multiple Sclerosis

Hashimoto's Thyroiditis

Type 1 Diabetes (Juvenile onset diabetes)

Type 2 Diabetes (Adult onset diabetes)

Schizophrenia

Bipolar Disorder

Depression

Chronic Fatigue Syndrome / ME

Any other diseases/medical conditions (please give details):

B2173 - Hypermobility in young adults - 20/02/2014

Aims

Our over-arching objectives are to further study the basic epidemiology of hypermobility in young adults, and to extend our investigation into the relationship between hypermobility, pain and obesity. Our specific aims are:

1. To produce the first population-based data on the change in prevalence of joint hypermobility between aged 14 and 24. Novel epidemiology of joint hypermobility according to anatomical site, gender, socioeconomics and other basics.

2. To further study the association between hypermobility and pain cross-sectionally (both measured at aged 24) and prospectively (hypermobility at aged 14 with pain at aged 24).

3. To extend the investigation into the associations between hypermobility, pain and obesity by using pQCT measures of fat as well as Mendelian Randomisation (we previously only looked at DXA measures of fat)

4. To investigate the associations between hypermobility and additional symptoms including functional bowel disorders, fatigue and other features of autonomic dysfunction.

B2172 - Investigating epidemiological cognitive and genetic mechanisms underlying the development of psychotic experiences - 20/02/2014

Aims of proposal: The aims of this proposal fall within 3 work themes:

Work theme 1: Epidemiology and environmental risk. We aim to investigate the development of psychotic experiences, at-risk mental states and transition to psychotic disorder from childhood through early adulthood, and examine how social adversity and cannabis use affect these outcomes.

The main questions that we will address in Work theme 1 of this proposal are:

i) What is the prevalence and incidence rate of psychotic experiences, high-risk mental states, and psychotic disorder at age 24 years?

ii) What proportion of those with psychotic experiences or high-risk mental states at age 18 persist, remit, or transition to psychotic disorder at age 24?

iii) How do trajectories of psychosis using data from ages 12, 18 and 24, relate to changes in social and occupational functioning over this time period, independently of time-varying confounders?

iv) What is the effect of a) social adversity, indexed by measures of childhood maltreatment, harsh parenting, peer- or sibling-victimization or disturbed peer relationships, and b) cannabis use, and changes in these exposures over time, on incident psychotic experiences?

Work theme 2: Cognitive vulnerability. We aim to examine whether (i) cognitive models of psychosis based on deficits found in patients with schizophrenia in relation to source monitoring, reasoning bias and predictive coding are associated with psychotic experiences in the general population, and (ii) whether social adversity and cannabis use are associated with these deficits.

The main questions that we will address in Work theme 2 of this proposal are:

i) Are deficits in cognitive processes relating to source-monitoring, reasoning bias, and predictive coding in young adults associated with psychotic experiences at this age, and are these symptom-specific (as hypothesised for source-monitoring (hallucinations) and reasoning bias (delusions))?

ii) To what extent are associations between these cognitive processes and psychotic experiences independent of intellectual ability, adolescent depression, and other potential confounders?

iii) Are experiences of social adversity and cannabis use during adolescence associated with deficits in these cognitive processes, and to what extent might these deficits explain associations between these environmental exposures and psychotic experiences in young adults?

Work theme 3: Genetic risk. We aim to examine whether genetic risk for schizophrenia, based on risk score profiling, is associated with deficits in the cognitive processes described above, and explore how genetic risk for schizophrenia is manifest in relation to neurocognitive, psychopathological, and social phenotypes from childhood through to young adulthood.

The main questions that we will address in Work theme 3 of this proposal are:

i) Does schizophrenia liability as indexed by risk score predict:

* source-monitoring, reasoning bias or predictive coding performance?

* neurocognition (processing speed, working memory, and verbal and performance IQ)?

* psychopathology (psychotic experiences, negative symptoms, depression, anxiety, and autism spectrum disorder traits)?

* social-environmental stressors (social adversity and cannabis use)?

* reduced social and occupational functioning?

ii) Do patterns of association between risk score and neurocognition and psychopathology differ by developmental stage (childhood (0-12), adolescence (13-18), and early adulthood (19-24))?

iii) How does risk of psychotic experiences at age 24 vary in relation to risk score and co-exposure to social adversity or cannabis use?

B2171 - Language acquisition amongst children with dyslexic symptoms - 20/02/2014

Aims: To explore whether children exhibiting dyslexic symptoms related to reading difficulties at 9y differ in their language acquisition during the first 3y compared to children with normal reading abilities.

B2170 - Genetic and non-genetic factors for the early perinatal prediction of coronary artery disease in adulthood - 20/02/2014

Aim: To develop and validate a clinical algorithm integrating genetic and non-genetic (clinical characteristics and cardiovascular imaging) factors for the perinatal prediction of coronary artery disease in adulthood.

B2169 - Thermal injuries in childhood and adolescence - a longitudinal analysis - 20/02/2014

The aim is to investigate longitudinal associations between thermal injuries and various demographic, social, familial and individual factors at different ages throughout childhood. Particular attention will be given to developmental and behavioural child-related exposures on burn outcome at various ages. Burn outcome will be divided into 3 age groups, 0-4.5y, 5-8.5 y and 9-11y. Adolescents will be looked at separately (16y).Children with repeated thermal injuries will be analysed separately.

Our 3 main hypotheses are:

1) Childen with poor coordination and higher scores on hyperactivity, conduct problems and general behavioural problems will be more likely to suffer from burns and scalds.

2) Child factors will be more predictive of thermal injuries compared to family and environmental factors.

3) Thermal injury patterns will vary with age and gender and gender trajectories will change with age. We expect boys to be more likely to suffer from burns during the pre-school period whereas girls will be more likely to suffer at school age when they start to help out with ironing, cooking etc.

B2168 - Investigation of the role of habitual exposure to high impact activity in the attainment of peak bone mass - 20/02/2014

Aims/hypotheses

* We will determine whether habitual exposure to high impacts influences peak bone mass (PBM), by investigating whether these impacts explain the relationship between habitual physical activity and PBM as measured by DXA

* We will examine whether effects of high impacts on PBM translate into greater bone strength, by studying relationships between high impacts and cortical bone strength as assessed by pQCT

* We will determine if a critical time exists in bone development when high impacts exert the greatest long term effects on PBM

* We will investigate whether relationships between exposure to high impacts and PBM represent a causal effect, as opposed to common dependence on intrinsic muscle strength (assessed by jumping mechanography), given physical activity affects muscle strength and muscle strength independently affects bone mass

* We aim to identify whether factors which influence PBM act via altered responsiveness to high impact activity

o We will determine whether individuals with low fat mass show weaker relationships between high impact activity and PBM. Whether such a relationship is explained by altered calorie intake will be investigated, along with the contribution of altered eating behaviour

o We will study whether interactions exist between high impact activity, PBM and constitutive factors affecting cortical bone development eg insulin, adiponectin, bone resorption

* What are the other benefits of high impact exercise for musculoskeletal health? We will investigate whether high impact exercise is associated with musculoskeletal pain, or aspects of hip shape implicated in the pathogenesis of osteoarthritis.

B2167 - Perceptual disturbance of body image as an early risk factor for eating disorders - 14/02/2014

Aims:

1. Investigate factors associated with differences between perceived/actual body size (6.5yrs).

2. Investigate whether such discrepancies predict symptoms of anorexia (14 yrs).

B2166 - Association of birth circumstances experience of parental separation of young women with the risk of preterm delivery - 03/04/2014

Preterm birth is the leading cause of childhood disability and infant mortality in the developed world. The rate of preterm birth has been increasing in recent decades for reasons which are poorly understood. The rate of preterm birth is approximately 8% in the UK, 12% in the USA and 20% among African Americans.

The risk of preterm birth is highest for older mothers (greater than 35 years) and teenagers. There is a moderate association with marital status of parents in Europe and the USA, and a somewhat weaker association with poverty.

Witt et al (AJPH 2104) reports, from a US cohort, a high rate of preterm birth to teenage mothers and a four fold increased risk of preterm birth for teenage mothers who had experienced pre-conception stressful life events compared to those who had not.

There is a strong linear correlation for historical rates (up to 1972) of birth to unmarried parents with current rates of preterm birth in US states r greater than 0.65, p=0.000 (cdc data, correlation unpublished).

Goodman and Greaves (IFS 2010) report, from the MCS, a 4x and 3x relative risk of parental separation for cohabiting versus married parents when their children were 3 and 5 years old. Parental separation was a significant adverse influence on cognitive and social development in the children. There are also studies which report associations of family structure with rates of smoking and obesity. These are recognised risk factors for preterm birth.

There is empirical evidence that early life experiences influence the risk of preterm delivery for young mothers. Longitudinal studies could reveal how birth circumstances, including the marital status of parents, influence the likelihood of becoming a teenage mother and how they affect the risk of preterm birth in young mothers.

This information may carry the potential for clinical benefits, such as the identification and support of women with high risk pregnancies, and assist in the development of strategies for the prevention of both teenage pregnancy and preterm birth.

B2165 - The neighbourhood level social and spatial distribution of people with psychotic and affective symptoms at age 18 - 13/02/2014

Aims

This study has five specific aims

1. To describe the prevalence of psychotic and affective symptoms at age 18 years according to neighbourhood-level characteristics at 18-years old, 12-years old, 7 years old and birth using advanced spatial epidemiology

2. To conduct Hierarchical Bayesian Modelling (HBM) to investigate the extent to which psychotic and affective symptoms share a common risk component at the neighbourhood level at each period of the life course

3. To conduct multilevel logistic regression to examine whether duration of exposure to neighbourhood level social disadvantage is associated with the risk of psychotic symptoms at age 18.

4. To examine whether maternal and child-reported perceptions of neighbourhood safety and cohesion are associated with elevated levels of psychotic symptoms, depressive and anxiety symptoms and internalising and externalising disorders in chilhdood

5. To explore the pathways through which exposure to neighbourhood social disadvantage over the life course is associated with psychosis risk, with particularly interest in the mediating role of urban living on the association between individual-level early life adversity, childhood cognitive ability and psychotic symptoms at ages 12 and 18.

B2164 - ALSPAC Epigenomics Strategic Award 2014 - 13/02/2014

Aims

* To enhance ALSPAC to incorporate detailed annotation of epigenomic features and additional epigenomic profiling to provide an internationally leading, widely accessible, population-based reference resource.

To exploit the unique scientific opportunities afforded by ALSPAC to identify epigenetic signatures of exposure, track their persistence over time, across generations and evaluate their relationship with development and disease.

To assess the genetic contribution to DNA methylation variation through leadership of a Genome-Wide Association Study Consortium

To develop a "statistical tool-kit" to facilitate the analysis of population-based epigenetic data

B2163 - Using Mendelian Randomisation to assess causal links between metabolic traits and vascular dysfunction in the young - 13/02/2014

Objectives

Genome-wide association studies (GWAS) have identified genetic variants associated with body mass index (BMI) and blood pressure (BP) in both adults and children (Speliotes 2012, and the International Consortium for Blood Pressure GWAS 2011).

We, at Vascular Physiology Unit, have shown that although greater childhood obesity is associated with adverse metabolic risk factors, there was no evidence of vascular damage by obesity at age 9-11 years in the ALSPAC subjects. Systolic BP was strongly associated with greater adiposity and also increased vascular dysfunction at that age (Charakida 2012). The causal direction and nature of the association between BMI and BP is unclear at this age.

I will investigate the effect of BMI, BP and other metabolic traits on vascular dysfunction ain the young by using a combination of Mendelian randomization and conventional analyses to unravel the complex association between BMI, SBP, metabolic traits and their causal role in vascular dysfunction.

I will be working in collaboration with Kaitlin Wade (PhD student at Bristol) on this project.

B2162 - The role of fathers in the perinatal period positive outcomes and resilience - 13/02/2014

Aims:

In this secondary analysis of the ALSPAC study, we have five aims.

First, we aim to establish what constitutes paternal involvement with the child in the perinatal period. We will be evaluating aspects of the father-infant relationship antenatally, as well as postnatally in terms of attitudes towards parenting, attachment with the child, infant temperament, father's mood and feelings, among others. Second, we will study those aspects of early father involvement that are associated with positive outcomes for the child in terms of scores on the SDQ (*others?). Third, we are interested to know whether the mental health of fathers provides a protective effect to the mental health and wellbeing of the mother. Fourth, we are interested to establish how the quality of the father-mother relationship effects the healthy emotional and behavioural development of the child. Finally, we are looking to identify those early factors involved in positive child outcomes in the father-infant relationship that are amenable to intervention.

B2161 - Applying MR to define risk factors causally related to lung cancer and their potential mediation by DNA methylation - 06/02/2014

Aim:To assess whether the association between modifable risk factors and lung cancer is mediated by DNA methylation.

B2160 - Effects of breastfeeding on childrens cognition the role of DNA methylation - 06/02/2014

Aims: The proposed project aims at investigating the potential mediating role of DNA methylation in the relationship between breastfeeding and children's cognition.

B2159 - Using siblings to understand family process in child behaviour problems - 06/02/2014

Aims:

We propose two linked projects; one addressing sibling, parent-child, and marital interaction quality as predictors of children's strengths and difficulties, and one addressing between- versus within-family risk factors for the development of adolescent antisocial behaviour.

B2158 - Excessive drinking and alcohol related harms in Adulthood ALSPAC at 24 - 06/02/2014

AIMS

We propose repeating the detailed MRI examinations on 125 participants from ALSPAC who were scanned at 18 years as controls for a study of psychotic symptoms (MRC, PLIKS) in order to test the hypothesis that differences in brain structure and dysregulation in function are associated with AU. Thus:-

1. We will compare MR imaging data from their first imaging session (age 18) to the second (age 24) to assess the cumulative impact of drinking alcohol during the intervening years on:

i) brain tissue macrostructure, grey and white matter, using voxel based morphometry (VBM) and cortical thickness measurements

ii) white matter microstructure, including standard diffusion tensor MRI measures (FA, mean diffusivity) and 'hindrance modulated orientational anisotropy', using diffusion MRI (dMRI), and multi-component relaxometry (mcR) to assess putative markers of myelin along specific pathways(52)

iii) activation of prefrontal cortex (PFC) during a task of working memory (n-back).

2. We will investigate whether MR imaging data (VBM, dMRI, mcR, fMRI as above) from the 1st session predicts use of alcohol during the intervening years.

Specifically we hypothesise that compared with those with limited or no drinking, those with greater cumulative alcohol consumption and those predominantly with a binge pattern during the intervening years will show: i) greater reduction in hippocampal, prefrontal, cerebellar volumes; ii) altered WM microstructure in those white matter tracts maturing later (PFC connections eg cingulum, superior longitudinal fasciculus (SLF)) compared with those maturing earlier (eg posterior limb of internal capsule; iii) greater activation during n-back task with unimpaired performance, in their 1st session and when comparing 1st and 2nd sessions.

3. We will investigate the relationship between current and cumulative alcohol consumption with MR imaging data (VBM, dMRI, mcR, fMRI as above) and from ICCAM protocol at the 2nd session, activation of PFC during inhibitory task (go-nogo(53)), activation of ventral striatum during reward task (MIDT(54)), activation of amygdala during stress (stressful images).

B2157 - GWAS on antisocial phenotypes - 06/02/2014

Study aim:

The Broad Antisocial Behavior Consortium has been established to identify genetic variants associated with antisocial behaviours. A series of meta-analyses of genome-wide association data are to be conducted on the following phenotypes: symptom counts of antisocial personality disorder, ratings of aggression, conduct problems, delinquency, and psychopathic personality disorder.

B2156 - Data mining of NMR metabolomics analysis of ALSPAC Child Mother and Fathers samples - 06/02/2014

Aims: To identify association between the available variables and the measured metabolites in order to facilitate hypothesis generation.

B2155 - Lipids heritability in GWAS - 06/02/2014

Aims: The aim of the project is to estimate the heritability of lipids and compare the coverage of this heritability by the main genotyping chips.

B2154 - Hypothesis-free Mendelian Randomisation - 06/02/2014

In genomics there are lots of non-variable base positions, because if a mutation were to occur there it would be deleterious. But of course there are many polymorphic sites that are deleterious too, and a large number that are potentially selectively neutral or functionally neutral.

An old idea for which GWAS data is now providing new evidence is that complex traits follow the infinitesimal model - where an infinite number sites each with an infinitesimally small effect exist. Of course this is not to be taken literally but the point is, is it the case that a very large number of methylation sites influence complex traits, each with a small effect?

B2153 - Evaluating LASER Learning About Safety by Experimenting Risk safety education schemes - 30/01/2014

AIMS

To assess whether children who have undergone LASER training suffered less accident and injury over time than a comparable group of children who had not experienced this training. To investigate two specific hypotheses:

1. If long-term accident rates differ by attendence at a LASER risk training intervention?

2. If long-term use of safety precaution measures differ by attendence at a LASER risk training intervention?

B2152 - Investigating the metabolic adiposity and growth phenotypes of variants in the CCND2 gene at birth and childhood - 30/01/2014

Further investigation offers the chance to understand the role of this allele in diabetes and growth. All the Decode findings reported were in adults. We now wish to use ALSPAC to investigate the following hypotheses:

1. the minor allele increases birthweight, BMI, weight and height in children, from birth throughout growth and maturity. We propose to examine all cross sectional time points , from birth to teenage years (the latest measurements), and if the data look positive, growth trajectories.

2. the association with BMI is driven by adiposity. We propose to examine DEXA derived measures of fat mass and lean mass at age 9 (as we did with FTO, ref Science 2007) and any other available ages

3. the minor allele when present in the mother increases growth in children (BMI, weight and height) . We propose to test the maternal allele's effect on offspring measures , correcting and stratifying by offspring genotype.

4. Exploratory analysis of glycaemic and adipokine measures - fasting glucose, and insulin, adiponectin, leptin and FFAs.

B2151 - Epigenome wide association study of BMI - replication of 278 identified markers using methylation data from ARIES - 30/01/2014

Proposal for Replication:

The 278 CpG markers associated with BMI at p[GCout]less than 10-7 in the primary analysis will be taken forward to the replication stage to be analysed or looked up in a set of independent replication cohorts. We propose undertaking this replication using methylation data on the ALSPAC mothers involved in the ARIES project.

B2150 - Elucidating phenotype effects of genetic markers associated with ankylosing spondylitis in adolescents - 30/01/2014

AIMS:

Specifically the primary objectives of this study are:

1) To determine if known genetic variants of Ankylosing Spondylitis (36 SNPs in total including SNP tagging HLA-B27 rs4349859) are associated with low back pain in adolescents aged 17 to 18 years in the population based birth cohort, ALSPAC.

2) To determine if a genetic risk score of the above variants is associated with low back pain in these adolescents at age 17 to 18 years.

3) To determine if known AS genetic variants (36 SNPs in total including SNP tagging HLA-B27 rs4349859) and/or the AS genetic risk score are associated with any of 216 metabolonomic variables, CRP and IL6.

B2149 - The lifecourse of the auditory system - 13/02/2014

Aims

1. Characterise the hearing of the cohort from the ages 7 to 14

2. Explore the associations of a range of exposures (physiological, environmental, genetic and epigenetic) with hearing at age 7 to 14

3. Directly assess the hearing of the ALSPAC cohort at age 24

4. Characterise the changes in hearing from age 7 to 24

5. Explore the association of a range of exposures (physiological, environmental, genetic and epigenetic) with the changes in hearing

6. Examine the impact of hearing loss at age 24 on educational outcomes & employment

7. Examine the association of hearing at age 24 with co-morbidities such as visual impairment, mental health, cognitive abilities and precusors to CVD.

B2147 - Prevalence and correlates of tongue ties in ALSPAC - 24/01/2014

Aims: To estimate the prevalence and correlates of tongue-ties in neonates in ALSPAC.

B2146 - Epigenetic variations of miRNAs are associated with hepatocellular carcinoma cancer susceptibility - 27/01/2014

The objective of this project will be to identify DNA methylation differences inmiRNAsin apparently normal cells, which may increase the individual's likelihood of subsequently developinghepatocellular carcinoma. Identification of such links might provide a plausible biological mechanism by which life exposures could increaseHCCrisk and provide a rational basis for future dietary/environmental interventions aimed at reducing the development of abnormal DNA methylation and thus reducing the risk ofHCC.

B2145 - Impacts of early life residential mobility on BMI growth trajectories in adolescence and early adulthood - 16/01/2014

Aims: The aim of this project is to run growth trajectory analysis to examine the relationship between residential mobility and BMI/fat mass throughout childhood and adolescence. Growth trajectory analysis will permit differences in BMI/fat mass trajectories from key stages in life to be calculated, to examine critical periods of risk such as during schooling years (pre-school, primary, secondary).

B2144 - Studying the Population Prevalence of Large Mosaic Chromosomal Rearrangements in Children - 23/01/2014

Aims:

We propose to collaborate with ALSPAC to compare the prevalence of large (1 Mb or larger) mosaic deletions, duplications and loss of heterozygosity events between the ALSPAC population sample and children in our congenital disease project, The Deciphering Developmental Disorders (DDD) Study.

B2143 - Statistical methodology for population genetics inference from massive datasets with applications in epidemiology - 16/01/2014

Aims

To develop new methodology for epidemiological datasets, with a particular emphasis on handling massive amount of sequence data. Specifically, we will detect and account for genetic structure in the form of known familial relationships, distant relatives, and population stratification. We will develop methodology to correctly use rare variant information in Association studies to determine the causes of disease from such datasets. Further, we will improve the use of genetic instruments in mendelian randomization studies by extending the developed methods to an instrumental variable context.

B2142 - The relationship between pain and attention in childhood - 16/01/2014

Aim: To investigate the relationship between attention and pain in childhood.

Background: There is growing evidence of a link between pain and attention. Several studies have demonstrated that being in pain consumes our attention and reduces our effectiveness on current tasks (Moore, Keogh & Eccleston, 2012, 2013). Those with better attentional resources may also be better served by distractions from pain (Legrain, Van Damme, Eccleston, Davis, Seminowicz & Crombes, 2009; Verhoeven, Dick, Eccleston, Goubert & Crombez, 2012). In another strain of research, there is evidence that childhood intelligence, a concept closely related to attention, is related to various health outcomes such as life span (Whalley & Deary, 2001), late-onset dementia (Whalley et al, 2000), cardiovascular disease (Hart et al, 2004) and psychiatric disorders (Batty, Mortensen & Osler, 2005). The proposed research will extend and bridge these two areas of literature on cognition and health by investigating the relationship of chronic pain to intelligence and attention. This will extend our understanding of the relationship between a) childhood attention and experiences of pain and more broadly b) childhood intelligence and health outcomes.

B2141 - GWAS of fetal genome with hypertensive disorder of pregnancy - 16/01/2014

GWAS require large sample sizes and collaborative efforts. Identifying the maternal and fetal genetic contributions to pre-eclampsia is important for understanding the mechanisms causing this condition.

ALSPAC has already contributed to the GWAS of maternal genotype to hypertensive disorder of pregnancy with the same collaborative group proposing to look at fetal (offspring) genotype with this outcome. That project was done as part of B0757 (WT grant that funded maternal GWAS and had the aim to explore the relationship of maternal genotype to her phenotype in pregnancy and equivalent phenotypes postnatally). Phenotypic data was prepare by DA Lawlor and the GWAS completed by J Kemp. The collaboration is still on-going with a publication likely to be submitted Spring/Summer 2014.

We now wish to build on the existing collaboration and expertise to explore fetal genotype in relation to pre-eclampsia and the broader defined hypertensive disorder of pregnancy (HDP) and would like ALSPAC to contribute to that effort. The necessary offspring genome wide data and phenotypic data are available in ALSPAC.

The phenotype dataset, including with restrictions required for the collaboration analysis plan (e.g. singleton pregnancies, no previous hypertension, etc.) has already been prepared by DA Lawlor as it is the same as that used for the mother's GWAS.

GWAS analyses will be conducted by Kaitlin Wade, Phd student who already has experience of completing GWAS analyses with ALSPAC data, will complete the GWAS analyses according to the analysis plan. Her main PhD supervisor (Nic Timpson) has agreed her role on this project. DA Lawlor will provide the phenotypic dataset. All analyses will be conducted at the SSCM, University of Bristol and there is no need for involvement of a data buddy or material transfer agreement.

B2140 - Understanding participation and non-participation in HE for white working class and minority ethnic groups BIS - 09/01/2014

A full proposal will be drawn up by the successful contractors appointed by BIS to undertake this project but the principal aims are:

1) To examine potential gaps in in the current understanding of why these groups are less likely to progress to HE and test hypotheses using the ALSPAC dataset linked to NPD.

2) Qualitative interviews with groups of interest, in particular to establish what individuals felt were the barriers to higher education for them personally, and for those who made the successful transition what they felt were the factors contributing to HE participation.

B2139 - A GENOMIC CONSORTIUM OF PSYCHOTIC EXPERIENCES IN ADOLESCENTS AND YOUNG ADULTS - 10/01/2014

Aims

The aims of this study are as follows:

1. To conduct a meta- and mega-analysis genome-wide association study of psychotic experiences in adolescents and young adults by combining data from multiple samples including ALSPAC. Further analyses will investigate the effects by chromosome location and variant class, and explore gene-gene and gene-environment interactions in the combined datasets.

2. To test whether genes influencing risk for adult psychiatric conditions such as schizophrenia and bipolar disorder and major depression (using polygenic risk scores) are shared with those for psychotic experiences in adolescence and young adulthood in a dataset of the combined samples including ALSPAC.

3. To conduct genome-wide complex trait analyses (GCTA) of psychotic experiences in adolescents and young adults in the combined dataset in order to estimate the measured heritability of these trait experiences.

B2138 - Psychopathology in parents of children with Copy Number Variants - a comparison with population-based rates - 09/01/2014

AIM OF THE PROJECT

To examine in already collected high-quality data the prevalence and severity of psychopathology in parents of children with Copy Number Variants by comparing them to population-based rates provided by the ALSPAC birth cohort.

B2137 - Retinal Microvascular Architecture Blood Pressure and Cardiac Structure in Adolescence - 09/01/2014

Adiposity and blood pressure have been associated with derangements in cardiac structure and the retinal microvascular architecture in both adults and children. These derangements in adults including left ventricular (LV) hypertrophy (a consequence of increased left ventricular mass) and retinal diameters are associated with an increased risk of myocardial infarction and cardiovascular disease (CDV) mortality. To further our understanding of these associations, the link between the microvasculature and cardiac structure and to tease out the separate and synergistic impact of CVD risk factors, studies need to be undertaken in children and young adults assessing both the microvasculature and cardiac structure, before the disease process is established.

The measures of cardiac structure (left atrial size (LA size), relative wall thickness (RWT) and posterior wall thickness (PWT)) and the retinal microvasculature, provide surrogate measures of CVD which can be assessed non-invasively, are highly reproducible and track through childhood and early adulthood. The identification of a strong link between the microvasculature and measures of cardiac structure could potentially allow further risk stratification to identify sub groups at increased risk of coronary heart disease (CHD), who would not normally be identified by assessment of traditional risk factors. To date these studies have only been undertaken in adults and the results have been varied, a likely consequence of assessing populations with advanced disease, where confounding is difficult to fully adjust for. The Avon Longitudinal Study of Parents and Children (ALSPAC) has followed a cohort of 14,541 children from birth to late adolescence, with measures of adiposity, blood pressure, retinal microvascular architecture and cardiac structure. The ALSPAC study provides the ideal setting to further our understanding of the link between the microvasculature and cardiac structure.

Hypothesis: We hypothesised that retinal microvascular measures (potential predictors) would be associated with derangements in cardiac structure (outcome), independent of cardiovascular risk factors and body mass index (BMI) in adolescence.

Variables: The current study would include all children with cardiac images and ambulatory blood pressure acquired at the 17 year clinic and retinal images acquired at the 11+ year clinic. Other measures to be included in the analsyis are: Gestation, age, mother smoking during pregnancy, mother drank during pregnancy, BMI 17 year clinic, systolic and diastolic BP at the 17 year clinic, sex, paternal SES, height 17 year clinic, pubertal stage at measurement. With the exeption on the ambulatory BP data at the 17 year clinic I have all of the data required for the analysis.

The associations between retinal diameters (potential predictors) and cardiac measures (outcomes) will be modelled using multiple linear regression. The associations between retinal diameters and cardiac measures will be presented unadjusted, a second model including retinal diameter (separately for each retinal vascular measure) gestation and sex, and potential confounding factors (paternal SES, maternal smoking during 1st three months pregnancy, pubertal stage at measurement outcome and height and height2). A third model will include potential mediating factors BMI and systolic BP at age 17 years.

B2136 - Noise and Air Pollution effects on childrens cognition health and wellbeing in the ALSPAC cohort The NAPA Study - 09/01/2014

AIM - This four year study will examine longitudinal associations of road traffic noise exposure and air pollution on the development of children's cognition, cardiovascular health and psychological wellbeing in the ALSPAC (Avon Longitudinal Study of Parents and Children) cohort. This study will model environmental exposure relating to noise and air pollution in the home and school environments in the ALSPAC databases using established, validated modelling methods, for different time-points across childhood (prenatal, preschool, childhood, adolescent). This environmental exposure modelling will enable the examination of longitudinal associations and critical periods for noise exposure and air pollution effects on children's cognition, health, and wellbeing to be examined. The influence of environmental noise and air pollution on the developmental trajectories for these outcomes will also be examined.

B2135 - Genetic association study of endophenotypes related to autism spectrum conditions - 17/04/2014

Aim:

The role of common variants in ASC and related endophenotypes can be investigated using genetic association studies. While candidate gene association studies have identified a few variants that have been replicated, the majority of GWAS results have not been replicated (Berg and Geschwind 2012). Possible reasons for the failure of GWAS studies could be: 1) the high clinical and genetic heterogeneity underlying ASC; 2) the need for much larger sample sizes than previously thought; 3) The effect sizes of a single common variant is much smaller than previously thought, suggesting multiple epistasis. One solution to these problems is to test for genetic associations for underlying endophenotypes. Many of the underlying endophenotypes such as attention to detail, systemizing ability and empathy are quantitative traits present in the general population. Individuals with ASC are usually present at one end of the curve of these traits. Understanding which genetic variants, and by extension, which genetic and biological networks contribute to these traits will help us understand, in part, the variants that contribute to ASC. Due to the complex nature of these endophenotypes, a model-free GWAS would be the best approach to understand these traits. These studies must be sufficiently powered and must include a replication sample in order to be reliable. We have a number of different online psychological tests of empathy, attention to detail, systemizing, mathematical ability, and synaesthesia that are sensitive to individual differences in the general population and that are related to the autism phenotype. Many of them have a genetic component and are polygenic. We are interested in identifying the genes that show association with these traits.

B2134 - Sexual physical and emotional abuse and cardiometabolic and reproductive health in middle age - 09/01/2014

Specific aims are:

1. To study associations of abuse in childhood including sexual, parental physical and emotional abuse with cardiometabolic health in middle age (Framingham CVD risk score, atherosclerosis (cIMT, arterial distensibility), pulse wave velocity, adiposity, blood pressure, lipids, insulin, glucose, inflammatory markers).

2. To study associations of abuse in childhood including sexual, parental physical and emotional abuse with women's reproductive health across the lifecourse (age at menarche, menstrual regularity, time to conception, seeing a physician for possible infertility, pregnancy outcomes: pregnancy losses, preterm delivery, mode of delivery, birth weight, parity, age at menopause).

3. To describe longitudinal patterns of intimate partner physical and emotional cruelty throughout the life course, and of physical and emotional abuse of offspring, in men and women.

4. To compare maternal and paternal reports of IPV.

5. To examine patterns of IPV across two generations in the same families.

6. To examine associations of longitudinal patterns of intimate partner physical and emotional cruelty with cardiometabolic (men and women) and reproductive health (women).

7. To examine whether any associations identified in aims 1, 2 and 6 are mediated by established cardiometabolic risk factors such as smoking, alcohol consumption, eating disorders, adiposity, and mental health.

8. To examine whether any associations identified in aims 1, 2 and 6 are mediated by differential DNA methylation.

B2133 - The long-term effects of antidepressant medication exposure during pregnancy on child development - 09/01/2014

Aim

To investigate the long-term effects of prenatal exposure to antidepressant medication on child cognitive and behavioural development compared to the effects of untreated maternal depression.

B2132 - Childhood dietary patterns obtained using cluster analysis and risk factors for CVD in ALSPAC - 09/01/2014

Foods are generally consumed in combination; therefore dietary recommendations should consider diet as a whole, rather than individual foods or nutrients. We know that dietary intake throughout the life course is involved in the development of lifestyle diseases, including cardiovascular disease (CVD) and obesity which are currently endemic in the UK. This project aims to provide an insight into nutritional life course exposures and the potential of these exposures to affect markers of CVD.

Studies have previously linked childhood obesity with CVD in adulthood (Lloyd et al., 2010) and therefore asfood behaviours established in childhood/adolescence may ultimately go on to affect adult cardiovascular health it is important to adopt a healthy lifestyle early in life in order to decrease later disease risk. Observing dietary patterns throughout the life course should be beneficial in calculating the time point at which nutritional intake may be most important and also whether tracking one type of dietary pattern over a period of time or changing to a different diet pattern renders an individual more/less likely to be at risk of disease. Dietary patterns are primarily derived via two statistical methods: cluster analysis (CA) and principal component analysis (PCA). Both of these methods have been found to give similar results in the ALSPAC study at 7 years of age (Smith et al., 2011).

Tracking over time is easier to quantify for patterns that have been derived using cluster analysis as this method assigns an individual to one category only at each timepoint. Change in category can then easily be determined. In comparison, PCA results in a score for each individual for each pattern obtained. We will therefore examined patterns obtained from CA in the first instance.Four clusters have been observed in ALSPAC using food diary data at 7, 10 and 13 years of age (Northstone et al., 2013). We will use this information to investigate whether dietary patterns and their tracking have any implication upon known risk factors for CVD (fat mass, blood pressure, CIMT and blood lipids) observed in the cohort at 15 and 17 years of age. Socioeconomic status is a major confounder for dietary intake (Northstone et al., 2012 & 2005). It is hypothesised that there will be a correlation between dietary patterns and measured risk factors for CVD, such that a more healthy pattern will infer decreased risk and that any associations may strengthen with pattern tracking (e.g. where an individual is consistently assigned to the same pattern over time).

B2130 - 2D4D digit ratio and autistic traits - 19/12/2013

Please note: This is a mini-project that Anna Guyatt (Wellcome 4 year phd student) and Bernice Knight (clinical lecturer) will be working on. DR has direct access and will liaise with Kate Northstone to anonymise the IDs (this has already been discussed with Kate).

Background and Aims: Autism spectrum disorders and associated traits are over-represented in males. A popular hypothesis to explain this gender bias is the 'extreme male brain' theory (EMB), which is an extension of the empathising-systemising theory of sex differences in cognitive styles (Baron-Cohen 2002; Baron- Cohen and Hammer 1997). It suggests that male brains are hardwired for the drive to understand and construct systems based on if-then rules (i.e., systemize) while the female brain is programmed for the drive to understand the mental state of others and experience appropriate reactions (i.e., empathizing). The EMB hypothesis suggests that beyond the biological sex, higher levels of fetal testosterone underlies the male brain (Auyeung and Baron-Cohen 2008). Baron-Cohen has suggested that the deficits observed in autism of extreme systemising and less empathising may suggest that higher exposure to testosterone during fetal life may be aetiologically linked to autistic traits. The ratio of the index finger (2nd digit) to the ring finger (4th digit), commonly referred to as 2D:4D is a commonly used putative marker of fetal testosterone relative to fetal estrogen activity. Although a number of studies have tried to test the relationship between 2D:4D and autism/traits, the samples have been relatively small and selected; and the results are inconclusive. There is a lack of population based studies.To address this gap in the literature, we aim to study the association between 2D:4D and autism and its component traits, testing the extreme male brain hypothesis.

B2129 - Early life adversity and cardiometabolic health and cognitive function in mid-life - 19/12/2013

Aim 1. To determine the relationship between early life adversity and cardiometabolic health and cognitive function in mid-life.

Study design: We will estimate the association between each of several measures of early life adversity (SEP measured by parental education and occupation; major life events such as parental divorce, death or illness; parental mental health and addiction; warmth, affection and satisfaction with parent-child relationships; perception of happiness of childhood; parental physical or emotional cruelty; sexual abuse; mobility of family indexed by number of schools attended) and 1) trajectories of cardiometabolic health in the ALSPAC mothers or 2) the single measures of cardiometabolic health in the ALSPAC fathers. In both the ALSPAC mothers and their partners, we will also assess the extent of clustering of dimensions of early life adversity, and whether these dimensions have effects on health that are greater or less than would be predicted from their independent associations.

Aim 2. To clarify the role of adult adversity in the association between early life adversity and cardiometabolic health and cognitive function in mid-life.

Study design: We will determine the extent to which social mobility (change in SEP between early life and adulthood), adult relationships, social support and neighbourhood factors mediate or modify the association between early life adversity and trajectories of cardiometabolic health and cognitive function. Within ALSPAC, we will examine male-female differences in the health consequences of early life adversity, using data from male-female partners (using couples who have been together throughout the period of the ALSPAC cohort, as identified by Yoav Ben-Schlomo and Alison Teyhan); these couples are matched at least partially for adult SEP and other life circumstances, but not necessarily for early life adversity.

Aim 3. To examine which factors mitigate or exacerbate the association between early life adversity and cardiometabolic health and cognitive function in mid-life.

Study design: We will examine the roles of trajectories of smoking, alcohol use, depression, and of DNA methylation as mediators or moderators of the association between early life adversity and cardiometabolic health/cognitive function.

B2128 - The impact of iodine perchlorate and thiocyanate status on childhood cognitive and thyroid function - 01/05/2014

Aims

We therefore propose to i) study the impact of iodine, perchlorate and thiocyanate (another iodine-thyroid disruptor) levels on adolescent thyroid function and IQ using the 882 ALSPAC children who have urine samples available from age 15 who also have had thyroid function measured and their IQ assessed. ii) We also propose to measure perchlorate and thiocyanate in the ALSPAC mums from urine taken during the first trimester, to see if they impact on offspring neuro-cognitive development at age 8 and childhood thyroid function age 7. We are proposing to measure these in the 2,300 women who have iodine measured already (or imminently) by the Rayman group. This has already been discussed with Margaret Rayman and Sarah Bath and we will proceed with a formal collaboration if this study is approved.

B2127 - Maternal mental health and infant development at one year association with breastfeeding - 19/12/2013

Aims:

1) To investigate whether attitudes towards breastfeeding and intention to breastfeed (at 32 weeks gestation) are related to maternal mental health during pregnancy (at age 18 and 32 weeks gestation).

2) To investigate whether antenatal attitudes towards breastfeeding are related to the amount of breastfeeding postnatally.

3) To investigate whether postnatal mental health (8 weeks postnatal) is related to the amount of breastfeeding.

4) To analyse whether type of infant feeding, independent of maternal mental health (prenatal and postnatal) is associated with child development (cognitive, behavioural and emotional) at 1 year, allowing for a range of confounders (SES, prenatal smoking, prenatal alcohol, BW, GA, infant growth, family support, parent's education).

5) To investigate to what extent breastfeeding may contribute to cognitive and emotional child development after allowing for a range of confounders (SES, maternal mood, infant growth, family support, parent's education).

B2126 - Nutrition and conduct problems The role of environmental risks and DNA methylation - 19/12/2013

Aim 1. Does poor prenatal nutrition (i.e., macronutrients, micronutrients and/or omega 3 fatty acids) impact with DNA methylation at birth, and does continued poor nutrition impact DNA methylation in childhood?

Aim 2. Is the relationship between prenatal poor nutrition and early onset conduct problems greater for those children whose mothers were stressed and depressed?

Aim 3. Is the relationship between nutrition, the key risk factors and an early onset of conduct problems partially explained by DNA methylation?

Aim 4. Use of whole genome-wide epigenetic approaches to identify developmental inter-relationships beween maternal depression and unhealthy nutrition in the prenatal and postnatal periods.

Aim 5. Use of conventional Mendelian Randomization to assess causal relationships between nutrition factors (prenatal and postnatal) and the early onset of conduct problems.

B2125 - Is maternal perinatal depression associated with psychotic-like symptoms PLIKS in late adolescence - 12/12/2013

Background

There is some evidence to suggest that adverse perinatal maternal life events are related to an increased risk of psychosis in offspring. There is, however, limited evidence linking maternal perinatal depression with future risk of psychosis in offspring. The only three studies identified investigate the same birth cohort and yield unclear results (Maki, Riekki et al., Jones et al., Maki et al.). In addition, maternal depression was not assessed using any standardised measure.

Maternal perinatal depression may influence the risk of psychosis in offspring via an effect on foetal development in utero as well as by exerting an environmental influence during infancy. Schizophrenia is considered to be a neurodevelopmental disorder and if there were an association between maternal perinatal depression and schizophrenia it would support a neurodevelopmental perspective.

Investigation of this possible association is important due to the relatively frequent occurrence of perinatal depression and the potential for intervention. Adolescents who report psychotic experiences may be at increased risk of developing a psychotic disorder therefore study of this group may yield important information regarding early life risk factors for psychotic disorders.

Maternal cognitive style is thought to be associated with depression in adolescent offspring. Such cogntive styles may also be related to offspring psychotic experiences and would again offer a potential target for intervention in those at hgh risk of psychotic disorder.

Objective

The primary objective of this study is to establish whether there is an association between maternal perinatal depression and the development of psychotic experience in their offspring during late adolescence.

Hypothesis

Our hypothesis is that maternal perinatal depression is associated with an increased of psychotic experiences in offspring in late adolescence.

Maternal perinatal depression may influence risk of psychosis in offspring through a number of interlinked mechanisms acting both during the intra-uterine period and during early childhood. In order to explore the mechanisms the association between paternal perinatal depression and adolescent psychotic experience will also be explored.

B2124 - Genetic predictors of attrition - 05/12/2013

Aim: The aim of this study was to determine whether genetic risk from common genetic risk variants for schizophrenia and ADHD, based on large, case-control genome-wide association studies could predict non-return of questionnaire data by children and parents, as well as non-attendance at clinic for data collection.

B2123 - Gender differences in parent-reported child health - 05/12/2013

Aims

To examine gender differences in carer reported child health from ages 5 to 16 (age range varies depending on item).

B2122 - Identification of genetic risk factors and assessing causality of modifiable exposures in adolescent depression - 05/12/2013

Objectives:

1) To detect genetic variants reliably associated with depression in adolescents via genome-wide association approaches in the ALSPAC and TEDS cohorts

2) To identify observational associations between depression and modifiable risk factors using the Mendelian randomization approach

3) To investigate the association between depression and patterns in DNA methylation

Given the paucity of significant findings concerning depression, our first aim will be to investigate the genetic architecture of, and potentially identify genetic variants reliably associated with, depression in adolescents via a combination of genome-wide approaches within both the ALSPAC and TEDS cohorts.

The second aim will be to use genetic instruments to investigate causality in associations between modifiable or environmental risk factors and depression. First, literature searches will be used to identify important observational or proposed environmental exposures for depression. Several of these, such as vitamin D, glycaemic traits, inflammation and physical activity, are available in ALSPAC. Observational associations will be calculated and, for those modifiable risk factors with suitable genetic instruments, MR will be applied to determine whether the association is causal. The ARIES data will be used to investigate associations between exposure to maternal depression and patterns of methylation throughout early development. In particular, we aim to investigate whether early life stress events, such as antenatal and postnatal depression, have an effect on methylation patterns in the offspring. Independent associations between adolescent depression and both antenatal and postnatal depression have previously been shown, which appear to involve different mechanisms. We propose to explore whether this is mediated through DNA methylation.

B2121 - Aid SAM project Antibiotics influence on obesity and cardio-metabolic disease - Sustainability of healthy Microbiome - 05/12/2013

Aim:

The Aid SAM project will examine associations between specific antibiotic treatments given to mothers during pregnancy (and lactation) and overweight/obesity in childhood as well as specific antibiotics given to children during early infancy (0-6 months) and overweight/obesity in childhood and later life. The three main cohorts we will use to investigate this is the Danish National Birth Cohort (DNBC), the Nothern Finland Birth Cohort (NFBC) and the Alspac cohort. Furthermore, an adult Danish population will be used to identify possible associations between antibiotics and CVD in adults through a data-driven approach. This approach may further help to identify the most interesting subtypes and combinations of antibiotics. The plan is to start of with analyses in the DNBC and then replicate analyses/interesting findings in the NFBC and ALSPAC. This approach gives more power to findings, which otherwise could be surpressed by/if multiple testing correction are applied. Findings will be dissiminated either in one or several publications, with possibility of back to back publication. The main applicant will perform analyses, but possible data-driven analyses will be performed by AB Jensen, bio-informatitician from Soren Brunaks Group. In addition other collaborators from Bristol in addition to George D Smith could come into play

B2120 - Investigation of parent of origin effects in relation to DNA methylation - 05/12/2013

Aim:

1) identify novel parent of origin variants in relation to DNA methylation in ALSPAC;

2) investigate the effects of known/established parent of origin variants (related to common disease) in relation to DNA methylation in ALSPAC;

3) Investigate the relationship between genotype, methylation and phenotype to better understand parent-of-origin effects on phenotype.

B2119 - Investigation of white blood cell counts/proportions in relation to DNA methylation - 05/12/2013

Aim:

Investigate the potential associations between established WCC genetic variants in relation to white blood cell counts/phenotypes and DNA methylation within ALSPAC.

B2118 - Use of ALSPAC to inform key questions for multiple therapeutic areas - 28/11/2013

Aims

This project aims to generate valuable information to prioritize obesity targets and will include:

a)Replication of genetic association with obesity related traits

b)Analysis of associations with lifestyle/biomarker/diet to generate mechanistic hypotheses.

B2117 - Investigating the causal effect of maternal obesity on pregnancy outcomes using Mendelian Randomization in ALSPAC - 28/11/2013

Aims

To perform Mendelian randomization analyses to investigate the causal effect of maternal pre-pregnancy BMI on a number of pregnancy outcomes using genetic variants combined in a weighted allelic score. Other related exposures including maternal waist-hip ratio, maternal glycaemia and fatty acid profile will also be considered in an Mendelian randomization framework.

B2116 - In utero exposure to heavy metals effects on child development - 28/11/2013

AIMS AND OBJECTIVES

The overall aims of the study are: (1) to identify the predictors of Pb, Cd and Hg levels in pregnancy with a view to providing advice and interventions that will minimise exposure at this vulnerable time; (2) to identify the predictive value of maternal levels in a variety of childhood outcomes up to the age of age 18 years. This will include a study of the effects of maternal genetics and epigenetics in modifying these relationships. All analyses will involves initial work in identifying and taking into account relevant confounders to determine the features of the mothers' backgrounds that are related to exposure to Pb, Cd or Hg exposure (e.g. age, educational levels, occupational exposure, smoking history, exposure to passive smoking, dietary components, etc.). Results will be presented as odds ratios or effect sizes with confidence intervals, and in unadjusted and adjusted models if appropriate. The complex causal analyses will be undertaken in consultation with Professor George Davey Smith (Professor of Clinical Epidemiology, University of Bristol).

B2115 - Negative outcome control study of breast feeding - 28/11/2013

I am currently writing a book chapter and paper about different causal methods and using breast feeding with different outcomes as an illustrative example (largely using published work, including some publications that have used ALSPAC data). I would like to include as an e.g. a negative outcome control study i.e. a study in which I would look at the association of breast feeding with an outcome that biologically it would not be expected to affect (but might be associated with via confounding).

ALSPAC has questions on whether the family home had ever been invaded by rats, dogs, cats, mice, cockroaches, pigeons, woodlice etc. (see picture attached with this email) which would be ideal as negative controls.

In both the book chapter and paper these analyses would be a small part of the whole document

I would look at the simple association of breast feeding with one or more of the 'animal/insect home invasion' responses - depending on how common they are in the cohort.

B2114 - The role of environment and executive function in the social patterning of health-related behaviours - 28/11/2013

Aim:

To assess the extent to which effects of environment on health-related behaviour are attenuated by executive function. In particular, to assess whether high executive function (in particular, response inhibition) negates the impact of exposure to environments that are more likely to promote less healthy choices.

Four health-related behaviours - diet, physical activity, smoking and alcohol consumption - will be explored, using measures taken between the ages of 10 and 15.

B2113 - Maternal pre-eclampsia and bone mineral density of the adult offspring - 28/11/2013

Aim: To assess bone mineral density (BMD) and bone mineral content (BMC) of offspring born from a preeclamptic pregnancy.

Hypothesis: We hypothesise, based on the limited available evidence on this topic, that offspring who were 'exposed' to preeclampsia will have a higher bone mineral density than those who were not exposed.

Exposure variables: Preeclampsia and gestational hypertension

Outcome variables: Bone mineral density and content (as measured by DXA and pQCT)

Confounding/mediator variables: SES, maternal smoking, maternal BMI, maternal ethnicity, maternal age, maternal alcohol consumption, maternal physical activity, maternal vitamin D & Calcium intake, offspring weight/height, offspring total body fat mass/lean mass, CTX, Insulin, parity, birthweight, gestational age.

Summary:

Preeclampsia is the leading cause of perinatal and maternal mortality and morbiditiy and effects around 3% of all pregnancies worldwide. The only current cure is the delivery of the placenta and thus often results in an iatrogenic preterm delivery. The fetus has the greatest demand for calcium during the third trimester, so consequently a preterm delivery can result in insufficient bone mineralization (Weiler et al. 2002). A recent study has suggested that in pregnancies compliated by preeclampsia additional mechanisms may exist which result in protective effects on long term bone health in the offspring, both in preterm and term births (Miettola et al. 2013). However, this study was limited by a small sample size and no maternal lifestyle information. This study warrants replicating with larger numbers and more comprehensive confounder adjustment.

We hope to use the ALSPAC data to explore the association between preeclampsia (and gestational hypertension) in term and preterm births with bone parameters from recently collected DXA and pQCT scan data.

References

Miettola S, Hovi P, Andersson S et al. Maternal preeclampsia and bone mineral density of the adult offspring. Obstetrics. Am J Obstet Gynecol 2013;20:443.e1-10

Weiler HA, Yuen CK, Seshia MM. Growth and bone mineralization of young adults weighing less than 1500g at birth. Early Hum Dev. 2001; 67: 101-12

B2112 - Exploring the fetal insulin hypothesis in ALSPAC - 28/11/2013

Aims

1) To investigate associations between offspring birthweight and offspring fasting glucose/insulin at birth, age 8.5 years, 15 years and 17 years.

2) To investigate associations between offspring birthweight allele score (known variants and genome wide prediction), birthweight and offspring fasting glucose/insulin

3) To investigate associations between offspring birthweight allele score (known variants and genome wide prediction), birthweight and offspring fasting glucose/insulin - with adjustment for maternal genotype to remove negative confounding.

4) To investigate associations between maternal birthweight and maternal fasting glucose/insulin in FOM1 clinic

5) To investigate associations between maternal birthweight allele score, birthweight and maternal fasting glucose/insulin

6) To investigate associations between offspring glucose/insulin allele score and offspring birthweight

7) To investigate the timing of effect of individual glucose/insulin variants

8) Bivariate GCTA of offspring birthweight and offspring glucose/insulin.

B2111 - Identification of patterns of methylation associated with age at menarche - 28/11/2013

Aims:

1) To identify differentially methylated regions (DMRs) that are associated with age at menarche. This will be tested in both ALSPAC mothers using recalled age at menarche, and in young participants using DNA methylation measured at 15-17 years and age at menarche reported at the 21/22 year visit.

2) To explore whether identified DMRs are already apparent at birth, or if they are established over the course of childhood and adolescence.

3) To understand how common genetic variation underlies differences in methylation relating to menarche timing.

B2110 - DIETARY PATTERNS IN PREGNANCY AND OFFSPRING GROWTH OUTCOMES A MULTI-COUNTRY ANALYSIS OF BIRTH COHORTS - 28/11/2013

Aims:

1) Characterise dietary patterns in pregnancy using data from English and Danish birth cohorts.

2) Compare dietary patterns between pregnant women living in England and Denmark.

3) Examine the relationship between maternal dietary patterns in pregnancy and size at birth.

4) Examine the relationship between maternal dietary patterns in pregnancy and offspring growth at year 7, 1 and 6 months.

5) Assess the relationship of change in maternal dietary patterns and childhood adiposity measures.

B2109 - Depression at 17 THEME 3 CONTINUITIES AND DISCONTINUITIES - Depression and Fatigue part of previous Wellcome Trust application - 14/11/2013

Adolescent depression is highly comorbid with other disorders, including persistent fatigue or chronic fatigue syndrome. Teenage years are a key period of change and provide an opportunity to look at the continuities and discontinuities of psychopathology from a developmental perspective. Heterotypic continuities could arrise in a variety of ways: because the two disorders share common or correlated risk factors (genetic or environmental); because one disorder contributes, directly or indirectly, to risk for the other; or because the joint pattern constitutes a distinct diagnosis entity. ALSPAC has repeated measures of psychopathology. These analyses will investigate the relationship between depression and fatigue, the direction of causality and potential explanatory variables such as physical activity levels and early stressful life events. This study will examine the role of both parental teenagers, including maternal depression and early childhood depression. The study will further examine a range of hypotheses about premorbid risk markers for persistent fatigue including the role of personality, childhood adversity (material and emotional), socioeconomic and physical activity factors.

B2108 - Quantifying the harms and costs of passive drinking in the UK - 14/11/2013

The overall aim of this proposal is to address the MRC, ESRC and Alcohol Research UK: Call for Alcohol Misuse Research theme "Quantifying the harms to non-drinkers". Such secondary harms or harms from passive drinking refer to the indirect harm (e.g. cognitive, developmental, psychological, domestic violence, crime, injury, and loss of productivity) to others (e.g. foetus, child/ren, partner, and society) resulting from someone else's drinking. Therefore, the overall aim of this project is to quantify the social, psychological and economic costs to families from either one or both parents' alcohol consumption.

To determine the indirect harms of parental drinking on the child, the project will:

1) longitudinally quantify the indirect harms across the child's lifespan (from foetus to aged ) from parental drinking on neurodevelopment and educational attainment, psychological well-being and substance use for the child

2) consider whether there are sex differences in indirect harms experienced

3) determine the harm resulting from different patterns of drinking over time, and whether changes in alcohol consumption/patterns of drinking result in changes in the associated harm

4) determine protective factors (resilience)

5) determine the combined harm of alcohol and domestic violence

6) determine the associated economic costs of parental drinking on the child by examining service utilization

To determine the indirect harms of partner drinking on the other partner, the project will:

1) longitudinally quantify the indirect harms across the partner relationship on psychological well-being and substance use

2) consider whether there are differences in indirect harms experienced, depending on the sex and sexuality of the partners

3) determine the harm resulting from different patterns of drinking over time, and whether changes in alcohol consumption/patterns of drinking result in changes in the associated harm

4) determine protective factors (resilience)

5) determine the combined harm of alcohol and domestic violence

6) determine the associated economic costs of parental drinking on the child by examining service utilization.

B2106 - Predicting oral language development to middle childhood and its implications for later achievement and wellbeing - 07/11/2013

Aim

To evaluate the potential of early life biological, parental and socio-demographic factors to predict natural language skills, and the extent to which these skills have an impact on school outcomes in (late) adolescence.

B2105 - Does eye colour change between 3 months and 5 years of age - 07/11/2013

Perceived eye, or iris colour varies as a continuous from blue to brown/black and is determined by the melanin pigment, quantity, packaging and type produced in the melanocytes of the anterior border layer and stroma of the iris. Brown eye colour is the result of abundant melanin pigment content and a higher ratio of pheomelanin to eumelanin. The number of melanocytes is not a determining factor. Blue eye colour results from the scattering of most blue wavelengths to the surface by collagen fibrils, in the presence of minimal melanin pigment. (1)

Once thought to be an example of simple Mendelian inheritance where brown colour was dominant and blue colour recessive, iris colour is now known to be a polygenic phenotypic characteristic with a myriad of possible combinations of parent and child eye colours. For example, two blue-eyed parents may produce a brown, green-hazel, or blue-eyed child. (1)

It is accepted that infant eye colour at birth does not necessarily correlate with resultant childhood and indeed adult eye colour, although it is found to be roughly stable by six years of age. (2) There is much anecdotal evidence of eye colour changing from one extreme of the spectrum to other in the first year of life. One study investigated this, finding a decrease in the number of light irises. (3) Congenital conditions affecting iris colour include albinism, in which the iris may be red or violet and heterochromia in which the two irises are different colours. (4)

The main contributory genes for iris colour are HERC2 (hect domain and RCC1-like domain-containing protein 2) and OCA2 (oculocutaneous albinism II) on chromosome 15, which account for around 74% of variation. Depression of OCA2 transcription results in a blue-eyed individual. A further 14 genes have been identified as contributing, however many of these play a greater role in determining skin and hair colour. Given the complex inheritance model of eye colour it is therefore difficult to predict final outcome based on the eye colour of the parents alone. (1, 4)

Many parents in the neonatal unit, ophthalmology and paediatric clinics enquire about changes in their child's eye colour, however literature is limited on the topic and the timing and nature of the change in eye colour in healthy neonates and young children is not well described.

ALSPAC is a vital resource in the study of child development and has contributed to much influential work on the topic of child development and paediatric disease. Simple data were collected regarding iris colour at various stages in the first 2 years of life and later at age 5. To our knowledge, this data has not been analysed to look at change in eye colour over time.

Understanding the nature of eye colour change in young children will broaden the knowledge base of both clinicians and patients or relatives and may aid in the understanding of iris development, which is important as it appears to be closely linked with brain development. (1) To date eye colour has not been found to be associated with visual acuity, but has been linked with reaction time, shyness, noise-induced hearing loss and ability to overcome seasonal affective disorder. (4) The individual iris is so unique in terms of colour, pattern and features that it can be reliably used in identification in place of a passport. (5)

The study team would be interested to investigate whether there was a change in iris colour between the age of 3 months and 5 years; at what point these changes occur and what form these changes take.

The study team are experienced in working with ALSPAC data and have paediatric ophthalmological clinical experience. Dr Creavin is an academic ophthalmology trainee whose research interest is ophthalmic epidemiology.

References

1. Sturm RA & Larsson M. Genetics of human iris colour and patterns. Pigment Cell Melanoma Res. 22;544-62

2. Bito LZ, Matheny A, Cruickshanks KJ, Nondahl DM, Carino OB. Eye color changes past early childhood: The Louisville Twin Study. Arch Ophthalmol 1997;115:659-63

3. Matheny AP and Brown Dolan A. Changes in eye colour during early childhood: sex and genetic differences. Annals of Human Biology 1975;2(2):191-6

4. White D and Rabago-Smith M. Genotype-phenotype associations and human eye color. Journal of Human Genetics 2011;56:5-7

5.Dougman J. Probing the uniqueness and randomness of IrisCodes: results from 200 billion iris pari comparisons. Proc. IEEE 2006;94:1927-35

B2104 - Associations between one-carbon pathway metabolite measures genetic and epigenetic variation within ALSPAC - 05/12/2013

Aims:

1. To detect genetic variants (using GWAS) associated with one-carbon pathway metabolite measures.

2. Investigate how pathway measures are associated with downstream molecular phenotypes (e.g. Epigenetic and metabolic profiles) in the selected subset of individuals.

B2103 - Communication difficulties peer victimization and mental health - 31/10/2013

AIMS

The main aim of the study is to explore the relationships among speech, language and communication needs, peer victimisation during childhood and adolescence, and mental health across the lifespan. The research questions are:

* Are levels of reported peer victimization across different SLCN groups (such as stuttering, other speech difficulties, and developmental language difficulties) significantly greater than for cohort members without such needs? Where possible we will take into account data from cohort members with non-SLCN disabilities.

* How do measures of mental health and emotional well-being in these groups compare across the lifespan?

* To what extent does peer victimization contributes to mental health in these groups across the lifespan?

* Does SLCN remain a risk when other factors are controlled for?

* Have levels of reported peer victimization in SLCN groups changed in response to initiatives to tackle bullying?

A further aim of the study is to develop a framework for future collaborative work involving the co-applicants and in the longer term other birth cohort researchers in the international academic community.

We plan to use data from the National Child Development Study and the Millenium Cohort Study as well as ALSPAC, because we wish to explore the impact of SLCN across the lifespan. However, ALSPAC offers the richest source of information in many respects. First, parental report of stuttering and developmental speech difficulties is verified by a trained researcher, which is not the case for any other British birth cohort study to date; second, parents, teachers and the cohort members themselves provide report of peer victimization; third, it provides a wide range of mental health measures.

Mental health and peer victimisation will both be considered as outcomes in different models. We will consider a variety of models as appropriate for the different outcome variables, including different types of multivariable regression such as binary and multinomial logistic regression and hierarchical linear regression. We would also conduct path analysis to examine direct pathways between SLCN and mental health, as well as indirect pathways via peer victimization over and above the effects of individual and socio-demographic factors and life events.

HYPOTHESES

Based on prior research, we hypothesise that cohort members with SLCN will be more likely to experience bullying and mental health problems than controls without these conditions. As suggested above, we expect that we will find direct pathways between SLCN and mental health, as well as indirect pathways via peer victimization, over and above the effects of individual and socio-demographic factors and life events.

B2102 - Novel Methods to Study Diet andObesity Compared to Genetics and Other Lifestyle Factors Agent-Based Modelling - 31/10/2013

Our specific aims are:

1. Derive empirical lifestyle patterns using cluster and/or factor analysis in a cohort of British

children.

2. Develop a mathematical model to simulate the association between derived dietary patterns and

other lifestyle factors (breakfast consumption, family dinner, breastfeeding history) and demographic

covariates (age, sex, socioeconomic status) with body fat using agent-based modeling (ABM).

3. Test the model using data collected from children aged 10 to 13 years over 4 time points (2004,

2006, 2008) to determine which variables are most strongly associated with changes in body fat over time

as children transition into adolescence.

4. Examine whether and how associations between dietary patterns, lifestyle factors, and obesity

shift when genetic data are included in the model (subset analysis*).

5. Reproduce aims 1 through 3 in a large prospective cohort of American children aged 10 to 13 y.

B2101 - Shared genetic determination of refractive error with age and ethnicity - 31/10/2013

Aims: To assess the genetic correlation between refractive error in (a) European vs. East Asian adults, (b) European children vs. European adults, and (c) European children vs. East Asian adults.

Hypothesis: The above genetic correlations are high (i.e. greater than 0.5), which implies that the higher prevalence of myopia in East Asians compared to Europeans is not simply genetic in origin.

Variables: Refractive error will be based on autorefractor measurement. Within each of the 3 subject cohorts, refractive error will be rank-transformed to a give a Normal Score, using Blom's method. (Our ultimate aim is to compare the refractive error of individuals of different ethnicity/age after accounting for absolute differences due to the environment in which they grew up. Also, heritability analysis is not robust against departures from normal trait distributions).

Analysis method: The degree of genetic relatedness between all pairs of individuals in 2 cohorts combined will be calculated using the GCTA program (for the 3 sets of 2 cohorts listed as a, b and c in the Aims above). Bivariate variance components analysis will be carried out using GCTA, as described [4].

Preliminary work: We have used bivariate GCTA in ALSPAC YPs to show that the shared SNP-heritability across childhood is high (greater than 0.7) (unpublished results). Too few ALSPAC mothers have refractive error information for estimation of its SNP-heritability (unpublished results).

Precautions to ensure the identity of participants cannot be revealed: Under certain circumstances, access to high-density genotype data is sufficient to reveal the identity (e.g. surname) of an individual [5]. We propose the following scheme to make such identification impossible (given current knowledge):

a) Create a list of the SNPs present on the genotyping platform used for each of the 3 cohorts (ALSPAC, Rotterdam, Nagahama).

b) Identify SNPs genotyped in all 3 cohorts. Sort the list by chromosome, then by genomic position.

c) From the list generated in step (b) randomly delete 5% of SNPs.

d) From the list generated in step (c) randomly re-order the SNPs within chromosomes (i.e. shuffle the order of SNPs on chromosome 1, then shuffle the order of SNPs on chromosome 2, etc.).

e). Send the list generated in step (d) to each site (ALSPAC, Rotterdam, Nagahama).

f) At each site, an analyst links refractive error and genotype data. The order of subjects in the data file is then randomised, and the unique subject identifier (e.g. "ALN") is replaced with a new identifier based on file order, e.g. ALSPAC1, ALSPAC2, ALSPAC3, ... ALSPAC9999.

g) For the data file generated in step (f), the analyst at each site sorts the order of SNPs so that it matches the order of SNPs in the circulated list (e). SNPs missing from the list are deleted.

g) For the data file generated in step (g), the analyst at each site replaces the SNP name with a new name based on chromosome and file order, e.g. chr1snp1, chr1snp2, chr1,snp3, ...chr22snp3455.

h) The analyst at each site sends the file generated in step (g) to a central site for GCTA analysis.

NB. Without knowing the order of SNPs in the circulated list (e), the order of SNPs in the data files (h) is unknown, and thus cannot be used to infer identity....yet it can be used to calculate relatedness of subjects whose SNPs are sorted in the same order.

References

1. Pan CW, Ramamurthy D, Saw SM (2012) Worldwide prevalence and risk factors for myopia. Ophthalmic and Physiological Optics 32: 3-16.

2. Morgan IG, Ohno-Matsui K, Saw SM (2012) Myopia. Lancet 379: 1739-1748.

3. Verhoeven VJM, Hysi PG, Wojciechowski R, Fan Q, Guggenheim JA, et al. (2013) Genome-wide meta-analyses of multiancestry cohorts identify multiple new susceptibility loci for refractive error and myopia. Nature Genetics 45: 314-318.

4. de Candia Teresa R, Lee SH, Yang J, Browning Brian L, Gejman Pablo V, et al. (2013) Additive genetic variation in schizophrenia risk is shared by populations of African and European descent. American Journal of Human Genetics 93: 463-470.

5. Gymrek M, McGuire AL, Golan D, Halperin E, Erlich Y (2013) Identifying personal genomes by surname inference. Science 339: 321-324.

B2100 - Longitudinal genome-wide association study GWAS for refractive error - 31/10/2013

Overview.

We will request funding to employ a post-doctoral RA to carry out these analyses. The RA will be based at the PI's institution (Hong Kong Polytechnic University) and supervised by the PI and co-I's.

We seek approval from the ALSPAC Executive Committee to run the proposed analyses on the blue crystal computing cluster. The analyses are very computationally intensive (fitting a mixed model for each of millions of SNPs). We will include in the grant any funds specified by the Executive Committee required to cover this computing time as well as other appropriate costs incurred by ALSPAC. (NB. The longitudinal GWAS for BMI, which examined ~3 million SNPs, required approximately 8648 days of computing time to complete).

Aim.

To identify genetic variants influencing refractive error trajectory (either in the general population or in subjects classified as spending a high/low amount of time reading or outdoors).

Methods.

The refractive error and genotyping data has already undergone QC filtering for use in a closely related project that has received Exec approval: B1352 'CREAM (Consortium for Refractive Error and Myopia) 1000-genomes meta-analysis'.

Preliminary analysis of refractive error trajectories using linear mixed models are very promising (for example, as part of the above amendment work, we have been able to identify known myopia SNPs that (a) act early in childhood and retain stable effects during childhood, (b) exert a progressively increasing effect during childhood, and (c) interact with time spent outdoors or time spent reading.

However, fitting the model for each SNP currently takes ~1 minute. We propose to test simplified models and examine the robustness of fixed effects estimates, in order to minimse the time required to fit each model. Once optimised, we will conduct three longitudinal GWAS analyses for three models:

Model 1. Test for SNP main effects and 'SNP x age' interaction.

Model 2. As model 1, plus a test for 'SNP x nearwork' interaction.

Model 3. As model 1, plus a test for 'SNP x time outdoors' interaction.

We will aim to examine the ~4.5 million very high confidence imputed (quality metric RSQR greater than 0.8) very common variants (minor allele frequency, MAF >=0.1) SNPs in the 1000G-imputed dataset.

B2099 - Associations of hypertensive disorders of pregnancy with adolescent offspring cardiac function and structure - 31/10/2013

AIMS

* To investigate the associations between exposure to HDP and blood pressure trajectories during pregnancy with offspring cardiac structure and function.

HYPOTHESIS

We hypothesize that the cardiac function and left ventricular geometry in adolescents exposed to HDP is less favorable compared to offspring of normotensive mothers.

METHODS

We will use data from ALSPAC to investigate the association between preeclampsia and offspring cardiac structure and function. Of the 5,217 adolescent children investigated, 2,000 conceded to echocardiography.

The echocardiograph examination

Echocardiography was performed using a HDI 5000 ultrasound machine (Phillips) equipped with a P4-2 Phased Array ultrasound transducer using a standard examination protocol. All measurements were made according to American Society of Echocardiography (ASE) guidelines.

Definition of exposure variables

* Being born to a mother with preeclampsia or GH.

* Blood pressure trajectories during pregnancy

Confounding/mediating variables (available data)

Sex of offspring, birth weight, length of pregnancy, the adolescent's own blood pressure, maternal pre pregnancy blood pressure, maternal pre pregnancy BMI, maternal and offspring smoking and physical activity, age and parity of mother, height in adolescence, weight/fat mass in adolescence, occupational social class, maternal diabetes in pregnancy.

Outcome variables

Cardiac structure

* Left ventricular size indexed to height (LVMI)

* Left ventricular geometry (based on LVMI and left ventricular relative wall thickness)

Cardiac function

* Left ventricular systolic function (Ejection fraction etc.)

* Left ventricular diastolic function (E/A, E'/A')

Statistical analyses

All statistical modeling will be made in SAS (SAS Institute inc., Cary, NC, USA). We will use multivariate linear models to estimate the associations and adjust for potential confounders and mediators. A previous study based on the follow-up clinic at 17 years reported the prevalence of exposure to preeclampsia and GH in utero to be 2% and 15%, respectively.5 Assuming a similar prevalence in the subgroup examined by echocardiography, this would result in 40 study participants having been exposed to preeclampsia and 300 having been exposed to GH.

B2098 - Genome-wide analysis of association between genotype and methylation - 24/10/2013

Outline

DNA methylation data has recently been generated from ALSPAC samples at multiple timepoints using the Illumina HM450k DNA methylation array. Comprehensive genotype data also exists for the same samples. This project will integrate these two large-scale datasets to investigate the role of genetic variation in DNA methylation.

Aims

1. Genome-wide association analysis of methylation in children and mothers to identify both cis and trans associations between genetic variants and methylation

2. Analysis of change in genotype/methylation associations through the lifecourse

3. Comparison of genotype/methylation associations to published genotype/phenotype and genotype/outcome associations

4. Comparison of genotype/methylation associations to genotype/expression associations (published and within ALSPAC)

5. Comparison of genotype/methylation assocations to ENCODE regulatory regions

6. Analysis of proportion of methylation variance that is influenced by genotype (cis/trans) and non-genetic factors.

9. Single point genotype-stage interaction analysis

10. Genetic and non-genetic correlation over space and developmental stages.

B2097 - Analysis of correlation patterns in DNA methylation through the lifecourse - 23/10/2013

Outline

DNA methylation data has recently been generated from ALSPAC samples at multiple timepoints using the Illumina HM450k DNA methylation array. Genome-wide correlation analysis is now possible to (a) identify potential coregulation and (b) to inform dimension reduction strategies to data analysis. It is also possible to explore the correlation between timepoints to determine which CpG sites in the genome are functionally stable, and which change over time.

Aims

1. Windowed analysis across the genome to generate "methylation correlation maps" at all time-points

2. Genome-wide analysis of correlation between variable loci to identify networks of genes that appear to be coregulated

3. Analysis of correlation of methylation between timepoints at each site in the HM450k to identify stable and labile CpGs.

B2096 - Relationship between nicotine metabolism rate as determined by CYP2A6 genotype and smoking patterns in adolescence - 24/10/2013

Aims:

1. Examine patterns of cigarette use across ages 13 to 21 years and identify sources of heterogeneity in smoking phenotypes

2. Identify relationships between CYP2A6 nicotine metabolism group and smoking patterns across ages 13 to 21 years

3. Compare the relative influence of CYP2A6 nicotine metabolism group on smoking initiation vs. smoking escalation across ages 13 to 21 years

Hypotheses:

Relative to normal CYP2A6 metabolizers, reduced CYP2A6 metabolizers will:

1. Escalate cigarette consumption faster in earlier adolescence

2. Escalate cigarette consumption slower in later adolescence/young adulthood

3. Have higher levels of cigarette consumption at earlier stages in adolescence

4. Have lower levels of cigarette consumption at later stages in adolescence/young adulthood

We also predict that there will be no association between CYP2A6 metabolism group and smoking initiation.

B2095 - Sex specific differences in the placental syndrome and markers of placentation - 24/10/2013

AIMS

We aim to

1) Investigate sex-specific differences in the occurrence of early onset and late onset pre-eclampsia, SGA and preterm birth

Where studies currently have relevant data and/or in the future we also plan to add to this aim with the following two aims. However, this request is currently ONLY for aim 1 above.

2) Explore sex-specific differences in markers of placentation in maternal blood

3) Undertake (epi)genetic studies assessing methylation / imprinting differences.

B2094 - Rare deleterious mutations psychiatric disease and intermediate behavioural phenotypes - 22/05/2014

AIMS:

1. To assess the prevelance of rare deleterious mutations (RDMs) in control cohorts (ALSPAC and TWINSUK) and in neuropsychiatric disease cohorts sequenced as part of the UK10K project.

2. To assess the phenotypic correlates of carrying such mutations.

B2093 - Gender nonconformity sexual orientation and distress - 24/10/2013

The present study aims to address these previous research gaps and limitations by examining associations between prospective measures of childhood gender non-conformity and subsequent negative social interactions, poorer self-image, and distress. A wider range of forms of negative interpersonal reactions and types of distress will be examined than in previous studies.

B2092 - OXTR and Autism Like Traits in ALSPAC - 30/01/2014

Aims - We aim to associate OXTR methylation level with measures of autistic like traits in cord blood derived from 1000 boys from the ALSPAC study.

Hypotheses - We hypothesize that (1) a relationship between methylation and traits exists and (2) that this relationship may depend on rs53576 genotype.

Rationale - Methylation of DNA exists in all human cells. While tissue-specific variation in DNA methylation has been observed, recent work indicates that, on the whole, methylation patterns are relatively conserved across tissue types within individuals. Published work from Connelly identified increased DNA methylation of a regulatory region of OXTR in ASD temporal cortex derived from Brodmann's area 41/42 that resulted in concomitant decreased transcription of OXTR. This brain region, a portion of superior temporal sulcus (STS), has been strongly implicated in social perception by virtue of its role in biological motion perception and theory of mind. Two of these ASD-specific DNA methylation changes (CpG sites -934 and -860) were also apparent in the blood of ASD individuals, and unpublished data from the PI indicates that methylation of CpG site -934 may be heritable. Importantly, this region of OXTR is not present on the current arrays used in recent large scale, methylome-wide studies in ASD; thus it is necessary to assay this region using other methods for replication. We recently replicated these methylation changes in a separate sample of male ASD individuals and their unaffected male siblings derived from the Simons Simplex collection. These data suggest that 1) increased DNA methylation of OXTR may lead to reduced OXTR gene expression in the ASD brain, 2) DNA methylation increases track with the ASD phenotype and 3) peripheral blood can be used a biomarker of brain methylation.

Data from the Connely lab establish an important relationship between measures of OXTR DNA methylation in the blood and perception of animacy in dynamic displays. The attribution of social meaning to these displays is consistently disrupted in ASD. Among typically developing individuals, viewing these displays recruits brain regions associated with mentalizing processes, including STS, temporal poles, and medial prefrontal cortex. Given the likely mediating role of oxytocin in social perception, we predicted that individual differences in OXTR methylation might affect response in these brain regions when viewing animate motion in dynamic displays. We found that higher levels of OXTR methylation predicted greater activity in STS and cingulate gyrus. Our results indicate that OXTR methylation may impact the degree to which individuals are sensitive to displays of animate motion. This perceptual sensitivity could be indicative of a social style that varies within the population and is compromised in ASD. Preliminary data in a larger sample of healthy Caucasians suggests that OXTR methylation may interact with a common functional variant along OXTR (rs53576) to influence the social brain. The A allele of rs53576 is related to decreased psychological resources, dispositional empathy and stress reactivity, as well as to structural and functional differences in oxytocinergic brain sites. We examined the relationship between OXTR methylation and response in anterior cingulate cortex to social attribution and emotional faces and find an inverse correlation based on rs53576 genotype.

Sample selection - 1000 male study participants weighted by autism like traits will be selected

Exposure Variables - NONE

Outcome Variables - Variables that fall under the catagories of communicative, social, and repetitive behavior; as in Table S2 [Steer, Golding, and Bolton, PLOS ONE 2010].

Confounding Variables - Although not considered a core requirement for the diagnosis of ASD, many children exhibit other traits such as learning difficulties, specific language impairment (SLI), ADHD, ODD/ CD, anxiety problems and special education needs.

Material Requested - 200 ng of DNA at 10ng/ul for genetic and epigenetic assays.

B2091 - An investigation into the confounding associated with genome-wide score and methods to minimise its impact - 10/10/2013

AIM

We plan to investigate the reasons for confounding of the genome-wide genetic BMI score and its extent using in ALSPAC and examine various means to minimise its impact any subsequent analysis.

Hypothesis

In an ongoing study of ALSPAC participants (Deanfield London Study) our recruitment is based on extremes of BMI percentages as determined by BMI associated common genetic variants. We used a genome-wide score that enabled us to reach a difference of 3 BMI units between the top and bottom percentages of BMI categories.

Preliminary data analysis on 200 subjects in the current study suggests that while the genetic score has as expected separated the population into two distinct BMI categories with mean difference of 3 BMI unit difference. However, the score itself is not totally unconfounded from environmental factors as was predicted at the start. This is likely is due to the use of a genome-wide score, instead of using a score from a limited set of strongly associated SNPs, that appears to have re-introduced confounding to some extent, although the reason behind these unexpected properties is unclear.

Methods

We will to explore this confounding and aim to answer the following questions.

a) What is the extent of the confounding of the genetic score i.e. what are the main confounders?

b) What is the main driver of this confounding: Genuine or horizontal pleiotropy? Vertical pleiotropy with SNPs acting on intermediate pathways to BMI or population stratification?

c) Can this confounding be controlled by adjusting for the main confounders?

d) Is this confounding less than what is expected by generation of groups by BMI alone? If yes, by how much?

e) In light of the above what are the limitations of our selected groups with differential BMI for the purpose of using them to study the main programme question i.e. adiposity-cardiovascular disease associations.

To answer the above questions we would require extensive data on confounders, the genetic score groups, obesity profiles and cardiovascular risk factors. In brief the following analysis will be performed.

Using standard regression model we shall investigate if the BMI genetic score is associated with an extensive list of confounders. We shall use adjustment methods for various confounders to investigate the the drivers of confounding and if their effect can be minimized. Intermediate pathway confounders will be exploited to investigate the presence or absence of vertical plieotropy.

Employing PCA (principle component analysis) we shall also investigate if there is a structure in the SNP sets used in the score and can PCA adjustment remove the confounding effect.

Using regression modelling we shall quantify extent confounding using conventional BMI and compare and contrast with the ones revealed from the genetic score analysis.

Using dummy data which shall be used to study the main questions from the ongoing study (Deanfield London Study) i.e. visceral adiposity-cardiovascular disease markers association, this way we can inquire into any limitation of adjustment for these confounding on any subsequent analysis on the real data when its available after study completion.

B2090 - Statistical methods to improve clinical interpreation of physiological data from real-time monitoring devices - 03/10/2013

The aim of this project is to develop the analysis of complex, high-dimensional, functional data collected from research into sleep, glucose and cardiometabolism. The identification of zeitgebers in sleep/activity, light and temperature, and their prediction of patterns in glucose and melatonin, will be explored. Ambulatory blood pressure is measured using personally-worn devices.

The outcome is blood pressure measured over time and the exposures of interest are age and sex, with adjustment for the usual confounders.

These types of data are becoming more widespread as the technology develops for personal measures of real-time events. The overarching characteristic is that they produce patterns over time. A recent review (Ullah & Finch, 2013) concluded that there is a lack of appreciation of the value of FDA for biomedical problems.

The aim of the proposed project is to develop clinically relevant statistical techniques for analysing real time complex data made available through recent advances in ambulatory physiological monitoring systems, and thereby establish:

1. the strengths and weaknesses of each statistical and methodological technique for generating comprehensive and holistic analyses of real time complex data series;

2. the extent to which these statistical techniques might offer more sophisticated interpretations of real time physiological data recorded from free-living patients, and thereby improve the clinical acuity of aetiological, diagnostic and prognostic investigations; and

3. the most appropriate format(s) in which such techniques might be made available for non-specialist biomedical technicians and clinicians to optimise the impact of these techniques on aetiological, diagnostic, prognostic and therapeutic decision-making.

A dedicated Work Package for each of these three objectives will involve an assessment of empirical evidence drawn from:

Work Package 1. continuously recorded measurements of interstitial glucose concentration, activity, ambient temperature and light from free living pregnant women with gestational diabetes in order to identify any occult glycaemic abnormalities capable of predicting macrosomia and/or abnormal neonatal glycaemic control - data that will support a robust comparison of the different analytical techniques examined;

Work Package 2. clinically relevant real time physiological data series provided by project partners from the commercial (industrial) and public (healthcare) sectors using recent advances in ambulatory monitoring systems for: body temperature; ECG, EMG and EEG; respiration; blood pressure; heart rate; and blood oxygenation - data that will allow the team to assess the generalisable utility of the analytical techniques developed in WorkPackage 1; and developmental workshops with commercial and public sector partners where mechanisms and associated tools for supporting the uptake, application and integration of the analytical techniques developed and tested in Work Packages 1 and 2 will be designed and implemented - data that will ensure that any advanced statistical techniques become available in a format that is accessible and useful to non-specialist biomedical technicians and clinicians.

B2089 - Prenatal lead exposure gene polymorphisms and child temperament - 26/09/2013

We propose to test three specific hypotheses for children experiencing a range of low-to-moderate prenatal BLL concentrations:

1)Higher BLLs will be associated with higher parent ratings of the child on negative temperamental attributes (grizzly, fretful, stubborn, demanding, unresponsive, active) and lower ratings on positive attributes (happy, alert, cuddly, sociable) at 4 weeks of age when the infants also have polymorphisms previously related to negative emotionality or heightened behavioral reactivity.

2)Higher BLLs will be associated with higher parent ratings of activity, approach, intensity, and distractibility at 6 and 24 months among children who also have polymorphisims previously shown to be related to negative emotionality or heightened behavioral reactivity.Higher BLls will be associated with lower scores on rhythmicity, adaptability, mood, persistence and threshold in the presence of the same gene polymorphisms.

3)Higher BLLs will not be associated with negative temperament traits at 6 and 24 months among children who have gene polymorphisms previously shown to be related to altruism or self-regulation.

In addition to gene-environment interactions, we will test for interactions between maternal hemoglobin and lead levels on the same outcomes to understand if maternal nutritional status acts as a protective or susceptibility factor for the assocation between lead exposure and temperament.

B2088 - Metabolomic and Epigenomic Mechanisms in Developmental Overnutrition - 26/09/2013

AIMS

Our overarching aim is to determine the role of metabolomic and epigenomic mechanisms in the relationships between maternal risk factors for developmental overnutrition and offspring adiposity and related metabolic outcomes. We will also determine the effects of these intrauterine mechanisms on greater adiposity and associated metabolic risk into the next generation. Three related aims with specific objectives are detailed below and illustrated in figure 1 of the research strategy.

Aim 1: To determine the role of metabolomic mechanisms in developmental overnutrition, by identifying:

1.1: The associations of established maternal developmental overnutrition risk factors (adiposity in early pregnancy, gestational adipose gain, gestational diabetes (GDM) and continuous measures of fasting and postload glucose and fasting insulin) with maternal pregnancy metabolome, quantified in serum by nuclear magnetic resonance (NMR) spectroscopy.

1.2: The associations of established maternal developmental overnutrition risk factors and pregnancy metabolome with fetal metabolome, quantified in cord serum by NMR spectroscopy.

1.3: The associations of maternal pregnancy and fetal metabolome with offspring adiposity (BMI, waist, skinfolds, fat mass) from birth through to early adulthood, and with metabolic outcomes (fasting glucose, insulin and lipids from mid-childhood to early adulthood; metabolome in infancy and in adolescence).

1.4: The extent to which maternal pregnancy and/or fetal metabolome mediate the associations of established developmental overnutrition risk factors with offspring adiposity and metabolic outcomes.

Aim 2: To determine the role of epigenetic mechanisms in developmental overnutrition, by identifying:

2.1: The associations of established developmental overnutrition risk factors with fetal genome-wide DNA methylation, analysed on cord blood white cell DNA, with the Illumina 450K HumanMethylation array.

2.2: The associations of pregnancy and fetal metabolome with cord blood white cell DNA methylation.

2.3: The associations of cord blood white cell DNA methylation with offspring adiposity and metabolic outcomes.

2.4: The extent to which cord white blood cell DNA methylation differences mediate the associations of established maternal developmental overnutrition risk factors with postnatal offspring adiposity and metabolic outcomes.

Aim 3: To explore the role of developmental overnutrition, including metabolomic and epigenomic mechanisms, on risk of greater adiposity and metabolic outcomes in two generations.

[Note. we have used the following notation in objectives 3.1-3.3: G0=index pregnant women on whom developmental overnutrition risk factors were measured; G1= offspring of G0; G2 = offspring of G1 and their partners]

3.1: We will determine whether the G1 females who have been exposed to higher levels of intrauterine developmental overnutrition, determined by a weighted score of G0 developmental overnutrition risk factors, enter their pregnancies with greater adiposity and more adverse metabolic outcomes than G1 females who are less exposed to developmental overnutrition by their G0 mothers.

3.2: We will determine the associations of G1 female exposure to developmental overnutrition with G2 cord serum metabolome, cord blood white cell DNA methylation, birth weight and infant adiposity.

3.3: We will compare the associations examined in 3.2 to equivalent associations with exposure to different levels of intrauterine developmental overnutrition in G1 males.

B2087 - Methylation of maternal and cord blood as a mechanism in G x E interaction - 26/09/2013

Aims: There are many relationships between features of lifestyle and other exposures to the parents that have been shown to be related to the growth, behaviour and development of the child, but there is rarely a convincing mechanism to explain how they occur. This study aims to determine, for each of the known relationships, whether DNA plays a part in the mechanism.

The hypothesis is that DNA methylation is a mechanism to 'explain' a number of relationships between the environment and measures of growth, cognitive development and behaviour. The presumed mechanism is shown diagrammatically as follows:

Exposure to parents ? Methylation of mother's and/or child's blood ? child outcome

Exposure variables: The proposed study will concentrate on exposures related to toxins (particularly cigarette smoking), ionising radiation (especially X-rays and radon levels in the residential areas in which the parents were born and currently live which can be linked to 3-digit postcode using published data), nutrition (especially related to fish intake and to dietary patterns in pregnancy), and stress (particularly acute stressors during the parents' life-course, chronic stressors using social circumstances, and measures of their anxiety levels). Exposures to the parents and grandparents will be included.

Outcome measurements will concentrate on growth, behaviour, intellectual development and educational attainments (including SATS results as well as the ALSPAC assessments of maths, reading, spelling, scientific understanding and phoneme awareness).

Confounders will be chosen based on the original reports of an association between an exposure and an outcome. It is important to recognise that we are mainly testing the possibility of DNA methylation explaining relationships that have already been reported.

A variety of statistical analyses will be undertaken: (i) relationship between prior exposures to the mother and her parents and methylation of the mother's blood; (ii) relationship between the mother's methylation pattern and that in the cord blood; (iii) relationshipbetween exposures to both parents and grandparents andthe methylation levels of the cord blood; (iv) determination of ways in which these methylation patterns may explain how relevant exposures have influenced outcomes.

B2086 - Does methylation mediate the effect of physical activity on obesity in childhood - 26/09/2013

Background

Evidence implies that there is an association between physical activity and DNA methylation and between methylation and obesity. I will therefore explore the potential mediating relationship of methylation in the relationship between activity and obesity, using epigenome-wide data which have only recently become available on this scale.

Objectives

Primary objectives:

1)Identify methylation variation associated with physical activity and then consider how this variation relates to obesity.

2)Use Mendelian randomisation to investigate causality in any associations between physical activity, differentially methylated regions (DMRs) of the genome, and obesity.

3)Investigate the underlying biological mechanisms that the DMRs may be acting through.

Secondary objective:

1)Explore the relationship between physical activity, DNA methylation variation and cardiovascular health in children.

B2084 - CLOSER SES DATA HARMONISATION - 19/09/2013

The Cohorts and Longitudinal Studies Enhancement Resources (CLOSER) project aims to provide and document a range of key variables that have been harmonised across multiple UK birth cohorts to encourage cross-cohort research on longitudinal data sets and permit compatrisons across as well as within cohort studies. Due to the restrictions on using and holding ALSPAC data (particularly data obtained through linkage) it is our aim to derive standardised measures from education, income and social class variables that are harmonised with derived data from the other cohorts. These variables, once derived, will be deposited back to ALSPAC with accompanying documentation and will not specifically be used for research outputs at this point other than documenting summary statistics. As such, there are no exposure, outcome or confounding variables to outline.

Documentation will be held by CLOSER and made readily available to researchers in an attempt to provide a suitable search platform for commonly requested variables and therefore encourage cross-cohort analysis of data.

B2083 - Use of cancer-related genetic scores to investigate association with intermediate phenotypes - 19/09/2013

Recently, and mostly thanks to genomewide association studies, a large number of DNA polymorphisms have been identified that are associated with cancer risk (http://www.genome.gov/gwastudies/). This has been the case particularly for breast and prostate cancer, and in a smaller proportion for colorectal and skin cancer. If these polymorphisms are combined in an overall score, the score will likely better explain variation in the trait than individual SNPs.

Additionally, several non-genetic cancer risk factors have been uncovered and validated, whilst findings for others have been inconclusive.

Aims & hypothesis

We propose to examine the relationship of genetic scores that reflect variation in cancer risk with exposures that have been associated with the same types of cancer, in ALSPAC children. We are also interested in running hypothesis-generating analyses using the genetic scores and metabolomic data when it becomes available.

In this way we will be able to define potential pathways through which the genetic risk factors exert their actions, and which will also indicate possible targets for treatment.

By examining this relationship in children we expect to identify relevant risk factors while overcoming the problem of reverse causation that may arise when investigating exposures in individuals already affected by the disease.

B2082 - Hypertensive disorders of pregnancy and long term paternal cardiometabolic health - 19/09/2013

Both pre-eclampsia and intrauterine growth restriction are associated with abnormal placentation. For successful placentation, tolerance against partner alloantigens is necessary(1). Several, but not all(2), epidemiological studies suggest that an increased risk of pre-eclampsia and of small-for gestational-age (SGA), may be transmitted through the father.

Large registry based studies from Norway and the USA have shown that men born to a pre-eclamptic pregnancy had a higher risk of fathering a pre-eclamptic pregnancy themselves, compared to men unexposed to maternal pre-eclampsia(3-4). Using data from the Norwegian registers, Lie et al. have shown that the increase in risk of a second pre-eclamptic pregnancy was somewhat greater when both pregnancies were fathered by the same individual, though an increased risk of a second pre-eclamptic pregnancy following a first pre-eclamptic pregnancy was observed regardless of the father's identity(5). Furthermore, the risk of pre-eclampsia in any pregnancy was 1.8-fold higher (95%CI: 1.2, 2.6) when the father had previously fathered a pre-eclamptic pregnancy in another woman(5). Similar results were reported in a study in California, that also reported that an increase in the risk of pre-eclampsia was associated with a change in partner amongst women without pre-eclampsia in a first pregnancy(6). In contrast, a similar analysis using data from the Swedish national registers found no important paternal influence on the risk of pre-eclampsia(2). A more recent study using the Norwegian registers found that partner change was associated with a reduced risk of preterm pre-eclampsia and SGA recurrence, and with an increased risk of SGA in a second pregnancy among women who did not deliver a SGA baby in their first pregnancy. However the risk of term pre-eclampsia was not affected by partner change(1).

Using data from the Norwegian registers once more, Irgens et al, found that fathering a first pregnancy complicated by pre-eclampsia pregnancy was not associated with an increased risk of paternal death from cardiovascular causes (term preeclampsia vs term non-preeclampsia HR=1.01, 95%CI: 0.81 & preterm preeclampsia HR=1.07 & 1.03; 95%CI: 0.55, 1.92). In contrast, women with pre-eclampsia had increased CVD mortality (HR=1.65; 1.01, 2.70 and HR=8.12; 95%CI: 4.31, 15.33 for term and pre-term pre-eclampsia versus term non pre-eclamptic women respectively). Authors concluded that whilst paternal genes in the fetus may increase the risk of pre-eclampsia in a particular pregnancy, such genes are probably not related to CVD risk(7). Similarly, Mylestad et al. found no association between fathering a pregnancy complicated by a hypertensive disorder of pregnancy (HDP) and a range of CVD risk factors measured some 18 years post pregnancy using data from the Norwegian HUNT study(8). The findings of these two studies are in sharp contrast with a consistent body of evidence suggesting that women with a history of pre-eclampsia and gestational hypertension (the hypertensive disorders of pregnancy, HDP) are at increased risk of CVD later in life(9).

To the best of our knowledge the study by Irgens et al. is the only one to have examined the association of fathering a pre-eclamptic pregnancy with future CVD risk in men. Our aim is to assess whether men who fathered a pregnancy complicated by HDP, prematurity or SGA have more adverse cardiometabolic health 18 years post-pregnancy compared to men who fathered a normotensive, term non-SGA pregnancy.

Exposures: HDP (normotensive, gestational hypertension, preeclmpsia), preterm delivery and SGA in the ALPSAC index pregnancy;

Potential confounders and mediators: Maternal & paternal age at pregnancy, maternal & paternal prepregnancy BMI, maternal & paternal smoking in pregnancy, parity, household occupational social class, alcohol consumption, physical activity, pregnancy diabetes, birthweight, gestational age.

Outcomes: Paternal adiposity, blood pressure, lipids, glucose, insulin, inflammatory markers, pulse wave velocity.

References

1. Wikstrom AK, Gunnarsdottir J, Cnattingius S. The paternal role in pre-eclampsia and giving birth to a small for gestational age infant; a population-based cohort study. BMJ Open 2012;2(4).

2. Cnattingius S, Reilly M, Pawitan Y, Lichtenstein P. Maternal and fetal genetic factors account for most of familial aggregation of preeclampsia: a population-based Swedish cohort study. Am J Med Genet A 2004;130A(4):365-71.

3. Skjaerven R, Vatten LJ, Wilcox AJ, Ronning T, Irgens LM, Lie RT. Recurrence of pre-eclampsia across generations: exploring fetal and maternal genetic components in a population based cohort. BMJ 2005;331(7521):877.

4. Esplin MS, Fausett MB, Fraser A, Kerber R, Mineau G, Carrillo J, et al. Paternal and maternal components of the predisposition to preeclampsia. N Engl J Med 2001;344(12):867-72.

5. Lie RT, Rasmussen S, Brunborg H, Gjessing HK, Lie-Nielsen E, Irgens LM. Fetal and maternal contributions to risk of pre-eclampsia: population based study. BMJ 1998;316(7141):1343-7.

6. Li DK, Wi S. Changing paternity and the risk of preeclampsia/eclampsia in the subsequent pregnancy. Am J Epidemiol 2000;151(1):57-62.

7. Irgens HU, Reisaeter L, Irgens LM, Lie RT. Long term mortality of mothers and fathers after pre-eclampsia: population based cohort study. BMJ 2001;323(7323):1213-7.

8. Mykelstad K, Vatten LJ, Salvesen KA et al. Hypertensive disorders of pregnancy and paternal cardiovascular risk: a population based study. Ann Epidemiol. 2011; 21:407-12.

9. Rich-Edwards JW FA, Lawlor DA, Catov JM. Pregnancy characteristics and women's future cardiovascular health: an underused opportunity to improve women's health? Epidemiologic Reviews In Press.

B2081 - Alcohol harms in the family - 19/09/2013

Aims relating to ALSPAC

This project aims to identify the mechanisms by which different levels, patterns and durations of alcohol consumption by one family member impact the health, well-being and life opportunities of other family members.

Hypotheses

Core hypotheses (children):

1. Having a heavy drinking parent in the household will have a negative effect on child outcomes at present and future waves.

2. Negative effects will be more pronounced when (a) the mother rather than father is a heavy drinker and (b) where both parents rather than only one parent are heavy drinkers.

3. Amongst children with a drinking parent, negative effects will be more pronounced where (a) other risk factors are in place, (b) the drinking has an effect on parenting behaviours and (c) the drinking negatively affects the relationships in the household.

4. Negative effects will be less pronounced where heavy drinking is not present at all waves either due to cessation or the drinker leaving the household.

5. Negative effects will be less pronounced where children have protective or resilience factors in place.

Core hypotheses (partners)

1. Having a heavy drinking partner (HDP) will have a negative effect on the other partner's (OP) well-being.

2. Having a HDP will reduce the OP's relationship satisfaction and increase the likelihood of relationship breakdown.

3. Negative effects for the OP will be more pronounced where (a) the OP drinks significantly less/less often than the HDP (b), the OP experiences other concurrent risk factors and (c) the HDP's heavy drinking persists across multiple waves.

4. Negative effects on the OP will be less pronounced where protective or resilience factors are in place.

Exposure:

Drinking measures

High level of consumption

High score on dependence screeners

Perceived drink problems

Outcome measures:

Child development:

- Cognitive

- Behavioural

- Social

- Psychological/emotional

- Parent/child relationship

Child health:

- Developmental milestones

- Health problems

- Accidents

Adult (mother and partner) well-being:

- Mental health

- General health

- Quality of life

Mother and partner relationships:

- Relationship satisfaction

- Relationship breakdown

- Domestic abuse

Moderators/mediators

Parenting behaviours, style, resources and self-efficacy

Family organisation (e.g. regular mealtimes)

Social support

Parental mental health*

Household composition (e.g. no. of children)

Marital status*

Socioeconomic status

Demographic characteristics (e.g. age, gender, ethnicity)

Financial measures (e.g. income, debt)

Housing situation and characteristics (e.g. social housing, safe environment, neighbourhood deprivation)

Residential area characteristics (e.g. area-level deprivation)

*Indicates risk, resilience or protective factors which are also outcome measures in their own right.

B2079 - Deductions about human traits and health from ABCC11 genotype - 12/09/2013

BACKGROUND

The ABCC11 gene encodes the multidrug resistance protein 8 (MRP8) (Kruh et al., 2007). This protein is involved in transport of many small molecules in normal physiology, in a variety of cellular and biological contexts. There is strong evidence suggesting that genetic variation at ABCC11 has pleiotropic effects. In particular, a functional non-synonymous SNP (rs17822931), also known as 538G-A or G180R, determines human earwax type (Yoshiura et al., 2006) and axillary osmidrosis (Nakano et al., 2009;Martin et al., 2010) and is associated with apocrine colostrum secretion from the mammary gland (Miura et al., 2007). It has also been related to breast cancer risk, although this is more controversial [(Toyoda and Ishikawa, 2010) and references therein].

rs17822931 genotype AA determines dry earwax type, while the presence of at least one G allele (GA or GG) determines wet earwax type. There are marked differences in rs17822931 allele frequencies across ethnic groups (Yoshiura et al., 2006;Toyoda et al., 2009;Toyoda and Ishikawa, 2010). There is a higher frequency of the A allele in East Asians and therefore higher prevalence of dry earwax type. In contrast, the wet earwax type is more prevalent in European and African populations due to higher frequencies of the G allele.

There is a close histological and functional relationship between ceruminous and apocrine sweat glands. This relationship is believed to explain the connection between earwax and axillary odor (Martin et al., 2010). AA homozygous individuals for rs17822931 display little of the characteristic axillary odorants (Preti and Leyden, 2010;Martin et al., 2010). In contrast, a study of Japanese individuals showed that essentially all individuals with axillary osmidrosis were GG or AG for rs17822931 (Nakano et al., 2009). This indicates that the G allele is necessary and sufficient to cause axillary odor, whereas AA genotype effectively marks non-odorous individuals.

In a recent study (Rodriguez et al., 2013) we have shown for the first time that there is a strongly significant (P=3.7x10^-20) differential usage of deodorant according to rs17822931 genotype. This represents the first evidence of a behavioural effect associated with rs17822931, that is directly relevant to the pharmacogenetics of body odour (Brown, 2013).

Two remarkable findings in relation to the behaviour of axillary deodorant use were that nearly 80% of European genetically non-odorous still use deodorant, whereas one in 20 individuals genetically odorous did not use it. This opens the possibility of a more complex scenario to explain the genetic basis of this human behaviour. To explore this possibility, an analysis of association at the whole genome level would therefore be required. However, a genome-wide analysis of genetic factors associated with deodorant usage has not been performed to date.

In addition, the potential role of ABCC11 genetic variation on other traits has not been studied yet. An interesting field is audition. One of the causes of hearing loss, pain and dizziness is cerumen impactation (McCarter et al., 2007). Ear wax impacts on audition and therefore, the involvement of rs17822931 on ear wax determination makes ABCC11 a good candidate for audition variation among individuals. A more controversial role of earwax is its potential involvement on earache. A common idea among GPs is that earwax does not cause earache and that one of effects of ear infection is the melting of earwax. However, in a pilot study in ALSPAC (approved by the executive, B586) we have found a significant association between earache at age 6-30 months and rs17822931. Muc more detailed analyses are required to understand this novel association and with the great depth of phenotypes involved, this needs an RA for at least a few months, it is not "an afternoon's work.". Similarly, the known role of rs17822931 in apocrine glands opens the possibility that ABCC11 could exert another pleiotropic effect, also acting on breast size. An interplay between breast size, breastfeeding and body odour should also be analysed.

HYPOTHESIS

That the functional SNP rs17822931 in ABCC11 has pleiotropic effects on earache and hearing, additional to its known effects on earwax, deodorant use and colostrum secretion.

AIMS

1.- To perform a phenome scan of all earache and hearing related phenotypes in ALSPAC in relation to rs17822931

2.- To conduct Genome-wide Association Studies on all reported and candidate pleiotropic effects associated with rs17822931, with special reference to deodorant use, earache and hearing.

3.- To access to record linkage data in order to gain more information from GP records to be added to the existing variables already available in ALSPAC

REFERENCES

Brown S. The Pharmacogenetics of Body Odor: As Easy as ABCC? J Invest Dermatol 2013; 133: 1709-1711.

Kruh GD, Guo Y, Hopper-Borge E, Belinsky MG, Chen ZS. ABCC10, ABCC11, and ABCC12. Pflugers Arch 2007; 453: 675-684.

McCarter DF, Courtney AU, Pollart SM. Cerumen impaction. Am Fam Physician 2007; 75: 1523-1528.

Martin A, Saathoff M, Kuhn F, Max H, Terstegen L, Natsch A. A functional ABCC11 allele is essential in the biochemical formation of human axillary odor. J Invest Dermatol 2010; 130: 529-540.

Miura K, Yoshiura K, Miura S et al. A strong association between human earwax-type and apocrine colostrum secretion from the mammary gland. Hum Genet 2007; 121: 631-633.

Nakano M, Miwa N, Hirano A, Yoshiura K, Niikawa N. A strong association of axillary osmidrosis with the wet earwax type determined by genotyping of the ABCC11 gene. BMC Genet 2009; 10: 42.

Preti G, Leyden JJ. Genetic influences on human body odor: from genes to the axillae. J Invest Dermatol 2010; 130: 344-346.

Rodriguez S, Steer CD, Farrow A, Golding J, Day IN. Dependence of Deodorant Usage on ABCC11 Genotype: Scope for Personalized Genetics in Personal Hygiene. J Invest Dermatol 2013; 133: 1760-1767.

Toyoda Y, Ishikawa T. Pharmacogenomics of human ABC transporter ABCC11 (MRP8): potential risk of breast cancer and chemotherapy failure. Anticancer Agents Med Chem 2010; 10: 617-624.

Toyoda Y, Sakurai A, Mitani Y et al. Earwax, osmidrosis, and breast cancer: why does one SNP (538Ggreater than A) in the human ABC transporter ABCC11 gene determine earwax type?FASEB J 2009; 23: 2001-2013.

Yoshiura K, Kinoshita A, Ishida T et al.A SNP in the ABCC11 gene is the determinant of human earwax type. Nat Genet 2006; 38: 324-330.

B2078 - Risk and resilience to educational underachievement associations between education language and social disadvantage - 12/09/2013

Aims:

i. Examine language and communication skills as risk and resilience factors in relation to populations at high-risk of educational underachievement.

ii. Determine the extent to which language skills play a role in educational outcomes at GCSE, once school characteristics and socioeconomic factors have been accounted for.

Hypotheses:

1) Language ability in early childhood will be a significant factor in explaining variation in educational outcomes, once school characteristics and socioeconomic factors have been accounted for.

2) Young people with language difficulties will be less likely to have positive educational outcomes upon leaving school.

Variables:

Exposure variable: Language ability (a composite measure based on WOLD comprehension and expression scores, Children's Communication Checklist scores).

Outcome variable: Educational outcomes at school-leaving age (GCSE or equivalent).

Confounding variable: school characteristics (school census data, for example: number of children eligible for free school meals), socioeconomic background (composite based on home ownership, overcrowding score, and maternal education), child characteristics (e.g. ethnicity, first language).

Method:

Secondary analysis of the ALSPAC data will examine the complex associations between language and educational attainment in order to understand which young people are at risk of educational underachievement in secondary school.

The research team will consist of Dr Sarah Spencer (applicant for the ESRC Future Research Leaders research funding) and Dr Yvonne Wren (academic mentor and advisor on the project). The project will form part of a wider research programme examining the associations between language and learning in secondary schools in areas of social deprivation (working with two school partners).

The ALSPAC data will be discussed with both the project policy steering group and a group of young people (participants in Stage 2) to further develop specific research questions and following analysis. This will ensure that findings are relevant for key policy questions and educational practice. The policy steering group will include representatives from: partner schools (senior management), the third sector (Mary Hartshorne, Head of Quality and Outcomes for ICAN, the children's communication charity), The Communications Trust (Wendy Lee, Professional Director), the think-tank Centre for Labour and Social Studies (CLASS), and the Royal College of Speech and Language Therapists (Mark Hope, RCSLT).

The project will employ a post-doctoral research associate (statistician) to work closely with the research team.

Analysis will include:

- filtering variables where distribution is such that they have no potential in the modelling process;

- grouping of risk and resilience factors based on existing research theory;

- grouping children into those who have and do not have profiles of assessments which indicate the presence of language difficulties;

- calculation of whether the presence of language difficulties decreases the likelihood of achieving five or more GCSE grades at A*-C grade or equivalent (a measure of good educational outcomes);

- running a series of univariable regression analyses to test the strength of associations between exposure and confounding variables with the outcome variable (school attainment);

- multivariable regression modelling to derive a final set of variables independently associated with educational attainment at the end of compulsory schooling.

This project will use the recently analysed language scores taken when children were aged 8 years. These include the built files from the Wechsler Objective Language Dimensions (WOLD). Sarah Spencer was involved in the process of analysing and scoring the WOLD samples, along with colleagues at the University of Sheffield and Dr Yvonne Wren.

Outcomes: Users of the research findings will be provided with a richer understanding of the role of language in educational attainment and how this interacts with socioeconomic factors. Target journal: British Educational Research Journal.

B2077 - Association between paternally inherited GNAS SNP alleles and birth weight - 12/09/2013

Aim: Determine whether variations in the paternally expressed GNAS splice variant XL-alpha S affect normal fetal growth?

Background: The term pseudohypoparathyroidism (PHP) refers to several rare, yet related human disorders. PHP type Ia (PHP-Ia) is characterized by an abnormal regulation of calcium and phosphate homeostasis because of resistance toward parathyroid hormone (PTH) in the proximal renal tubules; affected patients furthermore have developmental abnormalities referred to as Albright Hereditary Osteodystrophy (AHO) and often resistance towards other hormones such as TSH and GHRH that mediate their actions through Gs-alpha-coupled receptors. PHP type Ib (PHP-Ib) is characterized by hypocalcemia and hyperphosphatemia due PTH-resistance, typically without evidence for AHO. PHP-Ia and PHP-Ib are both imprinting disorder that are caused by maternal mutations within or up-stream of the GNAS locus on chromosome 20q13.3. This complex locus encodes the stimulatory G protein (Gs-alpha; GNAS exons 1-13) as well as several splice variants thereof, including XL-alpha S (GNAS exons 2-13, plus an XL-specific first exon), the extra-large form of Gs-alpha that is expressed only from the paternal, non-methylated GNAS allele.

Hypothesis: Are variations in XL-alpha S associated with normal fetal growth?

Very recently, we discovered through a collaboration with colleagues in France that paternal GNAS mutations are associated with intrauterine growth retardation (IUGR) (Richard et al., JCEM, 2013). Interestingly, mutations in GNAS exon 1, i.e. the exon specific for Gs-alpha, do not seem to lead to severe IUGR. This suggests that XL-alpha S, which uses the XL-specific first exon, contributes primarily to growth retardation. Conversely, biallelic XL-alpha S expression, as observed in patients with patUPD20q, is associated with enhanced fetal and probably also post-natal growth.

Our observations, which are surprising, led us to conclude that normal XL-alpha S expression from the paternal GNAS allele is essential for the prevention of IUGR and that XL-alpha S expression from both parental alleles results in much enhanced growth rates.

To investigate these findings in rare human disorders further and to determine whether the paternal GNAS haplotype is associated with fetal growth, we now propose to re-analyze some of the recently published GWAS data (Horikoshi et al 2013), namely the data from ALSPAC mother-child pairs.

The investigative plan would be as follows:

1) Define the region of interest at the GNAS locus on chromosome 20q13.3 and select SNPs from the maternal and fetal GWAS data within this region.

2) Deduce the paternally inherited allele, where possible, across the GNAS locus for each of these SNPs.

2) Use these deduced paternal allele data to determine whether inheritance of paternal (but not maternal) alleles is associated with impaired growth.

If this provides further evidence for a role of XL-alpha S in fetal development, we would then seek replication of the associations in further studies, e.g. in the EGG Consortium. If the association holds up, we could search in IUGR patients for paternal mutations in exon XL or its regulatory regions, i.e. in the exon specific for XL-alpha S; the identification of such XL-specific mutations would obviously be very exciting, as not much is known about the role of XL in normal human biology. In fact, our recent birth weight data for patients with either paternally or maternally inherited GNAS mutations have provided the first hints regarding its role in humans.

B2076 - Identifying genetic variants influencing common ENT infections - 05/09/2013

Background: Recurrent ear, nose and throat (ENT) infections and their sequelae (recurrent and chronic illness, high risk for language delay, learning and behavioural problems) are common and costly paediatric health issues caused by complex interactions among pathogenic, genetic and environmental factors. The middle ear, nose and throat may be conceptualized as a unified organ, which are susceptible viral and bacterial infection from similar pathogens. Genetic epidemiological studies (both in the BLATS sample and in Norwegian twin study) have found significant genetic correlations between susceptibility to ENT infection indicating the presence of shared genetic risk factors influencing these illnesses.

Aims: The proposed project aims to identify genetic variants influencing common ENT illnesses. We have previously conducted genome wide association (GWAS) analyses of common ENT infections within the Brisbane Longitudinal Adolescent Twin Study (BLATS) and are seeking to replicate and extend these findings through collaboration with the ALSPAC study.

Exposure Variables: NA

Outcome Variables: As minor ENT infections are very common among children we will analyse surgical interventions performed to mediate these infections to focuss on more severe and reccurent illness. As such ENT illness will be identifed using parental reprts of tonsillectomy, adenoidectomy and myringotomy (the insertion of grommets) derived from the child focused questionnaires at 103 months (8years KS questions A6 b, c and e) and 140 months (11years KW questions A3 b, c and e).

Confounding variables: There are well established sex differences in susceptibility to some ENT illnesses as such sex will be included as a covariate in all analyses.

Analyses: Univariate GWAS analyses of tonsillectomy, adenoidectomy and myringotomy will be conducted by David Evans while he is in Bristol in October 2013. The summary statistics from the analyses of the ALSPAC data will be shared with Sarah Medland and Robyn Choi to allow genome-wide meta-analysis of the BLATS and ALSPAC results.

No raw data or samples will be transfered or shared between ALSPAC and BLATS.

B2075 - Genome-wide association study of red blood cell membrane phospholipids during pregnancy - 05/09/2013

Aim:

To detect genetic variants reliably associated with red blood cell membrane fatty acids (FAs).

Hypothesis:

We hypothesise that variants across the genome will be associated with FA levels during pregnancy.

Variables:

The exposure variable will be imputed maternal genotype, while antenatal FA levels will be the outcome.

Data on 40 different FAs were extracted from antenatal blood samples taken from ALSPAC mothers, these included saturated, omega-3, omega-6 and omega-9 FAs. Genome-wide association analyses will be performed on each of the FAs available in ALSPAC, using a univariable linear regression model, regressing FA level on maternal genotype.

Previous studies have found associations with omega-3 and omega-6 Fas and both the FADS gene cluster on Chromosome 11 and the ELOVL2 gene on Chromosome 6 (1, 2). We propose to investigate whether these findings are consistent among pregnant women, and whether any further associations are found with other FA families.

1. Lemaitre RN, Tanaka T, Tang W, Manichaikul A, Foy M, Kabagambe EK, et al. Genetic loci associated with plasma phospholipid n-3 fatty acids: a meta-analysis of genome-wide association studies from the CHARGE Consortium. PLoS genetics. 2011;7(7):e1002193. Epub 2011/08/11.

2. Tanaka T, Shen J, Abecasis GR, Kisialiou A, Ordovas JM, Guralnik JM, et al. Genome-wide association study of plasma polyunsaturated fatty acids in the InCHIANTI Study. PLoS genetics. 2009;5(1):e1000338. Epub 2009/01/17.

B2074 - The effect of marital relationships on cardiovascular outcomes in men - 10/09/2013

Aims:

To understand the role of marital relationship quality in the development of cardiovascular risk factors

Hypothesis:

Poor quality marital relationships are associated with worsening cardiovascular risk factors.

B2073 - Determining novel causal risk factors for CVD An original genome-wide Mendelian Randomisation approach - 29/08/2013

Background:

There are now many powerful GWAS based on large sets of meta-analysed data from multiple studies and the number of GWAS in literature is rapidly increasing. These studies provide robust effect estimates for the associations of single nucleotide polymorphisms (SNPs) across the genome with phenotypes of interest. For example, associations for all SNPs across the genome in relation to anthropometric phenotypes are available from the GIANT (Genetic Investigation of ANthropometric Traits) consortium involving meta-analysed data on up to 250,000 individuals (1-3). The GIANT GWAS observed many loci predicting variation in BMI (32 loci) and fat distribution (29 loci) at genome-wide significance level.

However, many loci will exist beyond those established using the stringent genome-wide cut-off level that are in reality reliably related to the phenotype of interest. Data from the GIANT height GWAS (N=183,727 individuals) identified 180 loci associated with height at genome-wide significance levels, explaining 10% of the phenotypic variation in height. However, the authors further estimated, based on recently developed methods (4), that there were in fact 697 loci (95% CI: 483-1040) with effects greater or equal to those identified from the GWAS which would explain a total of 15.7% of the phenotypic variation in height. Preliminary data from the GIANT consortium supports the conclusion that many of the associations that were observed but did not reach genome-wide significance are in fact real associations (J. Hirschhorn, Personal Communication).

Furthermore, when all SNPs across the genome are fitted simultaneously and the variance explained by all the SNPs together is estimated, 45% of the phenotypic variance in height can be explained (5).Together with the fact that for SNPs explaining 0.01% variation there is 99% power to get the direction of the association correct in a sample size of 129,000 individuals, this suggests that robust GWAS with large sample sizes can reliably inform the development of genome-wide polygenic instruments.

The inclusion of a potentially vast number of 'risk-alleles' across the genome would therefore explain significantly more phenotypic variation than instruments based on individual genetic variants or several established genetic variants together. As such, genome-wide polygenic scores provide a platform from which to develop a novel application of the Mendelian Randomization approach using genome-wide instruments that would incorporate a much larger proportion of genetic information than has otherwise been explored previously, resulting in considerably greater power for detecting causal effects for novel phenotypes of interest.

Aims:

The aims of this project are to develop and apply an original genome-wide Mendelian Randomization approach in order to: i) identify of novel causal risk factors for adult CVD, and ii) examine their impact on childhood and adolescent CVD-related traits

Hypotheses:

We hypothesise that the application of genome-wide allele scores for indexing traits known to be related to CVD-related phenotypes, such as adiposity, lipids and inflammation, will accurately index CVD risk and that these scores can subsequently be extended to explore more novel predictors such as iron status, fatty acid profile and uric acid.

Exposure variables:

genome-wide SNP data and phenotypic data for established CVD-related phenotypes (BMI, lipids, inflammatory markers) and novel predictors in CVD (iron status makers, fatty acids, uric acid)

Outcome variables:

Blood pressure, flow-mediated dilation, intima-media thickness

Confounders:

Maternal eduation, paternal education, family income, parental occupational class, child IQ, maternal smoking

References:

1. Speliotes EK, Willer CJ, Berndt SI, et al. Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index. Nat Genet 2010; 42(11): 937-48

2. Lango Allen H, Estrada K, Lettre G, et al. Hundreds of variants clustered in genomic loci and biological pathways affect human height. Nature 2010; 467(7317): 832-8

3.Heid IM, Jackson AU, Randall JC, et al. Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution. Nat Genet 2010; 42(11): 949-60

4. Park JH, Wacholder S, Gail MH, et al. Estimation of effect size distribution from genome-wide association studies and implications for future discoveries. Nat Genet 2010; 42(7): 570-5

5.Yang J, Benyamin B, McEvoy BP, et al. Common SNPs explain a large proportion of the heritability for human height. Nat Genet 2010; 42(7): 565-9

B2072 - Association between perinatal risk factors and child cognitive and emotional development - 29/08/2013

Aims:

There is growing evidence that perinatal maternal depression is associated with impairments in child cognitive development. However, there is very little empiracal evidence of the long term impact. There is only one small UK study which has investigated the association between postnatal depression and academic achievement at the end of school. Data from large prospective studies is therefore needed. Furthermore, the developmental trajectory of cognitive impairment is unclear and can only be tested in longitudinal studies with repeated assesment of cognition across domains

B2071 - Evaluation of prenatal and perinatal risk factors for obsessive compulsive disorder in the ALSPAC pre-birth cohort - 29/08/2013

Although obsessive compulsive disorder (OCD) is clearly known to have a strong genetic component, twin and family studies have consistently demonstrated a significant role for additional, non-genetic factors in the pathogenesis of the disease(Pauls, 2008). Despite this, only four studies have examined the potential contributions of various non-genetic factors in the development of OCD. In these studies, excessive maternal weight gain, hyperemesis of pregnancy, medication use during pregnancy, nuchal cord, hypoxia at birth, unspecified problems during pregnancy or in the perinatal period, and assisted delivery (forceps or Caesarean section) were associated in at least one study with increased risk of OCD(Geller et al., 2008, Grisham et al., 2011, Sampaio et al., 2009, Vasconcelos et al., 2007). In contrast, tobacco or illicit drug use during pregnancy, primiparity, low birthweight, hypertension or pre-eclampsia, and preterm birth were not found to be OCD risk factors. However, these studies had multiple limitations; all but one were retrospective, and the one prospective cohort study only examined a few variables. Therefore, there is a great need to examine a variety of candidate non-genetic OCD risk factors in a prospectively collected, population-based sample.

We have previously examined the relationship between pre- and perinatal risk factors for Tourette Syndrome (TS), a neurodevelopmental disorder that is etiologically and clinically related to OCD, in the ALSPAC cohort (Mathews, in press). We found that inadequate maternal weight gain during pregnancy, parity, and maternal alcohol and cannabis use were all associated with increased risk for TS or chronic tics (CT). Other pre/perinatal exposures that had previously been reported, most notably maternal prenatal smoking and low birth weight, were not associated with TS or CT in the ALSPAC cohort.

We propose to utilize the ALSPAC cohort to study non-genetic risk factors for OCD in a prospective manner, using the same approach used to study TS/CT, through the following specific aims:

Aim 1: Examine the association between previously reported prenatal and perinatal OCD risk factors and those previously found to be identified with TS/CT and the presence of OCD using a nested, case-control design within the longitudinal, prospective, population-based ALSPAC sample.

The ALSPAC study includes an assessment of obsessive compulsive symptoms and associated distress and impairment as a part of the Development and Well Being Assessment (DAWBA) parent interview. This self-report questionnaire was completed by ALSPAC mothers as part of the age 7, 10, and 14 questionnaires. We propose to use a definition of OCD that we have previously used in our work on examining perinatal risk factors for tic disorders; this definition corresponds to a DSM-IV-TR lifetime diagnosis of OCD. The presence of recurrent obsessions or compulsions (defined as a response of "sometimes" or "often" to one or more of the seven available questions about contamination, cleaning, checking, repeating, touching, arranging, or counting symptoms) at any of the three timepoints, is required for a diagnosis, along with sufficient severity and/or impairment to meet DSM-IV-TR criteria. This is defined as symptoms that were severe enough to take up at least an hour a day ("waste a lot of time",) cause significant distress ("upset a great deal"), or cause interference/impairment ("quite a lot" or "a great deal" answered to any of the five questions about interference (with family, friends, school, or hobbies). As is consistent with the DSM-IV-TR criteria, recognition that the symptoms are excessive is not required in children.

Exposures of interest will include prenatal and perinatal factors reported to be associated with either OCD or OCD symptom severity in at least one previous study, as well as those examined in our study of tic disorders, including birth weight, maternal weight gain, Apgar scores, paternal age, hyperemesis of pregnancy, increased maternal stress during pregnancy, maternal smoking, alcohol, illicit drug, and caffeine use, as well as obstetrical complications (such as forceps delivery and neonatal hypoxia).All children who do not meet OCD criteria (or subclinical OCD criteria, as defined by OCD symptoms with minimal impairment or distress), and do not have autism or intellectual disability will be included as controls.Both univariate analysis and multivariate analysis using logistic regression will be performed.We hypothesize that maternal smoking, paternal age and perhaps other environmental variables will be associated with the development of TS/CT in this population.

Aim 2: In the subgroup of ALSPAC subjects with OCD, examine the non-genetic risk factors identified in Aim 1 for association with co-occurring anxiety disorders, ADHD, and symptom severity.

In addition to the OCD assessments, ALSPAC subjects have been screened for DSM-IV diagnoses of other anxiety disorders (separation anxiety, social anxiety, and generalized anxiety), and ADHD at three different time points thus far (ages 7, 10 and 14). In this aim, we will evaluate each subject with OCD for the presence of additional co-occurring anxiety disorders and/or ADHD. We will then perform both univariate and multivariate analyses to test for an association between the presence of co-occurring disorders and the same previously reported prenatal and perinatal risk factors. We hypothesize that at least one of these variables will prove to be associated with OCD-associated comorbidities.

Table 1. Data requested for proposed ALSPAC study.

Concept

Specific Measure

Person

Source

Time Point(s)

Prenatal Risk Factors

Medications, smoking, alcohol, recreational drug use, family history, maternal/paternal age

Mother

Questionnaire

8 weeks gestation to 8 weeks post-partum

Prenatal Risk Factors

Hyperemesis

Mother

Questionnaire

8 weeks gestation to 8 weeks post-partum

Maternal stress

Life Events

Mother

Questionnaire

18 week gestation & 8 weeks post-partum

Perinatal events

Birthweight, Apgar scores, obstetrical complications

Mother

Obstetrical and neonatal record

Birth to 4 weeks

OCD

Checklist/screen for DSM-IV OCD criteria

Child-based

Questionnaire

Ages 7, 10, 14

ADHD

Checklist/screen for DSM-IV ADHD criteria

Child-based

Questionnaire

Ages 7, 10, 14

Anxiety disorders

Checklist/screen for separation anxiety, generalized anxiety, and social anxiety

Child-based

Questionnaire

Ages 7,10, 14

REFERENCES:

Geller, D. A., Wieland, N., Carey, K., Vivas, F., Petty, C. R., Johnson, J., Reichert, E., Pauls, D. & Biederman, J. (2008). Perinatal factors affecting expression of obsessive compulsive disorder in children and adolescents. J Child Adolesc Psychopharmacol 18, 373-9.

Grisham, J. R., Fullana, M. A., Mataix-Cols, D., Moffitt, T. E., Caspi, A. & Poulton, R. (2011). Risk factors prospectively associated with adult obsessive-compulsive symptom dimensions and obsessive-compulsive disorder. Psychol Med, 1-12.

Mathews, C. A., Scharf, J. M., Miller, L.L., Macdonald-Wallis, C., Lawlor, D.A., Ben-Shlomo, Y. (in press). Association between pre- and perinatal exposures and Tourette syndrome or chronic tic disorders in the ALSPAC cohort. Br J Psychiatry.

Pauls, D. L. (2008). The genetics of obsessive compulsive disorder: a review of the evidence. Am J Med Genet C Semin Med Genet 148C, 133-9.

Sampaio, A. S., Miguel, E. C., Borcato, S., Batistuzzo, M., Fossaluza, V., Geller, D. A. & Hounie, A. G. (2009). Perinatal risk factors and obsessive-compulsive spectrum disorders in patients with rheumatic fever. Gen Hosp Psychiatry 31, 288-91.

Vasconcelos, M. S., Sampaio, A. S., Hounie, A. G., Akkerman, F., Curi, M., Lopes, A. C. & Miguel, E. C. (2007). Prenatal, perinatal, and postnatal risk factors in obsessive-compulsive disorder. Biol Psychiatry 61, 301-7.

B2069 - Androgens in maternal serum during gestation and child androgen levels in autism spectrum conditions and autistic traits - 29/08/2013

Aims: 1) To test if maternal free and total testosterone are elevated during pregnancy in autism spectrum conditions (ASC), and are correlated to number of autistic traits. 2) To test if maternal androgen levels mediate the reported relationship between gestational complications (i.e. hypertensive and hyperglycemic disorders of pregnancy) and autism risk. 3) To test if children with ASCs have elevated levels of androgens, and if number of autistic traits are correlated with elevated levels of androgens during childhood and adolescence.

B2068 - Investigating the effects of disclosure control - 15/08/2013

Aims: To develop an anonymisation policy for ALSPAC to be implemented for use of any release which may include linked NHS data. The policy needs to be submitted with the application of the Information Goverance Toolkit which needs to be in place to continue receiving and gaining further section 251 support. Further to this policy, we aim to explore anonymisation techniques determining the most secure level of anonymisation with the least effect upon the quality of the data for research. Using previous research on datasets which have been anoymised to different levels and using different techniques.

The anonymisation policy, for the IG Toolkit, will need to include the minimum level of anonymisation needed for release files of linked NHS data, k-anonymisation on quasi-identifiers.

Hyptheses: To determine the most secure method of anonymisation with the least impact on the quality of the data for research.

The hypotheses will be explored using a previous research question published by Kate Northstone. The research used to test the impact is as follows:

Maternal fish intake and child dietary patterns and associations with educational outcome at 16 years of age.

Outcomes: Child achieved 5 or more GCSE's at grade C or above, including maths and english.

Primary exposures:

1) Fish intake during pregnancy (none, 1-340g and greater than 340g)

2) Omega-3 intake (none, any actual intake split into tertiles)

3) Child Dietary patterns derived from PCA at 3,4,7,9 and 13 years of age

Confounders:

Gender

Maternal age

Maternal education

Housing

Maternal life events

Birthweight

Gestation

Maternal Smoking

Parity

Maternal and paternal occupation

IMD

Geography.

B2067 - Utilising multiple independent combinations of genetic variants to evaluate potential pleiotropy - 15/08/2013

We aim to develop a method to investigate potential pleiotropy in causal estimates derived using the Mendelian randomization approach. The ALSPAC data will be used as an illustrative example.

Exposure: height, Outcome: FVC lung function (unadjusted for height), instrumental variables: 20 genotypes listed below.

B2066 - Antenatal interpersonal sensitivity depression and subsequent mother-infant relationship quality - 23/08/2013

The aim of this study is to examine the precision of perinatal depression screening, including interpersonal sensitivity, for identifying mother-infant relationship and maternal mental health problems that continue into or emerge in the second year of life.

The study will answer the research question: how much of the variance in mother-infant relational quality is explained by interpersonal sensitivity (IPSM) and perinatal depression secreening (EPDS) scores measured during pregnancy?

B2065 - Maternal obesity associated metabolic conditions and neurodevelopmental and psychiatric disorders in children - 15/08/2013

AIMS

Our goal is to contribute to an emerging body of literature regarding the association between maternal obesity in pregnancy and neurodevelopmental and psychiatric disorders in children. To achieve this goal, our primary objective is to test theoretical models of the relationship between pre-pregnancy body mass index and other clinical manifestations of maternal insulin resistance (hypertension, diabetes) and three outcomes in children: autism; attention deficit hyperactivity disorder (ADHD); and schizophrenia.

HYPOTHESIS

We hypothesize that a high pre-pregnancy body mass index will be associated with an increased risk of adverse neurodevelopmental and psychiatric outcomes among children.

VARIABLES

Exposures (maternal): Pre-pregnancy body mass index, weight gain during pregnancy, hypertensive disorders of pregnancy, diabetes

Outcomes (children): Autism, ADHD, symptoms of schizophrenia

Covariates: Various factors will be considered as potential confounders or mediators of the hypothesized associations. These include cigarette smoking, substance use, alcohol consumption, infection, and depression and anxiety during pregnancy; postpartum depression and anxiety; maternal and paternal history of mental health conditions; socioeconomic status; race/ethnicity; maternal age at delivery; parity; prior pregnancy loss; child's sex; multiple birth; preterm birth; Caesarean section (planned/emergency); birth weight greater than 4000g; birth weight greater than 4500g; and intellectual disability in the child.

B2064 - Genome-wide and candidate gene association studies of visual and cognitive phenotypes and their inter-relationships - 15/08/2013

Aims:

1. To determine whether visual and cognitive phenotypes cluster together within a normal population cohort of children.

2. To determine the underlying genetic associations of visual and cognitive phenotypes on a genome-wide basis in a normal population cohort.

3. To extrapolate datasets from animal models of associated visual and cognitive disorders, e.g. genes expressed in interneuron populations both in the retina and CNS, and investigate these candidate genes (within the datasets obtained as above) for associations with visual and cognitive phenotypes in a normal population cohort (this mouse data is already available from my lab).

Hypotheses:

Eye development in different organisms produces dramatically different structures, like the compound eye of insects and the camera-like eye of vertebrates. Nevertheless, the molecular mechanisms underlying eye specification are highly conserved (1), and the study of eye development in animal models has proven to be highly informative of the regulatory events that control human eye formation. For example, Pax6 was identified as a 'master' regulator, at the top of the hierarchical network of transcription factors (TFs) involved in eye development, since loss-of-function mutations of the eyeless gene (the Pax6 Drosophila homologue) lead to an eyeless phenotype (2) and over-expression can direct the formation of histologically normal ectopic eyes in flies (2) and in some vertebrates. Furthermore, recent work has established that the evolutionary conservation of the visual system extends beyond eye specification (by genes like Pax6) to include the visual system circuitry that connects the eye to the brain (1). Pax6 mutations in mice cause the small eye phenotype, and human PAX6 mutations lead to eye malformations including aniridia and other anomalies, while homozygotes demonstrate malformations of the central nervous system (CNS)(3). More recent work has shown that heterozygote PAX6 mutations are also associated with previously unrecognised and subtle structural brain abnormalities and cognitive deficits in humans (4). Furthermore, distant regulatory enhancer sequences influence transcription of Pax6 in mice, and consequently lead to eye abnormalities without any associated mutations of the Pax6 gene itself (5). While Pax6 is the most well-studied gene influencing eye development, several others are known to regulate interneuron development in the retina and CNS in an increasing number of animal models. Based on these data, we would predict that children carrying genetic polymorphisms and/or mutations in genomic regions encompassing so-called retinal and CNS "interneuron genes" would manifest deficits in vision and/or cognition.

B2063 - Assessing linkage error and bias between ALSPAC and HES - 15/08/2013

Longitudinal studies are making increased use of routine health and administrative data as a means of informing missing data techniques and sustainable data collection. These advantages are dependent on the accurate interpretation of the linkage. Links between an individual and their routine records are established by comparing personal identifiers common to both datasets. The potential to do this accurately is impacted by the choice and application of the linkage algorithms and the quality and discriminatory potential of the available identifiers. Recent work by Goldstein, Harron and Wade (2012) demonstrated new methods to enhance the efficiency of the linkage process using multiple imputation (MI) techniques. Once linked, the onus is on the study team to provide the provenance of the data; describing the linkage methodology and assessing the quality of the linkage at an individual level.

Through the Project to Enhance ALSPAC through Record Linkage (PEARL) we are linking the study index children to their secondary health care records, held within the Hospital Episodes Statistics (HES) dataset. The accuracy of this linkage is of concern as the personal identifiers held in early HES data (pre 1997) will in some cases lack the discriminatory power to identify a single individual. The NHS Data Linkage Service linked a pilot sample of 3,198 study participants to their 1991-2012 HES records. The linkage algorithm varied depending on the ability of the identifiers to establish a 'true match'.

AIM: To provide evidence of the quality of the linkage between ALSPAC and HES, particularly in terms of population coverage. Ultimately to use the evidence (if the hypothesis is true) to seek HES permissions to alter the linkage methodology, specifically to use the prior informed imputation techniques proposed by Goldstein. To use ALSPAC data obtained through different channels (data abstraction) as a 'gold standard' to 'validate' the imputed output through replicating a known ALPSAC finding (this will be subject to a new research proposal with standard data access conditions).

HYPOTHESIS: That the linkage variables used by HES to conduct the match are insufficient to identify all possible ALSPAC records.

EXPOSURE VARIABLES: The administrative linkage data supplied to the NHS, residential address history (specifically if they lived within England & Wales or not), self-reported hospital admissions (including cause and date and length of stay).

OUTCOME VARIABLES: Linkage status, delivery location and date, birth weight, gestational age.

CONFOUNDING VARIABLES: These relate to the accuracy of the linkage variables: enrolment details (i.e. for new cases we won't have postcode at delivery) and indicators of address quality (participation status at delivery, home movement,house tenure, known birth outcome).

B2062 - Mining for complex patterns in epidemiological data - 15/08/2013

The aim of this project is to use advanced machine learning and data mining techniques to extract features and patterns from the ALSPAC data in an unsupervised manner. Techniques to be used include subgroup discovery and exceptional model mining, which find subpopulations that are statistically robustly different wrt. properties of interest compared to the overall population. Epidemiological properties of interest include very dense genetic data (genome wide single nucleotide polymorphism, copy number variation and sequence data), gene expression and gene methylation data and outcomes related to body composition, obesity, physical activity, health related behaviours such as diet and smoking and cognitive function.

B2061 - Effects of maternal alcohol consumption during pregnancy on childhood behaviour in the ALSPAC cohort - 15/08/2013

Development of behavioural characteristics is dependent on a complex interaction of genetic and environmental factors. It is also known that neonatal development can be altered by a variety of maternally derived exposures.

Alcohol consumption in pregnancy is an important health issue and the DOH currently advise that 'Pregnant women or women trying to conceive should avoid drinking alcohol' (http://www.dh.gov.uk/en/Publichealth/Healthimprovement/Alcoholmisuse/DH_...). This is due to significant evidence that maternal alcohol consumption has deleterious effects on the development of the unborn infant.

Fetal alcohol syndrome (FAS) is thought to be a leading cause of learning disability in the western world. Characteristics of FAS include; lower IQ, abnormal facial features and behavioural and mental health problems. Whilst FAS is caused by very heavy alcohol consumption for prolonged periods during pregnancy, it is thought that exposure to lower doses of alcohol in utero may cause less severe sub-optimal development, which is largely undetected. However, detecting these effects is problematic since alcohol consumption in the mother is heavily confounded by other lifestyle factors.

Proposed study

ALSPAC has collected information on maternal alcohol consumption through questionnaires at 12, 18 and 32 weeks of gestation as well as data regarding the drinking consumption of the mothers' parents. In addition quantity of maternal alcohol intake data is available related to the timing of fetal development; before pregnancy, first 3 months of pregnancy, at around the time first felt the baby move.

We also have genetic data on these mothers and children, and have shown that a common genetic variant in the ADH1B gene in mothers is associated with alcohol consumption levels during pregnancy. In addition we have shown that 4 genetic variants in ALSPAC children are related to their IQ at age 8, but only among children born to mothers who drank some alcohol during pregnancy. We plan to use these genotypes in an analysis of alcohol and children's behaviour to determine whether maternal alcohol consumption during pregnancy is likely to be causally related to problem behaviour in her offspring.

Children's behaviour problems (conduct problems and hyperactivity) have been assessed repeatedly from ages 4 to 16 years in ALSPAC, using the Strengths and Difficulties Questionnaire (SDQ) and the Development and Wellbeing Assessment (DAWBA). Based on these measures, three types of outcome are available for analyses: symptom scores (on the SDQ), diagnoses (using DAWBA), and longitudinal trajectories of conduct problems between ages 4-13 years (previously created by Barker and Maughan, 2009, using SDQ scores).

We will look at main effects of genotype on children's behaviour, and carry-out a stratified analysis to determine whether effects are due to exposure to alcohol rather than pleiotrophy.

References

Barker ED, Maughan B. Differentiating Early-Onset Persistent Versus Childhood-Limited Conduct Problem Youth. Am J Psychiatry. 2009;166(8):900-8.

Lewis SJ, Zuccolo L, Davey Smith G, Macleod J, Rodriguez S, Draper ES, Barrow M, Alati R, Sayal K, Ring S, Golding J, Gray R.Fetal Alcohol Exposure and IQ at Age 8: Evidence from a Population-Based Birth-Cohort Study.PLoS One. 2012;7(11):e49407. doi: 10.1371/journal.pone.0049407. Epub 2012 Nov 14.

Zuccolo L, Fitz-Simon N, Gray R, Ring SM, Sayal K, Davey Smith G, Lewis SJ. A non-synonymous variant in ADH1B is strongly associated with prenatal alcohol use in a European sample of pregnant women. Hum Mol Genet.2009;18:4457-66.

B2060 - Genetic study of smoking and nicotine dependence - 05/09/2013

Specific Aims:

The aims of this study are two-fold: 1. Identification of genes involved in nicotine dependence as measured by the FTND questionnaire; and 2 identification of genes involved in nicotine withdrawal as measured by the time to first cigarette (TFC), ascertained by the question "how soon do you smoke your first cigarette after you wake up in the morning".

Hypotheses:

If a trait is heritable, such as nicotine dependence, there must be gene(s) that influence the expression of the trait. Our hypothesis is, therefore, that since tobacco smoking and nicotine dependence have been demonstrated to be heritable, these traits must be influnced by some genes. Under this condition, if we collect a sufficient sample size, we should be able to detect some of those genes contributing to the traits by association analyses. To avoid selection bias, we plan to test all genes across the human genome.

Study Design:

We plan to use linear regression to analyze the association between genotypes and phenotypes. In the analyses, genotypes are treated as independent variables and pheotypes as dependent variables. Confounding variables, such as sex, age and population substructure will be used to exclude their effects. To maximize the coverage of the genome, genotype imputation will be performed to include all variants observed in the 1000 genomes project. The results from the ALSPAC sample will be combined with the results from other samples by meta-analysis.

B2059 - Dual trajectories of adolescent smoking and depression - 15/08/2013

Project outline:

Smoking and depression commonly co-occur in the general population. That is, individuals with depression are more likely to be smokers and smoke more heavily compared to individuals without depression, and smokers are more likely to report depressive symptoms compared to nonsmokers. In adolescents, there is also evidence of this relationship. It has been shown that depression and other mood disorders (e.g., anxiety) in adolescents increase the likelihood of experimental smoking and smoking initiation. Others have demonstrated that tobacco smoking among adolescents leads to increase depressive symptoms, which remit following cessation. Regardless of directionality, it is well-known that smokers with elevated depressive symptoms experience more difficulties when quitting smoking. Furthermore, concurrent depressive symptoms and tobacco use may interact synergistically to produce greater health risks than either disorder alone, especially for heart disease.

Better characterizing the developmental (longitudinal) relationship between these variables, particularly among adolescents, would be a significant contribution to the existing literature and provide evidence for the diversity in comorbidity of adolescent smoking and depression. This is an important area as both smoking and depression are related to increased use of other drugs and illicit substances, mental health distress, and physical health problems. Recently, much research has focused on modelling patterns in substance abuse and mood disorders across early developmental periods, but smoking and depression among adolescents have yet to be modelled in a dual trajectory analysis. Smoking trajectories for this cohort have been previously established and the data lend themselves to modelling trajectories of the development and early course of depression as well. The ALSPAC cohort presents an ideal dataset to be analysed as dual trajectories to model the comorbid development of smoking and depression in adolescents. Further, we can examine sociodemographic predictors and mental, behavioural, and physical outcomes of group membership.

Aims:

1. Examine the co-occurrence of smoking and depression among adolescents using dual trajectory modelling.

2. Explore outcomes between different trajectory groups, including:

a. mood symptoms (e.g., anxiety),

b. substance use (e.g., cannabis), and

c. biological markers (e.g., lung function).

We will use longitudinal latent class analysis to generate trajectories for adolescent smoking and depression, both separately and then in conjunction. Adolescent smoking will be based on self-reported smoking status. Adolescent depression will be based on the self-report MFQ.

Hypotheses:

We hypothesize that severity of tobacco use will be related to severity of depression (to be examined by cross tabulation). More specifically, we expect that adolescents who smoke will endorse higher levels of depressive symptoms, and that logical dual trajectories of adolescent smoking and depression will emerge. We also expect that there will be significant group differences, both in predictor variables (sociodemographics) and outcome variables (substance use, mood symptoms, and biological markers).

Variables:

Exposure variables. Smoking status will be determined by self-report during the clinical interview and depression will be determined by self-reported on the MFQ. These variables will then be modelled by dual trajectories which will elicit specific smoking x depression groups.

Outcome variables. Other substance use (e.g., cannabis), mood symptoms (e.g., anxiety), and biological markers (e.g., lung function). These outcome variables will be applied to both the groups that emerge from the individual trajectory models (smoking and depression) as well as those from the smoking x depression dual trajectory model.

Confounding variables. Smoking status and depression have also been shown to be differentially associated with gender, race, age, education and SES (housing tenure, crowding status and maternal educational attainment). Therefore these covariates will be included in our models. Another variable that has garnered attention recently is traumatic events in childhood, so we will explore the effect of early life stressors (e.g., abuse, deaths) on both smoking and depression.

B2057 - Funds to processes linked FE HE data - 01/08/2003

.2 The ALSPAC Cohort in Relation to Education Provision

The young people in the study span 3 academic years, referred to as the 'oldest', 'middle', and 'youngest' cohorts. The cases are unevenly distributed across the three years with approximately the following proportions: Oldest cohort - 25% Middle cohort - 60% Youngest cohort - 15%

2.3 Further & Higher Education, and Work Based Learning

In academic year 2007/08 the oldest cohort potentially entered Year 12 or may have left compulsory schooling. This means that they may no longer feature in the NPD, but for those undertaking further education, their educational participation should be picked up in the Individual Learner Record (ILR). In subsequent years they may also move into HE, where their participation would be picked up in the HESA Student Record. At these ages, the young people clearly become of prime interest to this department. Linking to the ILR and HESA data sets offers the potential to continue tracking the educational history of participants, offering the potential for in depth analyses of progression.

2.4 Publication Record

ALSPAC researchers have a strong track record of using linked education data. Over the past five years, 23 peer-reviewed papers have used linked data to investigate education related hypotheses.1-23 These publications used the wealth of data available from ALSPAC; incorporating the influence of genetic variation on attainment, and using detailed individual level data on social background and aspirations to help describe the impact of disadvantaged upbringings on life chances and aspirations. Evidence from ALSPAC, including linked education data, were used to contribute to the Independent Review on Poverty and Life Chances by Frank Field MP 'The Foundation Years: Preventing Poor Children becoming Poor Adults'24 and the Marmot Review 'Fair Society, Healthy Lives'.25

3. Project Summary

2.1 BIS will contract ALSPAC to conduct linkage to NPD/Data Service/HESA records to collect and process educational attainments for the ALSPAC cohort members from the age of 16 onwards. The linkage will focus on Further Education/ Vocational data provided in the ILR extract and Higher Education information provided by HESA and NPD.

2.2 A cost effective mechanism, using ALSPAC's existing linkage to the NPD, has been confirmed that will allow collection and linkage of ILR and HESA data alongside

KS5 data via the NPD. These data will follow on from the data collected from NPD under ALSPAC's contract with the DfE.

3. Proposed work

The key elements of the work to be undertaken are:

Arrange access to data & documentation Securely archive raw data Conduct linkage quality control work Anonymise the data set (remove personal identifiers, sensitive variables and replace NPD pupil IDs with a new unique ALSPAC ID) Reformat the data to ALSPAC standards to ensure compatibility with the linked schools data and self-reported participant data. Publish 'built' files of the data within the ALSPAC resource

Access and matching arrangements have been agreed as follows: Confirmation from the Department (BIS) that there is an ILR-NPD-HESA matched dataset; NPD and Dissemination Unit (Data Services Group) has advised us that the NPD-HESA matched dataset can be shared with ALSPAC under existing contractual arrangements with the Department for Education (DfE); NPD and Dissemination Unit (Data Services Group) has confirmed that the ILR-NPD matched dataset can be shared with ALSPAC once the contract with BIS has been confirmed.

Table 1 details the 5 elements of data linking included in the contract and the associated timings.

B2056 - Assessing the impact of partner smoking on cotinine levels in the ALSPAC mothers - 01/08/2013

Aim

To investigate the impact of partner smoking on maternal cotinine levels during pregnancy.

Hypotheses

Comparison of the magnitude of association of maternal and paternal smoking during pregnancy is a useful method for assessing whether smoking during pregnancy may have an intrauterine effect on offspring outcomes. (1) This has been used in ALSPAC to investigate the impact of smoking during pregnancy on offspring birthweight, blood pressure, trajectories of height and adiposity and attention deficit hyperactivity disorder. (2-4) This method assumes that the effect of passive smoking in utero on offspring of mothers who do not smoke but have partners who smoke is minimal. However, recent work in ALSPAC has demonstrated that maternal smoking is strongly associated with cotinine (a metabolite of nicotine) levels in non-smoking offspring during childhood and adolescence. (5) Therefore, it is possible that exposure to household smoking may be an important determinant of health outcomes. If this is the case, it may be necessary to control for this in comparisons of the effect of maternal and paternal smoking on offspring outcomes.

We aim to investigate the extent to which partner smoking affects maternal cotinine levels during pregnancy. Associations between partner smoking and maternal cotinine will be investigated using linear regression, stratified by self-reported smoking status of the mother. In addition, we will look at associations of partner smoking with cotinine in all mothers, adjusted for maternal smoking status and heaviness. It may be necessary to use cotinine cut offs to validate maternal self-reported smoking status.

Exposure variables

Paternal smoking status and heaviness

Stratify by maternal smoking status

Outcome variables

Maternal cotinine measured during pregnancy

Confounding variables

Age

Maternal BMI

1. Smith GD. Assessing intrauterine influences on offspring health outcomes: can epidemiological studies yield robust findings? Basic & clinical pharmacology & toxicology. 2008;102(2):245-56. Epub 2008/01/30.

2. Howe LD, Matijasevich A, Tilling K, Brion MJ, Leary SD, Smith GD, et al. Maternal smoking during pregnancy and offspring trajectories of height and adiposity: comparing maternal and paternal associations. International journal of epidemiology. 2012;41(3):722-32. Epub 2012/03/13.

3. Langley K, Heron J, Smith GD, Thapar A. Maternal and Paternal Smoking During Pregnancy and Risk of ADHD Symptoms in Offspring: Testing for Intrauterine Effects. American Journal of Epidemiology. 2012;176(3):261-8.

4. Brion MJ, Leary SD, Smith GD, Ness AR. Similar associations of parental prenatal smoking suggest child blood pressure is not influenced by intrauterine effects. Hypertension. 2007;49(6):1422-8. Epub 2007/04/04.

5. Stiby AL, Macleod J, Hickman M, Yip V, Timpson N, Munafo M. Association of Maternal Smoking With Child Cotinine Levels. Nicotine & tobacco research : official journal of the Society for Research on Nicotine and Tobacco. 2013.

B2055 - Injection drug use by the age of 21 socio-economic patterning parental substance use and early childhood adversity - 01/08/2013

Aims: The aim of this project is to investigate early risk factors of IDU in ALSPAC. Previous research has suggested that the onset of IDU is associated with family structure (not living with both parents, or in care or a foster home at any point) as well as early conduct problems, particularly school exclusion and childhood contact with the criminal justice system. Moreover, violence, criminality and financial problems in the family have been shown to be associated with increased risk as well as any types of carer substance use (Macleod et al 2012). However, these association have to date only been shown within the context of case control studies (Macleod et al 2012; Conroy et al., 2009; Tomas et al., 1990; Obot et al, 1999). To our knowledge there is no prospective evidence investigating the association between these early life risk factors and IDU in early adulthood.

Outcome variables: self-reported injecting drug use at ages 17 and 21

We will investigate IDU by age 17 and by age 21 and also create an outcome variable indicating IDU by age 21 (combining TF4 data with data from the 21yr questionnaire)

We propose to examine the following co-variates in relation to the outcome:

Indicators of socio-economic positioning

Indicators of early childhood adversity

- Contact with social services (mother self-report)

- "Child at risk" Register (linkage)

- Experience of victimisation (physical, emotional and sexual abuse during childhood)

- Antisocial behaviour

- Conduct disorder trajectories and early measures of conduct problems

- Alcohol, Smoking and substance use up to young adulthood

- Stessful life events in the child

- Post traumatic stress in the child

Educational measures:

- KS1 & KS2

- School exclusion and data on absenteeism (teacher reported, YP self-reported and linkage data)

Parental factors

- Parental substance use including smoking, alcohol problems, drug taking and injection drug use

- Indicators of family involvement with the police/court, criminal convictions

- Cruelty within the family (towards the carer, towards child), financial hardship

References:

Macleod J, Hickman M, Jones J, Copeland L, McKenzie J, De Angelis D, Kimber J & Robertson JR (2012): Early life influences on the risk of injecting drug use: case control study based on the Edinburgh Addiction Cohort. Addiction. Vol.108(4). pp. 743 - 750

Conroy E, Degenhardt L, Mattick RP & Nelson E (2009): Child maltreatment as a risk factor for opiod dependence:comparison of family characteristics and type and severity of child maltreatment with a matched control group. Child Abuse & Neglect. Vol.33. pp. 343 - 352.

Tomas JM, Vlahov D, Anthony JC (1990): Association between intravenous drug use and early misbehaviour. Drug & Alcohol Dependency. Vol.25. pp. 79 - 89.

Obot IS & Anthony JC (1999): Association of school dropout with recent and past injecting drug use among African American adults. Addicitive Behaviour. Vol. 24. pp. 701 - 705.

B2054 - Antisocial and callous behaviour the role of fish intake and their associated fatty acids - 01/08/2013

Background: Antisocial behaviour in childhood and adolescence has been associated with more serious offending in adulthood [1]. Recent evidence suggests that the consideration of calluous and unemotional traits may further define the psychopathology [2]. It is clear that individuals can have different trajectories with early onset persistent problems identifying a particularly high risk group [3]. Other research has also shown a number of antecedents reflecting child characteristics (such as uncontrolled temperament and low self-esteem), parenting skills and the home environment including inter-parental conflict [4, 5]. Studies have also shown associations between exposures during pregnancy and behaviour many years later [5]. But to date research on dietary influences and in particular the role of omega-3 fatty acids has been limited. What evidence exists warrants further investigation of these issues [6].

Aims: To examine and further refine the phenotype based upon potential comorbid characteristics such as particular facets of behaviour, motor skills, language impairments and IQ. To explore the associations of varying risk groups with fish intake and fatty acids.

Hypotheses: (a) That high intakes of omega-3 as reflected in high fish intakes and high blood levels will lower risk for antisocial and callous behaviour. Such effects may be more strongly associated with DHA.

(b) That the ratio of omega-6 to omega-3 fatty acids reflecting an inflammatory response index may independently increase risk of outcomes.

(c) That the fetal environment as reflected by maternal fatty acids and fish intake may 'program' the child to be more susceptible or more resilient to potential risk factors.

Outcomes: Antisocial and callous behaviour taking account of other comorbid conditions.

Exposures: Fish intake and fatty acids obtained from blood samples.

Confounders: Socio-economic, maternal psychopathology, parenting and the home environment.

Analyses are likely to be untaken in parallel both in the USA and Bristol.

References

1. Benda BB, Corwyn RF, Toombs NJ. Recidivism among adolescent serious offenders: Prediction of entry into correctional system for adults. Criminal Justice and Behavior 28:5 (2001), pp 588-613

2. Rowe R, Maughan B, Moran P, Ford T, Briskman J, Goodman R. The role of callous and unemotional traits in the diagnosis of conduct disorder. Journal of Child Psychology and Psychiatry 51:6 (2010), pp 688-695

3. Barker ED, Oliver BR, Maughan B. Co-occurring problems of early onset persistent, childhood limited, and adolescent onset conduct problem youth. Journal of Child Psychology and Psychiatry 51:11 (2010), pp 1217-1226

4. Bowen E, Heron J, and Steer C. Anti-Social and Other Problem Behaviours Among Young Children: Findings From the Avon Longitudinal Study of Parents and Children. London: Home Office; 2008. Report 02/08.

5. Barker ED, Maughan B. Differentiating Early-Onset Persistent Versus Childhood-Limited Conduct Problem Youth. American Journal of Psychiatry 166:8 (2009), pp 900-908

6. Kohlboeck G, Glaser C, Tiesler C, Demmelmair H, Standl M, Romanos M, Koletzko B, Lehmann I, Heinrich J, for the LISAplus Study Group. Effect of fatty acid status in cord blood serum on children's behavioral difficulties at 10 y of age: results from the LISAplus Study. American Journal of Clinical Nutrition 94:6 (2011), pp1592-1599.

B2051 - Identifying common genetic variants and putative genes associated with facial traits - 29/08/2013

Dysmorphic facial features play a prominent role in the diagnosis of a variety of classical neurodevelopmental disorders. For example, Down syndrome1, Prader-Willi syndrome2 and Foetal Alcohol Syndrome3 are all associated with characteristic facial features that are used as part of the diagnostic criteria. In recent years, the development of 3D geometric morphometrics (the statistical analysis of face shape) allowed researchers to identify more subtle facial dysmorphologies4. Hennessy et al5 found subtle differences in the 3D facial shape of schizophrenia patients compared to controls, such as a lengthened lower mid-facial height in schizophrenia patients. Hennessy et al6 also found that bipolar patients exhibited several facial dysmorphologies relative to controls and schizophrenia patients. The development of the face and the brain is closely connected7. Facial dysmorphologies therefore provide insight into the developmental origins of neurodevelopmental disorders, since the developmental biology of facial features is better understood than that of the brain5.

Craniofacial morphology is highly heritable8-11. Yet, fairly little is known about the genetic variants that influence normal craniofacial development in the general population. 3D geometric morphometric techniques can be used to identify these genetic variants, which could provide a valuable resource for future studies on craniofacial development and a variety of genetically determined neurodevelopmental disorders. For example, Paternoster et al12 found a significant association between a variant of the PAX3 gene and nasion position (the point in the skull where the nasal and frontal bones unite) in the Avon Longitudinal Study of Parents and their Children (ALSPAC) data set. Mutations in the PAX3 gene has previously been associated with Waardenburg syndrome13.

Evolutionary approaches to the study of facial traits provide three general facial traits that could be useful in the identification of genetic variants associated with craniofacial development: symmetry, averageness and sexual dimorphism. Symmetry indicates an individual's ability to resist environmental and genetic stresses during development14-16. It follows that fluctuating asymmetry (a deviation from bilateral symmetry in normally bilaterally symmetrical traits) is associated with a variety of genetic disorders and some indicators of poor health during development16-20. For example, Hammond et al19 found significantly higher facial asymmetry in young boys with autism spectrum disorders, compared to age/sex/ethnicity matched controls.

Facial averageness is defined as the proximity of a face to the sex-specific average face for that population21. In other words, how closely the face resembles the majority of same sex faces in the population. Symons22 hypothesised that average features could be functionally optimal as a result of the stabilising effect of natural selection. Theoretically, averageness might also denote genetic heterozygosity23. Few studies have investigated the relationship between facial averageness, genetic disorders and more general health. Nevertheless, genetic diseases are often associated with multiple facial dysmorphologies1,2,5,6, which do make these faces fairly distinctive compared to the population mean. Rhodes et al24 also found a weak positive association between facial averageness and general health scores.

Sexual dimorphism is defined as the phenotypic difference between males and females of the same species. In other words, how masculine or feminine a person is. Male and female faces diverge at puberty due to the action of sex hormones16,25. The age of onset, rate and extent to which faces become sexually dimorphic differ between individuals and are partly determined by genes26. Masculinity in male faces is generally assumed to serve as an indicator of immunocompetence21,27,28, although recent work has called the relationship into question28-30. Femininity in female faces does not seem to be associated with immunocompetence31,32, but is significantly associated with late follicular oestrogen levels33. Abnormal sexual dimorphism is also a characteristic of certain genetic diseases, such as Klinefelter syndrome34.

The primary aim of this study is to identify common genetic variants, and ultimately putative genes, that are associated with facial symmetry, averageness and sexual dimorphism using Genome-Wide Association (GWA) methodologies. We specifically chose the ALSPAC dataset because it is, to our knowledge, the largest dataset with both facial images and GWA data. To accomplish this aim, the 3D facial images will be manually delineated by defining 38 feature points in the software program MorphAnalyser (developed by Dr Tiddeman, Aberystwyth University, UK); this method is identical to the method used in Coetzee et al35. The delineated 3D images will then be used to calculate indexes for symmetry, averageness and sexual dimorphism in MorphAnalyser. The ALSPAC team have cleaned and imputed a GWA study dataset consisting of 8365 individuals with genotype calls for ~2.5 million common variants spread across the genome. We will use this resource to conduct a 2 stage (discovery and replication) genome-wide association study. Initially the discovery phase will include analysing ~ 5000 individuals that have both genotypic data and facial images. Power analysis (PowerGwas/QT version 1.0)36 indicate a sample size of 5000 is adequate to provide 80% statistical power to detect single nucleotide polymorphisms (SNPs) that explain as little as 0.8% of the variance in facial traits. The association between each of the ~2.5 million SNPs (exposure variables) and facial symmetry, averageness and sexual dimorphism (outcome variables) will be independently tested in the ALSPAC cohort using linear additive regression. SNP associations that exceed the standard significance threshold for genome-wide significance (p less than 5 x 10 -8)37, will be identified and replicated independently in additional cohorts, making up the second replication phase for the GWA study.

To determine which genes (and pathways) are most likely associated with these facial traits we will conduct a range of post-hoc analyses including (a) assigning SNPs to genes, (b) epistasis modelling and (c) pathway analyses. Briefly, multiple genes are ascribed to each SNP and these genes are then prioritised using epistasis modelling and pathway analysis38, allowing us to further identify which biological processes regulate these facial traits. In addition, we will calculate heritability estimates for each of the three facial traits; do a GCTA analysis to estimate how much of the phenotypic variance in the facial traits are explained by common SNPs; test the relationship between admixture and the facial traits (especially averageness); test the relationship between genome-wide heterozygosity and the facial traits (especially symmetry and averageness) using the ~2000 ALSPAC individuals who have whole genome sequencing data; and test the association between previously imputed classical HLA alleles and these facial traits separately for males and females. All GWA analyses will be conducted at the University of Bristol.

The second aim is to determine the association between health measures (exposure variables) and facial symmetry, averageness and sexual dimorphism (outcome variables). The health measures will be divided into prenatal risk factors (e.g. parental age, presence of gestational diabetes) and childhood health measures (e.g. body mass index, blood pressure and self-reported health). All three facial traits are generally assumed to indicate good health27, but studies testing these assumptions have suffered from various methodological drawbacks, including small sample sizes (~N=40-200). The size and quality of the ALSPAC data set, especially the wide range of physiological measurements, provides us with the ideal opportunity to test the association between health indices and these three facial traits in male and female faces respectively.

The third aim is to determine whether SNPs associated with these facial traits are also associated with traits proposed to indicate overall condition, specifically increased height and body mass index (BMI; within the healthy BMI range). To do so we will test the relationship between allelic scores of SNPs for the three facial traits, height and BMI.

To accomplish these aims we kindly request access to the following data in the ALSPAC dataset

Concept

Specific measure

Person

Source

Time point

Prenatal risk

Maternal age

Mother

Q

8-42 wks gestation

Prenatal risk

Paternal age

Mother

Q

12 wks gestation

Prenatal risk

Height & weight

Mother

C

1st trimester

Prenatal risk

Gestational diabetes

Mother

C

1st-3rd trimester

Prenatal risk

Blood pressure

Mother

C

1st-3rd trimester

Prenatal risk

Smoking

Mother

Q

18 wks gestation

Prenatal risk

Alcohol use

Mother

Q

18 wks gestation

Prenatal risk

General health

Mother

Q

32 wks gestation

Childhood health

Hospital admittance

Child

Q

4 wks-69 mths

Childhood health

General health

Child

Q

6-91 mths

Childhood health

Specific health problems (e.g. coughing)

Child

Q

4 wks-91 mths

Childhood health

Height & weight

Child

C

4 mths-17 yrs

Childhood health

Fat and lean mass from DXA scan

Child

C

9-17 yrs

Childhood health

Lung function

Child

C

61 mths-17 yrs

Childhood health

Grip strength

Child

C

11 yrs

Childhood health

Blood pressure & pulse rate

Child

C

37 mths-17 yrs

Childhood health

Blood pressure after exercise

Child

C

9-17 yrs

Confounding

Pubertal development

Child

Q

175 mths (or PUB7)

Images

Facial scans

Child

C

15 yrs

Genetic

Genome wide association data

Child

C

-

questionnaire=Q; clinic=C; weeks=wks; months=mths; years=yrs

References

1. Farkas LG, Katic MJ, Forrest CR, et al (2001) J Craniofac Surg, 12, 373-379.

2. Holm VA, Cassidy SB, Butler MG, et al (1993) Pediatrics, 91, 398-402.

3. Fang S, McLaughlin J, Fang J, et al (2008) Orthod Craniofac Res, 11, 162-171.

4. Hammond P. (2007) Arch Dis Child, 92, 1120-1126.

5. Hennessy RJ, Lane A, Kinsella A, et al (2004) Schizophr Res, 67, 261-268.

6. Hennessy RJ, Baldwin PA, Browne DJ, et al (2010) Schizophr Res, 122, 63-71.

7. Diewert V, Lozanoff S & Choy V. (1993) J Cran Genet Dev Bio, 13, 193.

8. Kohn L. (1991) Annu Rev Anthropol, 20, 261-278.

9. Hunter WS, Balbach DR & Lamphiear DE. (1970) Am J Orthod, 58, 128-134.

10. Nakata M, Yu P-I, Davis B, et al (1973) Am J Orthod, 63, 471-480.

11. Johannsdottir B, Thorarinsson F, Thordarson A, et al (2005) Am J Orthod Dentofac, 127, 200-207.

12. Paternoster L, Zhurov AI, Toma AM, et al (2012) Am J Hum Genet, 90, 478-485.

13. Tassabehji M, Read AP, Newton VE, et al (1993) Nat Genet, 3, 26-30.

14. Mather K. (1953) Heredity, 7, 297-336.

15. Van Valen L. (1962) Evolution, 16, 125-142.

16. Thornhill R & Moller AP. (1997) Biol Rev, 72, 497-548.

17. Sforza C, Dellavia C, Tartaglia GM, et al (2005) Int J Oral Max Surg, 34, 480-486.

18. Markow TA & Wandler K. (1986) Psychiat Res, 19, 323-328.

19. Hammond P, Forster-Gibson C, Chudley AE, et al (2008) Mol Psychiatr 13, 614-623.

20. Livshits G & Kobyliansky E. (1991) Hum Biol, 63, 441-446.

21. Rhodes G. (2006) Annu Rev Psychol, 57, 199-226.

22. Symons D. (1979) The evolution of human sexuality, Oxford University Press.

23. Thornhill R & Gangestad SW. (1993) Hum Nat, 4, 237-269.

24. Rhodes G, Zebrowitz LA, Clark A, et al (2001) Evol Hum Behav, 22, 31-46.

25. Farkas LG & Munro, IR (1988) Anthropometric Proportions in Medicine, Thomas, p29-56.

26. Mustanski BS, Viken RJ, Kaprio J, et al (2004) Dev Psychol, 40, 1188-1198.

27. Thornhill R & Gangestad SW. (1999) Trends Cogn Sci, 3, 452-460.

28. Scott IML, Clark AP, Boothroyd LG, et al (2012) Behav Ecol, 24, 579-589.

29. Rantala MJ, Coetzee V, Moore FR, et al (2013) P Roy Soc Lond B Bio, 280, 1471-2954.

30. Lie HC, Rhodes G & Simmons LW (2008) Evolution, 62, 2473-2486.

31. Rhodes G, Chan J, Zebrowitz LA, et al (2003) P Roy Soc Lond B Bio, 270, S93-S95.

32. Thornhill R & Gangestad SW. (2006) Evol Hum Behav, 27, 131-144.

33. Law Smith MJ, Perrett DI, Jones BC, et al (2006) P Roy Soc Lond B Bio, 273, 135-140.

34. Kamischke A, Baumgardt A, Horst J, et al (2003) J Androl, 24, 41-48.

35. Coetzee V, Re DE, Perrett DI, et al (2011) Body Image, 8, 190-193.

36. Feng S, Wang S, Chen C-C, et al (2011) BMC Genet, 12, 12.

37. Corvin A, Craddock N & Sullivan PF. (2010) Psychol Med, 40, 1063-1077.

38. Cantor RM, Lange K & Sinsheimer JS. (2010) Am J Hum Genet, 86, 6-22.

B2050 - Meta-analysis of maternal smoking during pregnancy and methylation in offspring - 18/07/2013

AIMS

To investigate the relationship between maternal smoking habits during pregnancy (i.e. smoking status, sustained smoking/smoking duration, smoking quantity) and DNA methylation levels in cord blood samples from newborn offspring utilising the ALSPAC-ARIES HM450 dataset. This analysis will form part of a meta-analysis across multiple study cohorts.

Overall research question: Is maternal smoking during pregnancy related to CpG site-specific methylation in newborns?

ANALYSIS PLAN

Exposure variable: Four questions have been drawn up to address issues relating to smoking habits throughout pregnancy, timing, dosage and paternal effects. It is acknowledged that not all individual study cohorts will have the relevant data to address all these questions. Hence, each study cohort should address those applicable.

1. Active smoking

a. Sustained active smoking versus no smoking (dichotomous): mothers who smoked during most of the pregnancy/into late pregnancy (2nd/3rd trimester) versus those who did not smoke at all during pregnancy (including those who quit prior to pregnancy).

b. Early pregnancy smoking versus no smoking (dichotomous): mothers who smoked during early pregnancy and quit later versus those who did not smoke at all during pregnancy (including those who quit prior to pregnancy).

c. Ever smoked versus no smoke (dichotomous): mothers who reported smoking at anytime during pregnancy versus those who did not smoke at all during pregnancy (including those who quit prior to pregnancy).

2. Passive smoking

Definition: any indication that mothers were exposed to passive smoking (i.e. partner smoked, other relatives/household members smoked, exposed at home, exposed at work, quantified e.g. greater than 1 hour per day). Perform analysis in non-smokers only, split into passive and non-passive smoking as appropriate (Dichotomous). If possible, perform analyses in the three sets as above.

3. Smoking quantity

Definition: if possible split mothers by 1-9 cigarettes per day, 10+ cigarettes per day, non-smokers (trichotomous). If possible, perform analyses in the three sets as above.

4. Smoking in biological father

If smoking status of biological father is known perform analyses on paternal smoking prior to pregnancy (yes/no, dichotomous).

Outcome variable: DNA methylation utilising the HM450 ARIES data on cord blood samples. If possible, use the raw beta values for all probes i.e. with no normalisations or transformations. Alternatively (or in addition) perform preferred QC and pre-processing analyses as necessary.

Statistical Analysis: Perform robust linear regression with individual CpG site methylation levels as the outcome variable and smoking status as the exposure of interest. Include any potential confounders on a cohort-specific manor. Summary statistics will be provided to Dr Jourbert at NIEHS enabling mixed/random effects modelling in downstream meta-analyses.

Confounders for ALSPAC-ARIES: Definition - any factor associated with the exposure variable (i.e. smoking variable) and plausibly associated with DNA methylation. Assess the potential confounding effects of the following variables and include within the statistical model as necessary: sex, genetic ancestry/ethnical background, social-economical background, maternal age, pre-pregnancy BMI, parity.

Possible Sensitivity analyses: Perform the primary model (sustained vs non-smoke) adjusting for cell composition if possible and adjusting/stratified for preterm birth.

Other stipulations: restrict analyses to singleton births. Do not adjust for gestational age or birth weight in the first instance as these may be on the causal pathway linking smoking, methylation and health outcomes.

B2049 - Socioeconomic distribution of excess weight in children - 18/07/2013

Aim:

We propose to go beyond prevalence-based methods to test the relationship between obesity and parental income amongst children and investigate the differences by race/ethnicity and gender.

Hypotheses:

1. a)Using Unconditional Quantile Regression (Joliffee 2011) with BMI Z-scores the independent variable, low socio-economic status will be associated with greater weight at the overweight and obese BMI Z-score thresholds.

b)When accounting for parental weight status (overweight or obese), the coefficient for the effect of income on child BMI Z-scores at the overweight and obese thresholds will be reduced

c) Comparing Ordinary Least Squares estimates for the effect of parental weight status and income on child BMI Z-scores will underestimate the effect at the overweight and obese thresholds.

2. a) The net concentration index for measures of child obesity will be negative

b) A significant proportion of the concentration index for measures of child obesity will be explained by parental and weight status. Including parental obesity status will reduce the independent effect of income on obesity status for children.

The results of this analysis has policy implications. If the coefficient is significant after controlling for parental obesity status, this may indicate that healthy weight initiatives should target poor children. If, however, the coefficient becomes insignificant, policies should target all children and particularly children with overweight or obese parents.

Exposure variables:

Income, parental weight status

Outcome variable:

BMI z-score (calculated using weight, height, gender and age)

Confounding variables:

Socioeconomic measures such as ethnicity, lifestyle behaviours including diet, TV viewing, physical activity, tobacco use, and sleep duration.

Reference List:

Jolliffe, D. (2011). Overweight and poor? On the relationship between income and the body mass index. Economics & Human Biology, 9, 342-355.

B2048 - CLOSER work package one Data harmonisation of measures of biological function and structure across the cohorts - 18/07/2013

Aims:

To facilitate cross cohort work by harmonising measures of biological structure and function across the UK birth cohort studies, starting with weight and height in the 1946, 1958, 1970, 2000 birth cohort studies, plus ALSPAC. To sue the harmonised measures in two demonstration papers that:

1) compare body size distributions and mean trajectories, across different phases of the life course, between cohorts, and

2) investigate how SEP inequalities (using measures harmonised in CLOSER work package 2) in body size trajectories, across different phases of the life course, differ between cohorts. To extend the harmonised dataset to include data from other birth cohort studies (e.g. HCS, SWS, Biobank) and other measures of biological structure and function (e.g. blood pressure and grip strength), if necessary.

B2047 - Modifiable risk factors for depression in adolescents - understanding the role of physical activity and obesity - 18/07/2013

We aim to investigate the association between objective measures of obesity and physical activity and depression in adolescents.

1. To investigate the association between obesity, measured objectively, and depression in adolescents, including the possibility of a bi-directional association

2. To investigate the association between physical activity, measured objectively, and depression in adolescents, including the possibility of a bi-directional association

3. To investigate the inter-relationship of these modifiable risk factors.

B2046 - Social and genetic trajectories from motor development to academic attainment via energy balance-related behaviour - 18/07/2013

The aim of this project is to examine the effects of infant motor development on adolescent energy balance-related behaviour (EBRB) (physical activity and sedentary behaviour), and to identify learning and development, behavioural and health-related factors that mediate these effects (study I). In addition, we aim to examine the effects of self-reported and objectively measured EBRB on adolescent self-reported and teacher-rated academic achievement, and to identify factors/processes that mediate these effects (study II).

We hypothesise that early infant motor development predicts adolescent EBRB via developmental, behavioural and health-related factors like learning, behaviour/psychopathology, language development, personality, motor abilities and behaviour, anthropometry and various physical and mental health measures. We also hypothesise that EBRB predicts academic attainment via social, psychological and health-related factors like cognitive function, self-esteem, academic motivation and goal setting, interpersonal and social skills, psychopathology and school enjoyment, sleep, stress, obesity and physical fitness.Because of partly explorative nature of the study, mediating variables will be specified during structural equation model (SEM) building.

In study I, infant motor development at the age of 6 and 18 months is the main independent factor. Dependent variables include objectively and subjectively measured physical activity and sedentary behaviour/time. Possible mediating factors include parent-reported, teacher assessed and/or clinically measured learning (e.g. learning abilities and performance), behaviour/psychopathology (e.g. emotional and behavioural problems), language development, personality (e.g. self-concept, sensation seeking and locus of control), motor abilities and behaviour (e.g. gross and fine motor skills), anthropometry (height, weight and fat mass) and physical and mental/psycho-social health measures.

In study II, independent variables include objectively and subjectively measured physical activity and sedentary behaviour/time from age 7 to 16 years. Dependent variables are academic achievement at age 16 years, including spelling, understanding mathematics and science and school experiences and aspirations. Possible mediating factors include teacher assessed and clinically measured learning (e.g. learning abilities and performance), cognitive function, self-concept and academic self-confidence, interpersonal and social skills and relationships, behaviour/psychopathology (e.g. emotional and behavioural problems), school enjoyment, anthropometry (height, weight and fat mass), physical fitness, as well as physical and mental health measures.

B2045 - UK10K Secondary proposal age at menarche - 04/07/2013

As part of an approved UK10K secondary proposal, we aim to perform an age of menarche whole-genome meta-analysis between ALSPAC and Twins UK. A UK10K secondary proposal covers any phenotype not included as a 'core' trait intended to be published as part of UK10K. We aim to analyse menarche and publish as a separate satelite paper at a similar time to the main UK10K effort.

There are two genetic datasets used in this project (that are already available within UK10K):

The ALSPAC UK10K sequence genotypes

Imputed UK10K genotypes from the wider ALSPAC GWAS sample

(We will perform two models, using the same statistical parameters used by the ReproGen consortium.

Model A: Menarche ~ SNP + Birth year

Model B: Menarche ~ SNP + Birth year + BMI (closest to age at menarche)

Model C: Menarche ~ SNP + Birth year + BMI (furthest time point from menarche available)

Similar to the core analyses in UK10K, we aim to perform a 4-way meta-analysis of the following strata:

Discovery sequence genotypes in ALSPAC

Discovery sequence genotypes in Twins UK

Imputed UK10K sequence genotypes from wider GWAS in ALSPAC

Imputed UK10K sequence genotypes from wider GWAS in Twins UK

We plan to share both individual level data (where possible) and summary level SNP results for meta-analysis. Only analysts registered on a UK10K data access agreement will be using the data - currently covers John Perry (KCL side) and Carolina Bonilla (ALSPAC side) for this project.

B2044 - Association between mitrochondrial copy number and chronic stress - 18/07/2013

Aims . The aim of this proposal is to determine whether there is an association between mitochondrial (MT) copy number and measures of chronic stress (particularly early childhood chronic adversity). This analysis will only be possible using the ALSPAC sample included in the UK 10K project as I need sequence data to answer this question.

Hypotheses

Based on preliminary data from a case control study of major depression I think that early childhood chronic adversity elevates MT copy number, through an unknown mechanism. From DNA sequence data I have observed that in both cases and controls there is correlation between the following measures and MT copy number: neuroticism, number of stressful life events, childhood sexual abuse.

Variables

A meausure of susceptibility to stress (neuroticism), number of stressful life events (we used the 16 item stressful life events questionnaires), and measures of childhood abuse (we interrogate specifically non-genital, genetal and intercourse). Meaures of MT copy number are obtained from the numbers of reads mapping to the reference MT genome, normalized by the reads mapping to the autosomes (I use read data only from one chromosome to get this measure).

Outcomes

A linear model including age and weight, is used to predict MT copy number.

Confounds

As far as we know, age and weight are the only relevant confounds.

B2043 - Unwanted pregnancy and psychosis in the offspring An analysis of the data from the ALSPAC - 04/07/2013

Background: Over the last decade, there has been a renewed interest in the role of environmental adversities in the development of psychotic experiences (1-3). It is becoming increasingly evident that such experiences should be understood as "endpoints of atypical developmental trajectories" (5, 6).

In our work at the University of Liverpool, we have also found that communication deviance seems to be especially prevalent in the mothers of psychotic offspring (4). In the same paper, we suggest that disruptions in the child's early development may explain the findings from large birth cohort studies that document subtle developmental asymmetries in children who are later diagnosed with Schizophrenia (10-12).

One risk factor that has been found to be associated with later development of psychosis in the offspring is the unwantedness of the pregnancy (7-9). Unfortunately, these findings have received little attention from the research community and consequently little or no attention has been devoted to explore the potential developmental pathways and mediators that could explain such relationship.

Overall aim: The current study has the primary aim to replicate Myhrman et al.'s findings (7) and secondarily to explore potential mediators of this previously reported association.

Project 1

Aims: To investigate the association between unwanted pregnancy and psychotic experiences in the ALSPAC dataset

Hypothesis: It is anticipated that unwanted pregnancy will be associate with increased likelihood of self-reported psychotic experiences in the offspring.

Exposure variable(s): Unwantedness of the pregnancy

Outcome variable(s): Psychotic experiences

Cofounding variable(s): Maternal history of psychosis, family history of psychosis, socio-economic variables.

Project 2

Aims: To investigate potential mediators of the relationship between unwanted pregnancy and psychotic experiences

Hypothesis: It is anticipated that unwanted pregnancy and paranoia in the offspring will be mediated by low self-esteem, poor self-concept and external locus of control

Exposure variable(s): Unwantedness of the pregnancy

Outcome variable(s): Psychotic experiences [e.g. 'delusions of being spied on' (D1) and 'delusions of persecution' (D2)].

Cofounding variable(s): Maternal history of psychosis, family history of psychosis, socio-economic variables.

Project 3

Aims: To investigate potential mediators of the relationship between unwanted pregnancy and psychotic experiences

Hypothesis: It is anticipated that unwanted pregnancy and self-reported psychotic experiences in the offspring will be mediated by neuro- and social-cognitive variables.

Exposure variable(s): Unwantedness of the pregnancy

Outcome variable(s): Social cognition, neuro-cognition and psychotic experiences

Cofounding variable(s): Maternal history of psychosis, family history of psychosis, socio-economic variables.

Planned analysis:

Paulo de Sousa (PhD student) will carry out the statistical analysis. Initially, basic association between symptoms of psychosis (PLIKSi) and unwanted pregnancy will be tested using binary logistic regression. In a second stage, several mediation models will be estimated using Mplus 6.1.

Bibliographic references

1. Bentall RP. Madness explained: Psychosis and human nature. London: Allen Lane; 2003.

2. Bentall RP. Doctoring the mind : is our current treatment of mental illness really any good? New York: New York University Press; 2009.

3. Varese F, Smeets F, Drukker M, et al. Childhood adversities increase the risk of psychosis: A meta-analysis of patient-control, prospective- and cross-sectional cohort studies. Schizophrenia Bull 2012;38(4):661-671.

4. De Sousa P, Varese F, Sellwood W, Bentall, RP. Parental Communication and Psychosis: A Meta-analysis. Schizophr Bull 2013: sbt088v1-sbt088.

5. Bentall RP, Fernyhough C, Morrison AP, Lewis S, Corcoran R. Prospects for a cognitive-developmental account of psychotic experiences. Brit J Clin Psychol 2007;46:155-173.

6. Bentall RP, Fernyhough C. Social predictors of psychotic experiences: Specificity and psychological mechanisms. Schizophrenia Bull 2008;34(6):1012-1020.

7. Myhrman A, Rantakallio P, Isohanni M, Jones P, Partanen U. Unwantedness of a pregnancy and schizophrenia in the child. Brit J Psychiat 1996;169(5):637-640.

8. Herman DB, Brown AS, Opler MG, et al. Does unwantedness of pregnancy predict schizophrenia in the offspring? Findings from a prospective birth cohort study. Soc Psych Psych Epid 2006;41(8):605-610.

9. McNeil TF, Schubert EW, Cantor-Graae E, et al. Unwanted pregnancy as a risk factor for off spring schizophrenia-spectrum and affective disorders in adulthood: a prospective high-risk study. Psychol Med 2009;39(6):957-965.

10. Cannon M, Caspi A, Moffitt TE, Harrington H, Taylor A, Murray RM, Poulton R. Evidence for early childhood, pan-developmental impairment specific to schizophreniform disorder: results from a longitudinal birth cohort. Archives of General Psychiatry 2002;59:449-456.

11. Jones P, Rodgers B, Murray R, Marmot M. Child development risk factors for adult schizophrenia in the British 1946 birth cohort. Lancet 1994;344:1398-1402.

12. Welham J, Isohanni M, Jones P, McGrath J. The antecedents of schizophrenia: a review of birth cohort studies. Schizophrenia Bull 2009;35(3):603-623.

B2042 - The Role of Epigenetic Processes in the Developmental of Psychotic Experiences and Disorders in a Non-Clinical Population ALSPAC Study - 04/07/2013

Aims of the Proposed Research

Paper 1: To investigate the role of perinatal insults on gene methylation in mother and child pairs, during pregnancy and at birth, respectively.

Paper 2: To investigate the role of gene methylation (genome-wide DNA methylation) in psychotic experiences at age 12 and 18 years, and a diagnosis of psychotic disorder at age 18 years.

Paper 3: To investigate the role of perinatal insults and gene methylation (genome-wide DNA methylation) in psychotic experiences at age 12 and 18 years, and a diagnosis of psychotic disorder at age 18 years.

Hypotheses

Obstetric complications are expected to result in differential methylation of mother and child gene pairs. Similarly, differential gene methylation in ALSPAC children is expected to be associated with psychotic experiences at age 12 and 18 years, and also with diagnosis of psychotic disorder at age 18 years.

An agnostic stance, rather than a targeted approach, will be used to investigate relationships between early adverse exposures, gene methylation and psychotic experiences. Hypotheses regarding specific gene candidates will not be considered prior to conducting the proposed research.

B2041 - Epigenetic processes mediating between early environment development and psychopathology - 04/07/2013

Summary of aims and objectives: This study will capitalise on environmental, biological and

behavioural data that, together with sequential DNA collections over four time points, from infant

and child saliva, are already available from the Wirral Child Health and Development Study

(WCHADS). This is an MRC funded cohort recruited in pregnancy and followed, so far, to age 5

years, established to identify prenatal, infancy and early childhood risks for child psychopathology.

There is a strong focus on early processes underpinning risks for the conduct disorders, but with

emerging findings also in internalising symptoms. The study has limited funding for genotyping but

none for epigenetics. It is distinctive among cohort studies in using a two stage design that enables

detailed observational and experimental data obtained during pregnancy, infancy and childhood to

be conducted on an epidemiological sample. We are not aware of any other studies that combine

such intensive measurement with sequential DNA collection early in life. We will carry out

comprehensive analyses of DNA methylation allowing us to develop a detailed picture of the

epigenome and gene regulation over early development and in relation to continuities and

discontinuities in early experiences, and stable and changing behavioural phenotypes. The case for

the application is made on the basis of the distinctiveness of the data available from this sample,

and also the degree of overlap and complementarity with collaborating studies, which will allow for

data sharing and replication of novel findings. So far collaborations on methylation analyses have

been established with Barker & Mills (NIH funded study) who have a study of methylation pathways

to conduct disorder using a subsample of ALSPAC participants; Generation R Holland, Teiemier;

McGill University, Canada, Meaney, O'Donnell. We also anticipate collaborative data sharing with a

much wider range of groups, especially those that have identified methylation over regions of

interest later in life, and wish to examine the contributions of early experiences in those regions.

Specific aims include a) to provide evidence on methylation patterns mediating links between

prenatal and early postnatal environmental exposures and later biological and behavioural

outcomes, b) examine the role of differential methylation in explaining gene by environment

interactions in early development, c) use environmental predictors to identify novel environment

sensitive regions of the genome for further study in relation to behavioural phenotypes, d) make use

of our repeated DNA and observational measures to extend findings in other studies, e.g. examine

earlier methylation patterns through infancy in pathways to conduct disorders identified in a

subgroup of the ALSPAC cohort (NIH; Barker & Mills) on the basis of methylation estimated at birth

and later childhood at ages 7 and 9 years.

B2040 - Exploring the developmental overnutrition hypothesis using an allelic score as an instrumental variable - 04/07/2013

AIMS - To determine whether there is a causal, independent intra-uterine effect of maternal BMI and glycemic profile on offspring adiposity and glycemic profile over the lifecourse

HYPOTHESIS - The developmental overnutrition hypothesis describes how intra-uterine conditions affect lifelong risk of offspring obesity. High maternal glycose, free fatty acid, and amino acid concentrations to which the fetus is exposured during pregnancy are proposed to result in permanent changes in appetite control, neuroendocrine functioning, or energy metabolism, leading to increased birth size and greater adiposity in later life. Since maternal BMI is positively associated with insulin resistance and glucose intolerance, and therefore higher plasma concentrations of glucose, fetal overnutrition is more likely among mothers with greater BMI during pregnancy.

EXPOSURE VARIABLES - Maternal pre-pregnancy BMI and glycemic profile during pregnancy (antenatal glucose/insulin)

OUTCOME VARIABLES - Offspring adiposity (BMI and DXA measure) from age 9 to 17

CONFOUNDING VARIABLES - maternal smoking, maternal age at delivery, paternal BMI, parental occupation, parental education, maternal parity, child sex

MEDIATORS - Offspring birthweight

INSTRUMENTAL VARIABLES - allelic score for maternal BMI and glycemic profile, generated from adiposity and insulin/glucose single nucleotide polymorphisms respectively.

B2038 - Infant antibiotic exposure and childhood bone mass - 20/06/2013

Background.

The intestinal microbiota has coevolved with the human genome, and numerous studies suggest that the gut microbiome and human physiology and metabolism are integrated. The composition of the gut microbiota has been associated with immune development and regulation (1), lipid deposition (2), and plasma glucose levels (3). In humans, treatment with vancomycin is associated with development of adiposity (4) and exposure to antibiotics in early life was recently linked to increased body mass index in childhood (5).

Potential effects of the gut microbiota on bone metabolism have only been investigated in a limited number of studies. In mice, absence of gut microbiota leads to increased bone mass and fewer osteoclasts in the trabecular bone as well as a lower number of CD4 positive cells and osteoclast precursor cells in the bone marrow. Colonisation of germ free mice normalised bone mass and the number of CD4 positive cells in the bone marrow (6). Furthermore, treatment of mice with penicillin, vancomycin or the combination of vancomycin and ampicillin is associated with increased bone mass and size (7).

Effects on bone health of increasing activity of selective gut microbes, through the use of prebiotics, have been assessed in a number of small laboratory and clinical studies. Compared to placebo, intake of a prebiotic (non-digestible oligosaccharides derived from lactose) increased trabecular bone mass in rats, possibly due to improved utilization of calcium and magnesium (8). In humans, treatment with prebiotics (short- and long-chain inulin-type fructans) has been shown to increase calcium absorption and bone mineralization during pubertal growth, and the effects appears to be modulated by common genetic variations in the vitamin D receptor (9). In addition, prebiotic and antibiotic treatments in humans are associated with changes in the secretion of glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide-1 (10, 11) and these gut hormones may play a role in the regulation of bone formation and resorption (12, 13).

The modulation of gut microbiota by antibiotics could potentially affect clinically relevant measures of bone mass and quality in humans, in particular attainment of peak bone mass, and, consequently, the risk of fragility fractures in adulthood.

Aims.

* To investigate if exposure to antibiotics in early life is associated with changes in total body bone mass in childhood.

* To determine if associations between early antibiotic use and subsequent total body bone mass persist after adjustment for potential confounding factors such as altered body composition.

* To examine if exposure to antibiotics in early life is likely to affect the risk of clinical events related to osteoporosis in later life, such as hip fracture, based on associations with hip BMD.

* To study the relative contribution of alterations in cortical bone size, thickness, density and turnover to relationships between early life exposure to antibiotics and bone mass which we observe, based on tibial pQCT scan measurements and CTX results.

Hypothesis.

Early life exposure to antibiotics influences gut microbiota, which changes bone metabolism. These alterations cause increases in bone mass in late childhood.

Exposure variables.

Antibiotics in the first 24 months of life.

Outcome variables.

* Indices of total body bone mass as measured by dual-energy x-ray absorptiometry at ages 9.9, 15.5 and 17.8 years.

* Hip BMD as measured at age 13.5 and 15.5

* Cortical bone indices as measured by tibial pQCT at age 15.5 years and 17.8 years

* CTX at age 15.5 years

Confounding variables.

Sex, height, weight, fat mass, lean mass, smoking in first trimester, breast feeding, Tanner stage, physical activity, vitamin D status, socio-economic status/maternal education, insulin, glucose, lipids, leptin, adiponectin, CRP

References.

1. Sommer F, Backhed F. The gut microbiota--masters of host development and physiology. Nature reviews Microbiology 2013; 11(4): 227-38.

2. Backhed F, Ding H, Wang T, et al. The gut microbiota as an environmental factor that regulates fat storage. Proc Natl Acad Sci U S A 2004; 101(44): 15718-23.

3. Karlsson FH, Tremaroli V, Nookaew I, et al. Gut metagenome in European women with normal, impaired and diabetic glucose control. Nature 2013; 498(7452): 99-103.

4. Thuny F, Richet H, Casalta JP, Angelakis E, Habib G, Raoult D. Vancomycin treatment of infective endocarditis is linked with recently acquired obesity. PLoS One 2010; 5(2): e9074.

5. Blustein J, Attina T, Liu M, et al. Association of caesarean delivery with child adiposity from age 6 weeks to 15 years. Int J Obes (Lond) 2013.

6. Sjogren K, Engdahl C, Henning P, et al. The gut microbiota regulates bone mass in mice. J Bone Miner Res 2012; 27(6): 1357-67.

7. Cho I, Yamanishi S, Cox L, et al. Antibiotics in early life alter the murine colonic microbiome and adiposity. Nature 2012; 488(7413): 621-6.

8. Weaver CM, Martin BR, Nakatsu CH, et al. Galactooligosaccharides improve mineral absorption and bone properties in growing rats through gut fermentation. Journal of agricultural and food chemistry 2011; 59(12): 6501-10.

9. Abrams SA, Griffin IJ, Hawthorne KM, et al. A combination of prebiotic short- and long-chain inulin-type fructans enhances calcium absorption and bone mineralization in young adolescents. Am J Clin Nutr 2005; 82(2): 471-6.

10. Cani PD, Lecourt E, Dewulf EM, et al. Gut microbiota fermentation of prebiotics increases satietogenic and incretin gut peptide production with consequences for appetite sensation and glucose response after a meal. Am J Clin Nutr 2009; 90(5): 1236-43.

11. Francois F, Roper J, Joseph N, et al. The effect of H. pylori eradication on meal-associated changes in plasma ghrelin and leptin. BMC gastroenterology 2011; 11: 37.

12. Tsukiyama K, Yamada Y, Yamada C, et al. Gastric inhibitory polypeptide as an endogenous factor promoting new bone formation after food ingestion. Mol Endocrinol 2006; 20(7): 1644-51.

13. Yamada C, Yamada Y, Tsukiyama K, et al. The murine glucagon-like peptide-1 receptor is essential for control of bone resorption. Endocrinology 2008; 149(2): 574-9.

B2037 - Fetal Sex and Maternal Prenatal Psychopathology - 20/06/2013

Rationale: Preliminary analyses in the Generation R project revealed a small but significant association between fetal sex and maternal prenatal psychological distress. Mothers of male fetuses appear to be more anxious and score higher on Global severity scale (GSI) of the Brief Symptom Inventory (BSI) at 20 weeks pregnancy. Mothers were not aware of fetal sex at the time of BSI completion.

Aims: To replicate the above findings in Alspac's large sample.

Hypotheses: We expect to find that fetal sex will predict differences in maternal reported prenatal mood, as per our findings in the Gen R sample.

Predictor variables: Fetal sex.

Outcome variable: Maternal mood (depression and anxiety) in pregnancy (preferrably before determination of fetal sex, but close in time to that point).

Confounding variables (optional): Parity, maternal age, ethnicity, maternal education, pre-pregancy BMI.

B2036 - Neurobiological pathways to conduct disorder trajectories - 20/06/2013

The societal impact of conduct problems (e.g., fighting, stealing) is profound, but the degree of impact is related to when conduct problems start (1). Compared with their later onset counterparts, individuals with an onset of conduct problems in early childhood are at high risk for persistent criminal behaviors and the development of antisocial personality disorder (2); these youth are often also impaired in multiple settings (social, educational and interpersonal) and are at increased risk for developing mental and physical health problems in adulthood (3). Research has highlighted that childhood onset individuals can present impaired cognitive (e.g., IQ, attention, inhibition) and emotional (e.g., callousness, anxiety, depression) function (4-6), and the role of neurobiological factors in explaining persistent offending in the early onset group has attracted attention. However, only a handful of neuroimaging studies to date have focused on children with conduct problems and these have often identified structural and functional atypicalities in affect processing and affect regulation areas of the brain (e.g. amygdala, orbitofrontal cortex and anterior cingulate cortex) (7). Most brain imaging studies, however, have either not assessed the timing of onset of conduct problems (8, 9), or are based on cross-sectional designs with retrospective reporting used to establish childhood onset (10). Moreover, few published neuroimaging studies have taken into account the risk environments (e.g., poverty, stressful life events, poor parenting) that associate with abnormal brain structure and/or function, and potential biological mechanisms (e.g., DNA methylation) that could at least partially explain brain differences for those exposed to chronic risk. These two limitations are important to redress, for at least three reasons. First, childhood onset children are shown to be exposed to a high incidence of prenatal and early postnatal risks that also associate with impaired (long-term) brain function and structure (11). Second, in certain studies, risk exposures explain differences in the cognitive functioning of delinquents (12). Third, a potential biological mechanism that can affect both the structure and function of the brain, on the experience of chronic risk, is epigenetics (13, 14). The potentially modifiable nature of environmental and epigenetic risk holds particular relevance for clinical and public health policies aimed at reducing the prevalence of conduct problems.

This application proposes the first systematic cross-national examination of potential neurobiological differences in different onsets of conduct problems in two comparable longitudinal epidemiological birth cohorts: The Avon Longitudinal Study of Parents and Children (ALSPAC; UK) and Generation R (GenR; The Netherlands). The proposal includes extensive measures of environmental stress exposures beginning prenatally and extending to late-childhood; DNA sampling from the same individuals at birth, age 7, age 9 (ALSPAC) and age 10 (GenR); brain imaging at ages 10 (GenR) and age 18 (ALSPAC); and the construction of developmental phenotypes of conduct problem trajectories between ages 4 and 13 (ALSPAC), and age 3 and 10 (GenR). This novel and innovative application has five specific aims:

Aim 1. Does structural and functional brain imaging differ between early childhood onset and later onset conduct problem trajectories?

Aim 2. Do any identified differences in brain structure and/or function associate with environmental risk exposure (prenatal and/or postnatal)?

Aim 3. Are risk exposure-to-brain associations at least partially explained by DNA methylation differences?

Aim 4. Is the impact of risk on brain structure/function and DNA methylation greater the earlier and more chronic the experience? (e.g., prenatal vs. postnatal).

Aim 5. Are the above Aims replicable in ALSPAC and GenR?

REFERENCES

1. Moffitt TE, Arseneault L, Jaffee S, Kim-Cohen J, Koenen KC, Odgers CL, et al. Research Review: DSM-V conduct disorder: research needs for an evidence base. J Child Psychol Psychiatry. 2008;49:3-33.

2. Moffitt TE. Life-course persistent versus adolescence-limited antisocial behavior. In: Cicchetti D, Cohen DJ, editors. Developmental Psychopathology. 2nd ed. NY: Wiley; 2006. p. 570-98.

3. Odgers CL, Caspi A, Broadbent JM, Dickson N, Hancox R, Harringthon H, et al. Conduct problem subtypes in males predict differential adult health burden. Arch Gen Psychiatry. 2007;64:476-84.

4. Fairchild G, van Goozen SHM, Stollery SJ, Aitken MRF, Savage J, Moore SC, et al. Decision Making and Executive Function in Male Adolescents with Early-Onset or Adolescence-Onset Conduct Disorder and Control Subjects. Biological Psychiatry. 2009;66(2):162-8.

5. Barker ED, Seguin JR, White HR, Bates ME, Lacourse E, Carbonneau R, et al. Developmental trajectories of male physical violence and theft: relations to neurocognitive performance. Arch Gen Psychiatry. 2007;64(5):592-9.

6. Barker ED, Oliver BR, Maughan B. Co-occurring problems of early onset persistent, childhood limited, and adolescent onset conduct problem youth. J Child Psychol Psychiatry. 2010;51:1217-26.

7. Blair RJR. Neuroimaging of Psychopathy and Antisocial Behavior: A Targeted Review. Current Psychiatry Reports. 2010;12(1):76-82.

8. Sterzer P, Stadler C, Krebs A, Kleinschmidt A, Poustka F. Abnormal neural responses to emotional visual stimuli in adolescents with conduct disorder. Biological Psychiatry. 2005;57:7-15.

9. De Brito SA, Mechelli A, Wilke M, Laurens KR, Jones AP, Barker GJ, et al. Size matters: Increased grey matter in boys with conduct problems and callousunemotional traits. Brain. 2009;132:843-52.

10. Fairchild G, Passamonti L, Hurford G, Hagan CC, von dem Hagen EA, van Goozen SH, et al. Brain structure abnormalities in early-onset and adolescent-onset conduct disorder. American Journal of Psychiatry. 2011;168:624-33.

11. Barker ED, Maughan B. Differentiating Early-Onset Persistent Versus Childhood-Limited Conduct Problem Youth. American Journal of Psychiatry. 2009;166:900-8.

12. Lynam D, Moffitt TE, Stouthamer-Loeber M. Explaining the relation between IQ and delinquency: Class, race, test motivation, school failure, or self-control ? J Abnorm Psychol. 1993;102(2):187-96.

13. Labonte B, Yerko V, Gross J, Mechawar N, Meaney MJ, Szyf M, et al. Differential Glucocorticoid Receptor Exon 1B, 1C, and 1H Expression and Methylation in Suicide Completers with a History of Childhood Abuse. Biological Psychiatry. 2012;72(1):41-8.

14. Jensen Pena C, Monk C, Champagne FA. Epigenetic Effects of Prenatal Stress on 11beta-Hydroxysteroid Dehydrogenase-2 in the Placenta and Fetal Brain. PLoS ONE. 2012;7:e39791.

B2034 - A large-scale haplotype reference resource UK10K - 20/06/2013

The aim is to bring together full genome genotype data from greater than 20,000 low coverage whole genome sequenced samples from multiple projects (all now in principle available), to construct a haplotype reference for imputation. The first phase, to be carried out during the next few months, is to evaluate different strategies for combining and using data for accuracy and practicality. Then in a second phase we would want to enable imputation by others for sample collections with genotype data. Here we just ask for permission for the first phase. Further discussion will be needed about how to establish access for the second phase.

B2033 - Examining if polygenic risk scores for ADHD from a clinical sample predict school performance and IQ in ALSPAC - 20/06/2013

Although individual genetic markers from genome-wide association studies (GWAS) usually explain limited heritability especially in psychiatric traits, polygenic scores can be a better way to summarise genetic effects of a large number of markers that do not individually achieve geneome-wide significance. (Dudbridge, 2013). This approach has been applied succesfully to schizophrenia (Purcell et al, 2009) and bipolar disorder (Hamshere et al, 2011).

Attention-deficit hyperactivity disorder (ADHD) is a highly heritable neurodevelopmental disorder. Traits of ADHD are present in family members of those with the conditions, as well as in the general population. Learning disabilities are common in ADHD with up to 40% of children with a diagnosis of ADHD presenting with them (Willcutt et al, 2000). In addition, neurocognitive deficits are seen in ADHD with executive function being the primary deficit (Willcutt et al, 2000). Given the attention problems that children with ADHD face, it is expected that their school performance will be affected.

Our hypothesis is that polygenic risk scores based on a clinical sample of ADHD will predict educational attainment and IQ in children from the general polulation.

Polygenic risk scores were calcualted on ALSPAC children using a GWAS of 727 ADHD patients and 5,081 controls (Stergiakouli et al, 2012) as a discovery sample (project B1342) and were provided by colleagues in Cardiff.

Aims of proposal:

To test if polygenic risk scores predict school performance in ALSPAC children using SATS school scores. We are expecting that higher polygenic scores for ADHD will be associated with worse performance in school.

To test if polygenic risk scores predict IQ in ALSPAC children using the WASI IQ score from Focus@3 clinic. We are expecting that higher polygenic scores for ADHD will be associated with lower IQ scores at age 15.

The training sample GWAS from Cardiff did not identify any genome-wide significant hits but it did find that 13 biological pathways enriched for SNP association significantly overlapped with those enriched for rare CNVs. These included cholesterol-related pathways. At the level of individual genes, CHRNA7, which encodes a nicotinic receptor subunit previously implicated in neuropsychiatric disorders, was affected by six large duplications in case subjects (none in comparison subjects) (Stergiakouli et al, 2012). Our hypothesis is that polygenic risk scores based on genetic variants from the GWAS mentioned above could predict obesity and smoking behaviour in the general population.

Aims of proposal:

To test if polygenic risk scores predict BMI at ages 7, 9 and 15 and lipid levels at age 9.

To test if polygenic risk scores predict smoking behaviour at age 15.

B2032 - Associations between trajectories of maternal depression with childs cognition and later psychosis-related outcomes - 20/06/2013

Project 1

Aims: To investigate the relationship between trajectories of maternal perinatal depression, and childhood neurocognition and social cognition.

Hypotheses: It is anticipated that more severe trajectories of maternal perinatal depression over time will be significantly associated with childhood deficits in neurocognition and social cognition in the study child.

Exposure variables: Maternal perinatal depression

Outcome variables: Social cognition (Theory of mind, locus of control, emotional recognition, social communication) and neurocognition (IQ, executive function, verbal comprehension, memory, attention, inhibition, reasoning)

Confounding variables: Family psychiatric history, mother's age at delivery, gestation, family ethnicity, parity, marital status, housing tenure, social class, disposable income, maternal education, urbanicity, smoking/drinking in and pre pregnancy, problematic partner relationship, maternal affective disorder (anxiety, suicidality), abuse of drugs, involvement with crime, child's gender, birthweight, breastfeeding in first year, childhood psychiatric disorder

Project 2

Aims: To investigate the relationship between trajectories of maternal perinatal depression and later psychotic-like experiences, at-risk mental state, and psychosis.

Hypotheses: It is anticipated that more severe trajectories of maternal perinatal depression over time will be significantly associated with the risk of later psychotic-like experiences, at-risk mental state, and psychosis in the study child.

Exposure variables: Maternal perinatal depression

Outcome variables: Psychotic-like experiences, at-risk mental state, psychosis

Confounding variables: Family psychiatric history, mother's age at delivery, gestation, family ethnicity, parity, marital status, housing tenure, social class, disposable income, maternal education, urbanicity, smoking/drinking in and pre pregnancy, problematic partner relationship, maternal affective disorder (anxiety, suicidality), abuse of drugs, involvement with crime, child's gender, birthweight, breastfeeding in first year, childhood psychiatric disorder

Project 3

Aims: To investigate whether the relationship between between trajectories of maternal perinatal depression and later psychotic-like experiences, at-risk mental state, or psychosis are mediated by cognition in childhood.

Hypotheses: It is anticipated that the association between more severe trajectories of maternal perinatal depression and the risk of later psychotic-like experiences, at-risk mental state, or psychosis in the study child will be stronger when the study child experienced cognitive deficits in childhood as well.

Exposure variables: Maternal perinatal depression, social cognition (theory of mind, locus of control, emotional recognition, social communication), neurocognition (IQ, executive function, verbal comprehension, memory, attention, inhibition, reasoning)

Outcome variables: Psychotic-like experiences, at-risk mental state, psychosis

Confounding variables: Family psychiatric history, mother's age at delivery, gestation, family ethnicity, parity, marital status, housing tenure, social class, disposable income, maternal education, urbanicity, smoking/drinking in and pre pregnancy, problematic partner relationship, maternal affective disorder (anxiety, suicidality), abuse of drugs, involvement with crime, child's gender, birthweight, breastfeeding in first year, childhood psychiatric disorder.

Planned analyses

We plan to examine trajectories of maternal depression over several time points using a latent class analysis. Maternal depression symptom data from pregnancy up to the study child at age 12 will be analyzed using group-based trajectory models in order to identify parents with chronic high levels of depressive symptoms. In Projects 1 and 2, we plan to run logistic regression to estimate odds ratios with a 95% confidence interval for the cognitive and psychosis-related outcomes. Multiple mediation analyses will then be carried out in order to explore the extent to which these associations are mediated by specific variables (eg. IQ, theory of mind). In order to examine the multivariate relationships in Project 3, we plan to carry out structural equation modeling. To overcome the issue of missing data, we plan to conduct sensitivity analyses using a range of auxiliary variables to carry out multiple imputations by chained equations.

We also plan to liaise with Jon Heron and Jonathan Evans in Bristol on their work with perinatal depression and trajectories.

B2031 - The long-term effects of adolescent cannabis use on cognitive functioning - 20/06/2013

Aims

The aims of this project are to assess the long-term effects of adolescent cannabis use on cognitive functioning. Previous research has suggested heavy cannabis use in the teenage years may lead to persistent neuropsychological deficits; however much of the research to date has been cross-sectional and therefore unable to assess whether pre-exposure group differences are driving the association. A recent longitudinal study found chronic heavy cannabis use was associated with a decline in IQ in those with adolescent-onset cannabis use, but not in those with adult-onset use (Meier et al, 2012). However this study had a number of important limitations, including small group sizes and failure to account for a number of potential confounding variables adequately. The present study will address these issues with an independent, larger sample, and assess other factors that may contribute to the relationship.

Research Questions

1. Is heavy cannabis use in adolescence associated with a decline in IQ?

2. Does the neuropsychological functioning of different cannabis-exposure groups differ in childhood, i.e. before onset of drug use? Do the exposure groups differ in other ways (e.g. early environment, socioeconomic status) that might influence neuropsychological functioning?

3. Does adolescent cannabis use affect cognitive function once pre-exposure functioning and other potential confounders (e.g. mental illness or socioeconomic status) have been accounted for? If so what is the size of this effect, and is this also reflected in academic acheivement?

4. Are any deficits seen globally across all neuropsychological functioning, or are they specific to certain domains (e.g. attention or decision making)?

Exposure variables:

1. Cannabis use. This measure will be defined according to lifetime reported usage between ages 13-18 years.

2. Cannabis dependence. This measure will be defined according to criteria for cannabis dependence between ages 16-18 years.

Outcome variables:

1. IQ change from childhood to adolescence. This outcome will be defined based on performance on IQ assessments completed at ages 8 and 16.

2. Neuropsychological functioning. This outcome will be defined by performance on cognitive tasks completed between ages 16-18 years.

3. Academic acheivement. This outcome will be defined by performance on academic assessments completed at school year 11 (Key Stage 4).

Confounding variables:

1. Pre-exposure neuropsychological functioning. Pre-existing differences or deficits in cognitive and academic ability are likely to be related to post-exposure functioning

2. Pre-exposure academic performance. Problems at school in childhood may influence cognitive development and may also be related to the initiation of cannabis use

3. Childhood temperament and behaviour. Childhood traits may influence cognitive development and may also be related to initiation of cannabis use

4. Mental illness (including depression, psychosis and conduct disorder) will likely influence neuropsychological functioning and task performance

5. Sex, socioeconomic status (e.g. parental years of education) and early environment/ parental factors (e.g. parental IQ or drug use) will likely influence neuropsychological functioning

6. Other substance use and dependence (including alcohol and tobacco) may influence neuropsychological functioning

7. Recent cannabis exposure at testing will likely affect performance on neuropsychological assessment due to acute (use in the past 24 hours) and residual (use in the past month) effects of the drug

Reference

Meier, M.H., Caspi, A., Ambler, A., Harrington, H., Houts, R., Keefe, R. S. E., McDonald, K., Ward, A., Poulton, R., & Moffitt, T. E. (2012) Persistent cannabis users show neuropsychological decline from childhood to midlife. PNAS, 109, 1-8.

B2030 - Polygenic effects of offspring and maternal genotype on development methods and model applications - 20/06/2013

Aim.

1. To develop and apply "GCTA" to genome-wide SNP data on mothers and children to resolve and estimate the contributions of the offspring and maternal genotype to dyadic outcomes, including gestational age and birthweight. This will require extending GCTA methodology to condition the genetic correlations between mothers on those among their offsping. The result of this approach will be compared with our own published findings already obtained by biometrical-genetic modeling of data based on extended kinships of twins and other informative relationships from the Virginia 30,000 study, the Virginia Birth Record Study ("VABRS"), The Virgini Children of Twins Study ("VACOTS"), and the Virginia Twin Study of Adolescent Behavioral Development ("VTSABD"). 2. Explore effects of genome-wide mother-child genetic incompatiblity on outcomes of pregnancy.

Background.

Biometrical-genetic studies of twin kinships, half-sibships and cousinships (VABRS, PI TP York) have demonstrated that differences gestational age is the effect of differences in both fetal genotype and maternal genotype. VACOTS (PI JL Silberg) has shown how the maternal genotype for antisocial behavior influences offspring depression. VTSABD (PI LJ Eaves) demonstrated that genetic influences on maternal anti-social personality exacerbated childrens' anti-social behavior through their exposure to environmenal adversity.

We propose to extend the GCTA method for using genome-wide SNP data to resolve these effects with unrelated subjects from ALSPAC. We will also attempt a preliminary resolution of genes that contribute specifically and separately to maternal and fetal influences on these dyadic outcomes. The results will be evaluated in parellel with new biometrical genetic analyses of the VBRS data (greater than 1,000,000 births).

Hypotheses.

The principal goal of this project is methodological and demonstrative. However, it is guided by the need to exploit genome-wide polymorphism data to test hypotheses about the underlying causal relationships between maternal and offspring genotype and multiple outcomes in human development. The two systems selected for initial study (gestational age and birth-weight) are models that illustrate the methodological and substantive issues. We will also apply the approach to birth-length and height at age 7 as a model system that may reflect the developmental amelioration of the environmental impact of the maternal environment. We have shown (above) that both maternal and fetal genotypes affect gestational age. Further details of the proposed model and approach are given in the attached document.

The method can subsequently be used to resolve the effects of maternal and offspring genotype on other developmental outcomes where it is expected parental characteristics and behavior influence the phenotypes of their children.

Variables

Exposure variables: 1. Genome wide genetic relatedness of mothers and offspring derived from identity by state indexed by genome-wide SNP data in mothers and children (see Yang et al., 2011).

Outcome variables: a) Birthweight and gestational age; b) Length at birth and height at 7 years. If the method works, we hope to extend the approach to embrace the environmental effect of genetic differences in maternal psychopathology on offspring outcome (not included in current variable request).

Confounding variables: Maternal age at parturition; Maternal and paternal smoking in pregnancy; parity; maternal BMI.

B2029 - Early Life Course Influences on Cognitive and Social Development - 20/06/2013

This proposal will address the need to better understand the interplay between behavioural and biological mechanisms in human development. It will make substantial contributions to our theoretical understanding of social and cognitive development, social behaviour, and their impact on health and behaviour in childhood, adolescence and early adulthood, integrating recent developments in epigenetics. It will develop the empirical knowledge base in these areas, in order to support the development of novel interventions, and create an international hub linked to existing major research groupings.

Intrapersonal, interpersonal and environmental influences (such as family environment, early adversity, and socioeconomic position) at different stages of the life course are critical to the development of behaviour. These influences need to be understood in order to develop and optimise interventions to improve health and wellbeing. However, knowledge of the behavioural and psychological mechanisms of behavioural control, their development through infancy, adolescence and early adulthood, and their relationship with social behaviour, health and wellbeing, remain poorly integrated, and are rarely (if ever) investigated within a single data set. We propose a cohesive programme of research intended to provide a comprehensive understanding of the relationship between cognition, social behaviour, and impulsivity and risk taking. This will be allied to a life course perspective, to understand the role of social and environmental influences at every stage of development into early adulthood.

The Avon Longitudinal Study of Parents and Children (ALSPAC) forms the core resource on which this proposal is structured, utilising the wide range of phenotypic and environmental measures available, in addition to biological samples, genetic and epigenetic information and linkage to health and administrative records. This proposal is a collaborative project across the Universities of Bath, Bristol, Cardiff and Exeter, and will be supported by a wider network of national and international collaborators. It will be structured into three main workstreams, corresponding to our three main aims.

Aim 1: Understand the cognitive precursors (e.g., attentional and perceptual processes) of social behaviour, and health and wellbeing.

Aim 2: Understand the developmental pathways, trajectories and mechanisms associated with social behaviour (in particular sexual behaviour and aggressive behaviour).

Aim 3: Understand social, cognitive and environmental influences on impulsivity and high-risk behaviours, and subsequent health and wellbeing.

Workstream 1 (Social and Cognitive Development): This work will focus on the cognitive precursors of social behaviour, and health and wellbeing. There is growing interest in the extent to which domain-general processes, particularly attentional and perceptual processes, play a role in the development of social cognition and theory of mind. In addition, social compliance, particularly in children, may depend on individuals' ability to adopt, maintain, and execute appropriate goals. As a consequence, executive control functions, including working memory, constrain the manifestation of social behaviour, including the impact of social context, parenting and imitation. However, a central problem that has limited progress in this area is the poor specification of executive control, particularly in children. Until recently, working definitions of the construct have relied on a loose collection of putative executive functions. Structural equation modelling has since provided frameworks for organizing these functions, with a focus on updating, inhibition, and shifting, but these still lack a clear theoretical basis. We will therefore examine the development of executive control in children using a principled approach that sets these candidate functions in a theoretical context. This follows directly from two claims: 1) executive function represents the individual's ability to maintain task goals (updating) and to use these to prevent them from acting inappropriately in response to external stimuli (inhibition), and 2) executive control has a temporal aspect that is not independent of previous experience (shifting). We have the expertise to employ precise measures of these functions and, crucially, manipulate them orthogonally to properly test their interplay. Armed with this suite of novel but theoretically-motivated tasks, the relationship between executive control, measures of attention/perception, measures of social context and parenting, and social behaviour will be investigated. We will explore the relationship of executive function in early life and later trajectories of social and cognitive development, social behaviour, and impulsivity and high-risk behaviour. This will be done in a new longitudinal study across three time points over three years. We will also explore atypical groups based on measures of autism spectrum disorder and attention deficit hyperactivity disorder, the developmental trajectories of these traits over time in ALSPAC, and use targeted recall studies of ALSPAC participants who score at the extreme of measures of executive function to investigate cognitive mechanisms in more detail, using both behavioural and fMRI methods.

Workstream 2 (Social Behaviour): This work will examine the developmental pathways, trajectories and psychological mechanisms associated with outcomes in two aspects of social behaviour that have significant societal impacts: sexual behaviour and aggressive behaviour. Life history theory provides a meta-theory for the coherent study of sociosexual and aggressive behaviour at functional, ontogenetic and mechanistic levels. It proposes that timing of important events across the lifespan, and the strategies employed to achieve such goals, are determined by flexible mechanisms that function to increase reproductive success in response to environmental conditions. Human behavioural ecologists have successfully applied this theoretical approach to societally-important issues such age of first reproduction, family size, and parental investment as a function of factors such as socio-economic status and childhood social experiences, and researchers in other disciplines have investigated the neural, endocrinological and psychological mechanisms underlying such behaviour. We will integrate work across these levels of explanation (function, ontogeny, and mechanism), with a particular focus on the development of emotional processing strategies, which play an important role in sexual and aggressive behaviour. Our underlying theory is that biases in emotional processing often reflect adaptive calibration of socio-cognitive mechanisms to the current environment. For example, links between hostile childhood environments and later aggressive behaviour are well established, and may be functional: when exposed to chronically hostile environments in development, aggression may be an adaptive, rather than a maladaptive, strategy in many cases. We will use the ALSPAC cohort to identify emotion processing strategies that mediate the relationships between childhood environments and social outcomes in adolescence and young adulthood. This will allow us to examine trajectory and development of social behaviours, investigating the role of genetic, epigenetic and social/environmental factors (including physical trauma such as head injury) on development. We will use these analyses to design targeted recall studies in the ALSPAC cohort, to investigate underlying psychological mechanisms using both behavioural and fMRI methods.

Workstream 3 (Health and Wellbeing): This work will examine the relationship between social and cognitive development, social behaviour and health behaviour in adolescence and early adulthood. Psychological models of health behaviour have traditionally focused on explicit decisions arising from cognitive appraisal processes. More recently, dual-process models have emerged which integrate evidence that automatic, impulsive processes also play an important (and perhaps dominant) role. Critically, a constellation of high-risk behaviours (e.g., aggressive behaviour, sexual behaviour, substance use) frequently co-occur, and many adolescents engage in these behaviours at levels harmful to health and wellbeing. It is therefore logical to focus on determinants of these multiple risk behaviours, as this may provide single targets for intervention with the potential for broad impact. Current dual-process models argue that interacting, neural systems control decision making, with an impulsive system focused on immediate consequences and a reflective system focused on future prospects. The reflective system governs the impulsive system; however, there are individual differences in the extent to which this is the case, and this is related to executive function. Therefore, factors which influence cognitive and social development in childhood may in turn influence impulsive and high-risk behaviours in adolescence and early adulthood, both directly (via individual differences in executive function) and indirectly (via exposure to peer groups and other environmental risks). We will explore the relationship between cognitive and social development in early life, and subsequent impulsive and high-risk behaviour in adolescence and early adulthood. We will identify the impact of environmental exposures at multiple time points (e.g., tobacco exposure in utero, in childhood in the home, in adolescence in the home and via peer groups) on subsequent impulsive and high-risk behaviours, and explore the mechanistic relationships between these variables using targeted recall methods to enable more intensive characterisation of relevant constructs, epigenetic markers of exposure, and Mendelian randomisation where possible.

B2028 - Analyses of Disparity in Energy intake Metabolism and Adiposity ADEMA A genome-wide association study - 20/06/2013

Aims

We aim to phenotypically refine measures of adiposity and metabolism to encapture a number of individuals that may potentially be described as metabolically healthy obese or metabolically unhealthy non obese and to then explore the potential common genetic variants that are specifically associated with these disparate profiles in ALSPAC Children. We are interested in further analysing other cohorts (TWINS UK) for similarities in these disparities. We also aim to assess replication of our GWAS and to perform a Meta analysis to improve power of results.

B2026 - An exploration of picky eating behaviour in ALSPAC - 06/06/2013

AIMS:

Is the presence of parent-reported "choosy" or "difficult to feed" behavior in children associated with GI symptoms (gastroenteritis, diarrhoea, vomiting, stomach ache and stool type)?

Is the presence of parent-reported "choosy" or "difficult to feed" behavior in children associated with alterations to either parent or child quality of life?

Is the presence of parent-reported "choosy" or "difficult to feed" behaviour in children associated with differences in the child's dietary intake at 1.5, 3.5 and 10 years or later food preference (e.g. large intakes of milk/dairy foods or sweet foods)?

Is early life dietary intake/ timing of weaning or complementary foods (from Infant FFQs at 6 & 15 months of age) associated with eating behaviors (choosiness or difficulty feeding)?

Is early life dietary intake/ timing of weaning or complementary foods (from Infant FFQs at 6 & 15 months of age) associated with reports of child GI symptoms (gastroenteritis, diarrhoea, vomiting, stomach ache and stool type)?

Is early life dietary intake/ timing of weaning or complementary foods (from Infant FFQs at 6 & 15 months of age) associated with differences in the child's dietary intake at 1.5, 3.5 and 10 years or later food preference (e.g. large intakes of milk/dairy foods or sweet foods)?

Is maternal dietary intake during pregnancy associated with eating behaviors (choosiness or difficulty feeding)?

Is maternal dietary intake during pregnancy associated with reports of child GI symptoms (gastroenteritis, diarrhoea, vomiting, stomach ache and stool type)?

Is maternal dietary intake during pregnancy associated with differences in the child's dietary intake at 1.5, 3.5 and 10 years or later food preference (large intakes of milk/dairy foods or sweet foods)?

B2025 - Weak instruments in a semi-parametric framework can lead to weak identification - 06/06/2013

Aim: To investigate the performance of semi-parametric methods for instrumental variable estimation (specificially the generalized method of moments, GMM, and structural mean models, SMM) with weak instruments.

Hypothesis: The use of weak instruments in a semi-parametric framework may lead to weak identification (that is, the optimization criterion for determining the value of the parameter estimates may be satisfied or nearly satisfied at multiple values of the parameters).

Methods: The performance of these estimators will be considered using simulated data as well as data from the ALSPAC study on the causal association of body mass index on the probability of early menarche using genetic variants associated with body mass index.

Exposure variable: Body mass index (measured at age 7.5).

Outcome variable: Early menarche (before 12 years). This variable has already been derived by RG.

B2024 - Genes Environment and Mediating Risk Pathways Understanding the aetiology of Alcohol Use Disorders - 06/06/2013

There is evidence that both particular genes (heritability as high as 60%) and particular environments contribute to vulnerability to subsequent alcohol abuse and dependence [Mcgue, 1999; Enoch and Goldman, 2001; Lesch 2005]. However, there is relatively little data on gene-environment interactions in the aetiology of alcohol use disorders (AUDs) [van der Zwaluw and Engels, 2009]. Further, little is known about the role of internalising behaviour in mediating the relationship between genes, environments and subsequent AUDs.

The Avon Longitudinal Study of Parents and Children (ALSPAC) provide a unique opportunity to try and determine the relationship between genes and environments in AUDs, through the mediation of internalising behaviour. First, ALSPAC includes data on genetic variants and on adverse environments (e.g. stressful life events (SLEs)). Second, ALSPAC includes comprehensive data on internalising behaviour experienced during childhood.

Heavy alcohol use is positively associated with the experience of environmental stressors such as job, health-related, social and legal stress [Dawson et al., 2005]. In turn, the behavioural response to stress is mediated by corticotrophin-releasing factor (CRF) [Arborelius et al., 1999; Binder and Nemeroff, 2010]. Studies involving animal models have shown that polymorphisms within the CRF receptor gene (CRHR1), together with the experience of environmental stress factors, result in greater alcohol consumption [Sillaber et al., 2001; Hansson et al., 2006]. Similarly, in humans, polymorphisms in the CRHR1 gene interact with negative life events to predict heavy alcohol use [Treutlein et al., 2006; Blomeyer et al., 2008]. Besides the CRHR1 gene, the CRF pathway consists of the following genes: POMC, UCN, CRH, CRHR2, UCN3 and UCN2 [PharmGkB. Date accessed: 13 March 2013]. These genes are relatively unexplored in terms of vulnerability to alcohol dependence.

It is often argued that AUDs are characterised by externalising behaviour [Kumpulainen, 2000; Englund et al., 2008]. Findings regarding the link between behavioural inhibition/internalizing symptoms and AUDs are less emphasised in the literature, although a few studies have shown that internalising symptoms, such as anxiety and depression, are associated with alcohol use [Loeber et al., 1999; Fite et al., 2006]. CRF has also been shown to play a role in internalising behaviours; indeed polymorphisms within CRHR1 have shown to have a significant association with anxious temperament and have an influence on the metabolic activity of local brain regions in rhesus macaques [Rogers et al., 2012]. There has been little work, however, on the relationship between variants in the CRF pathway and internalising behaviour in humans.

Methodology

1) Select variants from the genes involved in the CRF pathway based on a systematic review of the literature.

2) Include genotype in the models as a (a) quasi-continuous, (b) time-invariant predictor of latent continuous and/or (c) categorical variable

i. Test for association with the extended alcohol use phenotype measured by the 10-item Alcohol Use Disorders Identification Test (AUDIT) administered at 16 years of age or later [Heron et al., 2012].

3) Identify mediating pathways by which genes confer susceptibility

i. Hypothesized that CRF genes will be likely to confer risk via internalising behaviour evident in early childhood. Internalising behaviour will be measured by the parent-rated, emotional subscale of the Strength and Difficulties Questionnaire (SDQ), administered at 7 years of age or older as described by Araya et al. (2008) and Evans et al. (2008).

ii. Hypothesized that CRF genes will be related directly to alcohol use and risk pathways in adolescence that emerge concomitantly with AU and not involved in pathways with origins in childhood

4) Test GxE with environments previously shown to moderate genetic risk. Environmental factors such as SLEs will be measured using Section D of the parent-rated questionnaire "My Son's/Daughter's Health and Behaviour-42 months". SLEs will also be assessed by the "Life Events" questionnaire completed by the Mother of the "child" at 18, 30, 42 and 57 months as well as 5, 6 and 8 years and completed by the "child" at 16 years of age.

i. Regressing outcome variables onto (a) genotype (b) an environment, and (3) and interaction term reflecting the product of genotype and environment.

B2023 - Cross country variation of Child growth performance by mothers characteristics and household socio-economic status - 06/06/2013

Aim: The WHO Multi-centre Growth Reference Study(MGRS) used data of six national sites to propose a child growth standard that describes the optimal growth patterns. Our previous research has identified number of factors as influencing optimal child growth in different populations around the world. The aim of this study is to combine data on children and parents from numerous countries from all regions of the world to examine cross-country variation in child growth relative to the MGRS growth standard charts.

The information contained in the "ALSPAC data documentation" indicates that children of the 90's survey has child and mother physical measurements and other relevant variables for our research. Therefore, we are interested in to include survey data of Avon Longitudinal Study of Parents and Children (ALSPAC) for our sample.

Hypothesis : The socio-economic status , income, ethnicity, child birth characteristics, parental size and health detremines the optimal child growth.

The exposure variables of the study are

- Sampling details - sample weights, household weights

- Birth year, month, date

- Child ID [to allow us to identify repeat observations on the same child]

Birth circumstances

- Birth date

- Gestational age (weeks)

- Birth weight (g)

- Birth length (cm)

- Sex

- Whether single or multiple birth

- Birth order

- Ethnicity [this is not mentioned in the paper, but if available, so we can distinguish between caucasian and other groups]

Parental characteristics

- Age (years)

- Paternal height (cm)

- Maternal height (cm)

- Smoking status (Yes/No)

- Drug abuse (Yes/No)

- Alcohol consumption

- Educational level

- Years of education

- Employment

- Household and environment (needed to estimate socioeconomic status and impute per capita income)

Confounding variables are :

- Nutrition data

- Whether breast fed at time of measurement

- Whether exclusively breast fed at time of measurement

- Length of exclusive breast feeding

The outcome variables of the study are :

-- Date of anthropometric measurement

- Height/length (cm)

- Whether measurement was Recumbent length/standing height

- Body weight (g) .

B2022 - The Genetics of Infant Bronchiolitis in the Pathway to Asthma - 06/06/2013

We hypothesize that the enhanced asthma risk following infant RSV exposure is due to two non-mutually exclusive factors: (1) a genetic predisposition common to both diseases and (2) infant RSV infection acting as a causal agent in asthma development. We will use genetic epidemiological methods to determine the extent to which infant RSV infection plays a causal role in the development of asthma or if it merely serves as a marker of shared genetic risk with asthma. This study leverages multiple existing US based cohorts, including the Infant Susceptibility to Pulmonary Infections and Asthma Following RSV Exposure (INSPIRE; Hartert, PI), the Tennessee Children's Respiratory Initiative (TCRI; Hartert, PI), RSV Bronchiolitis in Early Life (RBEL I and II; Castro, PI), and Childhood Origins of Asthma (COAST; Lemanske, PI). This revised grant improves power for genetic studies and builds infrastructure to understand infant RSV infection and its respiratory sequelae by collaborating with longitudinal cohorts that have well-characterized respiratory infections in infants during the first year of life followed through to early childhood wheezing/asthma outcomes. We will first identify the genes associated with response to RSV infection (Aim 1) and then determine the genetic bases of shared RSV infection and recurrent wheezing/ early asthma susceptibility (Aim 2). This would be the first GWAS of RSV infection in infancy and its respiratory sequelae of recurrent wheezing/asthma.

We would like to use existing GWAS data from ALSPAC for replication of our primary findings.

Specific Aim 1a:

1a) We will identify the genetic determinants of the severity of RSV infection in the first year of life among ~2000 infants from multiple US cohorts with confirmed RSV exposure or infection. For GWAS genotyping, we will use the Illumina HumanCore + Exome BeadChip in European-Americans (EAs) and the Illumina Omni 2.5M + Exome BeadChip in African-Americans (AAs) and Hispanic-Americans (HAs).

Specific Aim 1b) We will perform a pathway analysis of genome-wide data that addresses limitations of SNP analyses to identify genes or pathways that are associated with severity of RSV infection during infancy.

Specific Aim 2: We will identify the specific genetic variants that lead to the shared genetic risk of severity of RSV infection and early childhood recurrent wheezing/asthma.

This proposed collaboration will address an important gap in understanding how severe infant RSV infection increases the risk of recurrent wheezing/asthma. The results will provide novel insights into both the timing and mechanism for developing primary prevention strategies.

Based on two papers from the ALSPAC cohort, both involving collaborator John Henderson, there are 284 infants hospitalized with infant bronchiolitis. The ALSPAC cohort has well characterized wheezing and asthma outcomes. Using this existing data, we would like to replicate our SNPs predicting severe infant bronchiolitis, measured as hospitalization (y/n). We would also like to replicate SNPs that examine risk of wheezing/asthma after hospitalization for bronchiolitis. We propose in Specific Aim 1b and in exploratory analyses for asthma outcomes to conduct pathway analyses. We would like to use existing ALSPAC data to conduct a replication of our pathway analysis. This will entail the analysis of existing GWAS data.

If the sample size for hospitalization with bronchiolitis followed to to wheezing / asthma outcomes includes enough children with DNA available, we would like to consider using your genetics lab for replication of 480 SNPS from Aim 1 and 480 SNPs from Aim 2 using cases a set of matched controls. At this point we do not know whether our primary SNPs will exist in your data set. We also do not know whether there will be enough children from the case group with DNA.

B2021 - Using linked health and administrative data to reduce bias in observational research - 06/06/2013

Aim

The overarching aim is to examine how linked health and administrative data can be used to avoid bias in prospective cohort studies, using the Avon Longitudinal Study of Parents and Children (ALSPAC) as an exemplar. This aim will be addressed using simulation studies and by examining three questions of epidemiological importance:

a) Is breastfeeding associated with IQ at age 15? Linkage to education data (GCSE results) will be used to examine the missingness mechanism for IQ, and may be used in imputation of the missing values.

b) Is smoking in the early teenage years associated with educational attainment at age 16? Data on smoking from the young people's GP records will be used to examine missing data patterns in self-reported smoking and to investigate misclassification. GCSE results from linked educational data will be used as the outcome in this analysis.

c) Is maternal smoking in pregnancy associated with depression at age 17? As for smoking, linkage to relevant data held within GP records will be used to look at the objectives below in relation to this outcome.

Objectives

1. To develop methods for using linked health and administrative data to examine patterns of missing data and model missingness mechanisms in longitudinal studies such as ALSPAC, focussing in particular on outcomes and exposures that are likely to be MNAR (missing not at random).

2. To incorporate linked health and administrative data in multiple imputation models to explore biases introduced by missing data in exposures or outcomes in observational studies.

3. To compare data in ALSPAC to equivalent outcomes recorded in linked electronic primary care records (GP data) to investigate misclassification in the self-reported outcomes and, in particular, to identify whether these are subject to differential or non-differential misclassification.

4. To develop methods to use both linked data and self-reported data to minimise the impact of measurement error on analyses in observational studies.

As one of the exemplars involves obtaining data on depression from electronic patient records, a further objective is:

5. To devise and modify existing algorithms for defining depression using electronic GP data, using information contained within Read codes and to use this information to estimate the prevalence of depression among ALSPAC teenagers.

Exposure variables

Breastfeeding, smoking in pregnancy, early teenage smoking (at 12/13 years) - from ALSPAC and linked GP records

Outcome variables

IQ at 15 years, GCSE results (linked data), depression at 17 years - from ALSPAC and linked GP records

Confounding variables

Maternal and paternal education, family occupational social class, housing tenure, family adversity index (and the individual components), family income, maternal and paternal smoking, maternal & paternal pre and post-natal depression, parental conflict, marital status (parents), maternal age at birth, maternal alcohol intake in pregnancy, family composition.

B2020 - Bio-social enhancements to the Millennium Cohort Study - 24/05/2013

1. Collection of height, weight and body fat.

As well as reflecting the substantive comments from earlier discussions this paper in setting out the main details of the enhancement, this paper outlines pre-and post- March 2015 costs, in order to enable a profiling of spend. In the original proposal all staffing costs were censored at March 2015, given that was the limit of the spend period. However, this was not in expectation that all the work would be completed by that point, but a reflection of the limits of the funding source. It was anticipated that the extension of staffing costs would be found by some other means (e.g. through the core CLS funding, or through a separate funding proposal).

This paper instead builds in staffing costs that are appropriate for the enhancement even when they extend beyond March 2015. However, for consistency with the earlier paper, the post-March 2015 totals are also shown excluding these post-March 2015 staffing costs.

Key elements of enhancement

The continued collection of height and weight will allow a robust understanding of contemporary children's physical and developmental trajectories over time across the UK and how this physical development relates to family context, child and family practices and behaviours, neighbourhood and environment, and other aspects of children's development, and wellbeing.

Height will be measured by trained and accredited interviewers using a height measure that is appropriate for teenagers and using best practice protocols. As usual we will check what the most up-to-date protocols are and ensure that the MCS team and the fieldwork agency are fully versed in them. This will also maximise comparability with measurement carried out for example on the National Child Measurement Programme (NCMP) using the same protocols.

Weight and body fat will be measured by trained interviewers using Tanita scales that capture both weight and body fat percentage.

Following full briefing, interviewers will practice the height, weight and body fat measurement on young people of the relevant age, as part of their training, and will be require to be accredited in height measurement before they can implement it in the field.

All measures will be captured in CAPI, alongside a record of any specific circumstances relating to the measurement that might have affected its accuracy. These data will be returned to CLS by the contracted fieldwork agency within four months of the conclusion of fieldwork.

The existing data manager team will check and clean the data, create appropriate derived variables and prepare it for release within six months of receipt from the fieldwork agency.

The data manager team will be able to provide value added to the physical measurements data by linking the height weight and body fat measurements to updated growth charts constructed according to standard methodology but based on contemporary growth patterns, using the National Child Measurement Programme (NCMP) data. We are currently in discussion with the Department of Health about access to measures collected in the NCMP but not currently deposited (specifically ethnicity). Growth charts based on national NCMP data and incorporating ethnic differences would be a more appropriate reference population than currently used growth charts. We are thus seeking to develop such contemporary growth charts employing the methodology used in the 1990 charts but based on a contemporary, nationally representative and multi-ethnic population.

2. Collection of saliva for DNA extraction.

This element represents a collaboration between Dr Sue Ring of Bristol University and the MCS team at CLS. The collection of saliva samples would enable a genetic record of both the child and their parents to be preserved. This would provide enormous potential for both genetic and epigenetic research on a young, nationally representative cohort and enhance the multidisciplinary, bio-social potential of the study both now and in the future.

There is already great interest in the potential of a DNA resource derived from MCS. Given the wealth of existing data collected in MCS from both survey questions and direct measures and assessments, there is huge potential to understand associations between genetic make-up and a whole series of outcomes relating to e.g. learning, dyslexia, obesity and overweight, behaviour and mental health.

The large sample size and national coverage of MCS are particularly beneficial: as well as offering detailed family-level, individual and contextual information, MCS enables analysis to explore the contexts of varying environmental exposures as well as genetic dispositions. In particular, the value of the oversampling of those from more disadvantaged socio-economic backgrounds is regarded as being particularly valuable in

There is clearly great potential from the collection of triads of samples (both biological parents and the cohort child) for the investigation of epigenetic processes. It is increasingly recognised that non-target tissue sources of DNA can be informative about the relationship between epigenetic variation and phenotype.

It is clear that, while attention would need to be given to ensuring the resource was both known about and used (utilising both the Access Committee and Closer in doing this), there would be a number of scientists ready to build proposals to exploit the data once they became available. For example, researchers who have already identified genetic data from MCS as offering enormous potential include, Silvia Parracchini who has expressed interest in utilising MCS to enhance her existing studies of genetic variants associated with dyslexia; and Caroline Relton, who is working on epigenetics using non-target tissues, and is developing an approach which places DNA methylation changes as in intermediate phenotype on a pathway between exposure and outcome, including such outcomes as obesity, and cognitive and behavioural outcomes.

With ensuing genome-wide genotyping, an MCS DNA back can be expected to provide an extremely valuable resource for analysis that is likely to be very well used. The success of the NCDS resource is testament to the volume of research that such a resource can invite, and we would expect certain of the key features of MCS, such as its demographic coverage, to enhance its utility.

In terms of the planned provision to result from this enhancement; the key element is the collection of saliva, from both the cohort member and from their co-resident natural parents, where applicable.

Such collection was successfully piloted at age 11, but we would expect that the change in age and the context of different instruments would require some additional pretesting. We would then implement in pilot, dress-rehearsal and main stage. We would also need to ensure proper briefing of interviewers and the available of appropriate subsidiary materials such as clear question and answer guidance.

The second key element is the preparation and storage of the samples, which would be undertaken in Bristol using a similar approach and protocols as were developed for the Age 11 pilot in relation to delivering the samples from the field, conduction quantification and extraction. Clearly in the main stage, this would take place on a much larger scale and would require adequate systems being fully in place for that

The third key element is the genotyping of the samples. This would also be undertaken by Bristol. While indicative support has been indicated for this element of the proposal, it would need to be aligned with the ESRC biosocial strategy which is expected later in 2013. Indicative costs for the genotyping would also need to cover staff to support accessing the samples and ongoing storage and maintenance.

Access to the sample would also need to be ensured through adequate resourcing of the Access Committee to support their existing work. The existing access arrangements for NCDS would clearly be suitable for accessing the genotyped data from MCS; and the learning that is being developed in relation to 'accidental' findings would also need to be built into procedures for MCS, as well as informing the consent process itself.

Substantive proposals for analysis would be subject to separate applications to relevant funding organisations but would be enabled and facilitated by this support.

3. Collection of physical activity data.

There is a great deal of interest in understand the patterns of physical activity, including sedentary behaviour, and how these relate to young people's growth patterns, including overweight, as well as to other aspects of their wellbeing and to their long-term outcomes and other.Self-report measures need to be extensive and detail to capture the range of patterns of physical activity and inactivity, and without a complex battery of questions can only provide limited insight into young people's activity patterns. Objective measures can be more convincingly obtained through direct measurement using accelerometers. Direct measures of physical activity can give a much better insight into patterns of moderate and intense activity, and into sedentary behaviour than report measures.

Accelerometers has been successfully collected not only in health-related surveys but also in MCS itself at sweep 4 (the age 7 sweep). Best practice in collection is also improving. At MCS4, 7-day wear was recommended. However, this was not only hard to achieve for many of the children, it is becoming accepted that two days of complete wear may be sufficient to understand activity patterns. Collection of data can contribute to ongoing debates about optimal forms and intensities of activity in relation to health and wellbeing. Combined with the planned age 14 diary, physical activity measures themselves can be enhanced by understanding the context of the activity as well as periods of non-wear.

There is substantial appetite within the scientific and policy community for utilising direct measures of physical activity and for repeating the measurement of physical activity at the critical age of age 14.

Thus the key element of this proposal is to implement collection of two full days of physical activity monitoring of MCS cohort members, using age appropriate and high quality accelerometers.

The proposed collection of physical activity using accelerometers would involve the young people being asked to consent to wear the accelerometer for 2 days, days that coincided with the days they completed a time diary. Parental consent would also be sought prior to the young person being approached.

There are two models that could be implemented. At the age 7 survey, those families that consented to wear the accelerometer were then posted from an external unit the accelerometer, and that unit, based at the Institute of Child Health (ICH) also dealt with follow-up, sending feedback and reminders to return. The ICH unit was responsible for charging the accelerometers, setting them in advance of posting them out, and downloading the data from them on return, before sending them out to the next batch of respondents. The first model would follow this approach but rather than an external unit, the fieldwork agency would themselves log the consenting cases, and send out the equipment, with a pre-paid envelope for return, download data on return and reset the devices for the next batch of consenting participants. On this model we would anticipate a 90 per cent consent rate and that up to 70 per cent of cohort families would return the accelerometers resulting in a gradual depletion of the stock.

A variant on this model (Model 1a) would be to integrate the enhancement fully into the MCS6 fieldwork. Interviewers would supply the accelerometers at the point of the survey having guided the cohort members on use, setting and administration. The interviewers would then be responsible for ensuring the devises were charged and set, and would need to be thoroughly briefed on this. They could then leave the accelerometers to be returned by post, as with the original version, and the fieldwork agency would need to ensure that reminders were sent in a timely fashion to maximise return. This would be more intuitive approach, in that distributing and implementing while in the household would accord with the general practice of the survey and enable questions to be dealt with on the spot, as well, potentially as encouraging wear. However, there would be an additional layer of complexity introduced as a result of the fact that the interviewers would need to be supplied on an ongoing basis with sufficient numbers to carry out the fieldwork, while the accelerometers were being returned, and data downloaded from the respondents. To ensure a smooth process would probably require a larger number of accelerometers than the total used at MCS4. The consent and return rates overall would be expected to be similar, though we could anticipate that a larger number would actually wear the devices prior to return increasing the overall data collection, and that thus the level of productive cases would be higher.

A second model would involve the interviewers not only administering but also collecting the accelerometers after the week containing the two 'wear days' had passed, and while they were in the area. This would increase fieldwork costs, possibly substantially and would require the interviewers themselves to be trained in downloading the data before resetting for subsequent participants or that they returned them in batches to the central office; but would increase the number of returned accelerometers, and thus reduce the total number needed / lost. It would obviate the need for requests for return, except in those cases where the interviewer was unable to follow up.

There are clearly advantages and costs associated with each of the approaches, and the tendering fieldwork agencies will propose and cost what they think is the optimal model. At present we judge this is likely to be closest to Model 1a, and we have estimated costs on that basis. For this we have assumed around 4000 accelerometers will be needed, rather than the 3000+ used in the age 7 survey, since at Age 11 the total stock was almost totally depleted by the end and left no room for flexibility in distribution.

As well as collecting the data, since these are complex data, to provide suitable outputs for users there would be the need to construct age-appropriate derived measures of activity and sedentary behaviour from the data, as was achieved for MCS4. This would be the key data deposit from this element of the data collection, though the 'raw' data would also be deposited for those who wished to work with it directly.

The derived variables would be constructed by an experienced data manager working with a statistician to produce the derived variables useable by the wider research community.

B2019 - Investigating the impact of maternal iodine and sodium status throughout pregnancy on outcome of the offspring - 06/06/2013

AIMS

This study aims to investigate the affect of iodine and sodium status throughout pregnancy on outcome of the offspring.

HYPOTHESIS

Iodine is required for the production of thyroid hormones which have a role in brain and neurological development during gestation and early life. The mother is an important source of thyroid hormones to the developing fetus particularly before the fetus is able to produce its own. Mild to moderate maternal iodine deficiency has been associated with a reduction in IQ and psychomotor development in the offspring and has also been linked to the development of ADHD. Excessively high or low intake of sodium throughout pregnancy can have adverse effects on both the mother and the offspring and therefore maternal sodium levels will also be analysed in the urine. Measuring iodine and sodium levels in maternal urine throughout pregnancy and analysing against offspring outcome will identify the most influential period of development on which iodine and sodium have an affect.

EXPOSURE VARIABLE

All maternal urine samples from each trimester

OUTCOME VARIABLE

Iodine, sodium and creatinine levels. Creatinine will be analysed to correct for urine volume.

CONFOUNDING VARIABLES

maternal age at delivery, mother's parenting score, HOME score, family adversity index, life-event score, intakes of omega-3 fatty acids and iron

child factors

sex, birthweight, preterm birth, breastfeeding, and ethnic origin

maternal factors

smoking status, alcohol intake, parity, maternal depression since birth and use of fish-oil supplements during pregnancy

markers of socioeconomic status

maternal and paternal education, housing status and crowding

B2018 - Peer Mediating and Moderating Effects Upon Parent-Child Relationships School Connectedness and Adolescent Substance Use - 24/05/2013

This study aims to:

a) Independently assess the predictability of early social experiences [family, school and peers] upon the initiation and progression of substance use in late adolescence, and examine if they vary in importance according to different substances [alcohol, cannabis, smoking] and/or level of use [experimental, occasional, regular].

b) Examine the extent to which family relations and/or school experiences in childhood and substance use in late adolescence are mediated by peer's substance use in early adolescence.

c) Create two models of substance use: one to test whether peer use is moderating the effect of parent-child relationships upon substance use in late adolescence; and the other to test whether peer use is moderating the effect of school connectedness on substance use in late adolescence.

B2017 - Foetal programming of childhood asthma - 24/05/2013

Aim:To determine if the critical periods of growth and asthma/wheeze phenotypes identified in the BiB cohort be replicated in other populations. (ii) To determine if there are links between growth in early life and asthma.

Hypotheses:That the relationships observed between asthma/wheeze and growth in the BiB and other cohorts will be replicated in the ALSPAC cohort.

Exposure variables: Asthma/Wheeze symptoms and diagnoses (examined as latent class phenotypes)

Confounding variables: maternal/paternal history of asthma, maternal/paternal height, maternal/paternal smoking, maternal BMI, gestational length, mode of birth.

Outcome variable: Trajectories of growth (length and weight).

Statistical analyses: Firstly Latent class analyses will be undertaken to determine discrete phenotypes of asthma to be established that are specific to the ALSPAC cohort. Latent class analysis (LCA) allows classification of individuals into groups based on conditional probabilities as within each class individuals will have a similar pattern of response. As these models work with probabilities rather than absolute values this allows children to potentially be fractional members of all classes and use probability to assign class membership. The first stage of LCA will be to determine the optimal number of classes to the data by evaluating the best fitting model using multiple indices of model fit including Akaikes Information Criterion, Bayesian Information Criterion, entropy and likelihood ratio test using bootstrapping as well as assessing the face validity and meaningfulness of the resultant classes. The second stage of the modelling process, to determine the relationship between co-variates including ethnicity, gender and the latent class groups of phenotypes, will be conducted using multinomial logistic regression adjusted for probability weighted class assignment. For the regression analysis we will include co-variates that are significant at the 5% level in the univariate analysis. Any variables with greater than 3% missing data will be tested at the end of the modelling procedure using imputation to determine the resultant sensitivity of results to missingness.

Separate models of growth, for height and weight, will then be created for each latent class grouping. Growth models will be undertaken using heirachical linear spline models using knot points for growth identified in previous studies undertaken using ALSPAC data.In line with previous ALSPAC growth analysis the source of measurement (height and weight) will be included as a covariate in the models. Appropriate adjustment for other known confounders such as gestational length, maternal height and childs gender.

B2016 - Children of Alcoholic parents Cognition Behaviour Mental Health and Alcohol Use Trajectories - 24/05/2013

Background:

Alcohol use disorders (AUDs) are highly prevalent, affecting 3.6% of the global population (Rehm, Mathers & Popova et al., 2009). AUDs impact on the physical (liver disease, brain damage and injuries) as well as psychological well-being of the affected individual. Furthermore, AUDs have a considerable impact on the affected individual's family, larger social circle and society as a whole. There is a considerable genetic component to AUDs with heritability estimates of ~50-60% (van den Bree, Johnson eta, 1998). As many as 15% of children report living with an alcoholic parent (US data reported by Grant, 2000) while 43% of Children of Alcoholic parents (CoAs) will themselves develop an AUD in adulthood (Grant, 2000). It is therefore important to understand the developmental pathways of alcohol use/ misuse in this high-risk population.

Children of Alcoholics:

CoAs have been consistently reported to have poorer academic achievement than children of non-alcoholic parents (non-CoAs) (e.g. Puttler, Zucker, Fitzgerald and Bingham, 1998; Diaz, Gual & Garcia et al., 2008). However, the evidence regarding impaired performance on cognitive assessments (e.g. WASI/WISC) is less clear, with some studies reporting worse full-scale, verbal and performance IQ in CoAs (e.g. Diaz, Gual & Garcia et al., 2008) (Yang & Kramer, 2012), while others report no difference (e.g. Kultur, Unal & Ozusta, 2006). There have been no studies based on a large scale longitudinal population-based sample.

One of the most consistently reported differences between children with and without alcoholic parents is increased problem behaviours. These include externalising and antisocial behaviours, as well as internalising and hyperactive behaviours. Externalising and antisocial behaviours have been reported in children with alcoholic parents from a very young age, even including infancy (Edwards, Eiden, Colder & Leonard, 2006). These behaviours then appear to persist throughout development into adolescence (Hussong, Huang & Curran et al., 2010). Internalising behaviours, such as negative affect and anxiety are less reliable reported. There have been some positive results in early childhood (Haugland, 2003), but the majority of studies have reported that internalising behaviours become more common in children with alcoholic parents during adolescence (Hussong, Cai & Curran et al., 2008). This increase during adolescence may be related to the onset of the child's own alcohol use.

There is some evidence that suggests that maternal and paternal alcohol use can have differential effects on offspring (Connell & Goodman, 2002) and that offspring gender can influence the impact of parental alcohol use (Eisenberg, Haugen & Spinrad et al., 2010). Social factors, such as parental-offspring relationships and peers, can also influence the effect of parental alcohol use on the offspring (Stice & Barrera, 1995).

Current proposed study:

There is currently an absence of large population-based longitudinal studies which examine the associations between parental alcohol problem use and offspring behaviour. While there have been a number of small-scale longitudinal studies using high-risk populations (e.g. Chassin, Rogosch & Barrera, 1991; Eiden, Edwards, Colder & Leonard, 2009) and some larger population-based comparative studies (e.g. Yang & Kramer, 2012), there have been no studies which have the breadth of information available in the ALSPAC data set.

We propose to use already collected ALSPAC data to address the important issue of parental alcoholism. We will compare with and without alcoholic parents in the areas of cognition, behaviour, psychiatric problems and substance use. Additional analysis will be used to see if offspring's own alcohol use contributes to any differences we find and to see if parent or offspring gender and offspring's peer group also have an impact.

Aims:

1. Conduct comparisons between CoAs and nonCoAs at an early age (i.e. age 8), before alcohol use initiation, on relevant indices reported in the literature, including behaviour, academic performance and cognition, social factors (family and peer relations), and mental health problems.

Sub aims: examine any evidence for gender-specific effects (i.e., parent or offspring)

2. Conduct similar comparisons at later ages (i.e. 8-15), when participants are increasingly starting to use alcohol. Here comparisons will also include alcohol and other substance use at different ages.

3. Examine the longitudinal alcohol use/ misuse trajectories for CoAs and non-CoAs and to what extent specific covariates (see above) play a role in any differences.

Analyses:

Analysis 1 and 2. ANOVAs, chi-square tests, or regressions where CoA (yes/ no) is the dependent variable.

Analysis 3. Trajectories already exist. Each individual in the sample has been assigned a probability of belonging to different categories based on repeated measures of alcohol use collected at different ages. We will plot the trajectories for the two groups. We will conduct regression-based analysis to determine whether CoAs are more likely to belong to certain alcohol trajectories compared to non-CoAs, before and after adjustment for covariates.

References:

Chassin, L, Rogosch, F, & Barrera, M. (1991). Substance use and symptomatology among adolescent children of alcoholics. Journal of abnormal psychology 100(4), 449-463.

Connell, A.M., & Goodman, S.H (2002). The Association Between Psychopathology in Fathers Versus Mothers and Children's Internalizing and Externalizing Behaviour Problems: A Meta-Analysis. Psychological Bulletin, 128 (5), 746-773.

Diaz, R., Gual, A., Garcia, M., Arnau, J., Pascual, F., Canuelo, B., & Garbayo, I. (2008). Children of alcoholics in Spain: From risk to pathology. Social psychiatry and psychiatric epidemiology, 43(1), 1-10.

Edwards, E. P., Eiden, R. D., Colder, C., & Leonard, K. E. (2006). The Development of Aggression in 18 to 48 Month Old Children of Alcoholic Parents. Journal of abnormal child psychology, 34(3), 409-423.

Eiden, R. D., Colder, C., Edwards, E. P., & Leonard, K. E. (2009). A longitudinal study of social competence among children of alcoholic and nonalcoholic parents: Role of parental psychopathology, parental warmth, and self-regulation. Psychology of addictive behaviors, 23(1), 36-46.

Grant, B.F. (2000). Estimates of US Children Exposed to Alcohol Abuse and Dependence in the Family. American Journal of Public Health, 90 (1), 112-115.

Haugland, B. S. M. (2003). Paternal alcohol abuse: Relationship between child adjustment, parental characteristics, and family functioning. Child psychiatry and human development 34(2), 127-146.

Heron, J., Macleod, J., Munafo, M. R., Melotti, R., Lewis, G., Tilling, K., & Hickman, M. (2012). Patterns of alcohol use in early adolescence predict problem use at age 16. Alcohol and alcoholism, 47(2), 169-177.

Hussong, A. M., Cai, L., Curran, P. J., Flora, D. B., Chassin, L. A., & Zucker, R. A. (2008). Disaggregating the distal, proximal, and time-varying effects of parent alcoholism on children's internalizing symptoms. Journal of abnormal child psychology 36(3), 335-346.

Hussong, A. M., Huang, W., Curran, P. J., Chassin, L., & Zucker, R. A. (2010). Parent alcoholism impacts the severity and timing of children's externalizing symptoms. Journal of abnormal child psychology, 38(3), 367-380.

Kultur, S. E. C., Unal, M. F., & Ozusta, S. (2006). Psychopathology in children of alcoholic fathers. Turk Psikiyatri Dergisi, 17(1), 3-11.

Puttler, L. I., Zucker, R. A., Fitzgerald, H. E., & Bingham, C. R. (1998). Behavioral outcomes among children of alcoholics during the early and middle childhood years: Familial subtype variations. Alcoholism: clinical and experimental research, 22(9), 1962-1972.

Rehm, J., Mathers, C., Popova, S., Thavorncharoensap, M., Teerawattananon,Y., & Patra, J. (2009). Global burden of disease and injury and economic cost attributable to alcohol use and alcohol-use disorders. Lancet, 373, 2223-2233.

Stice, E., & Barrera, M. (1995). A longitudinal examination of the reciprocal relations between perceived parenting and adolescents' substance use and externalizing behaviours. Developmental psychology, 31(2), 322-334.

van den Bree, M., Johnson, E. O., Neale, M. C., & Pickens, R. W. (1998). Genetic and environmental influences on drug use and abuse/dependence in male and female twins. Drug and alcohol dependence, 52(3), 231-241.

Yang, S., & Kramer, M. S. (2012). Paternal alcohol consumption, family transition and child development in a former Soviet country. International Journal of Epidemiology, 41(4), 1086-1096.

B2015 - Intrauterine stress effects on the intergenerational transmission of risk for adverse childhood experiences - 24/05/2013

Summary:

The proposed project will investigate the impact of foetal exposure to maternal depression on the intergenerational transmission of adverse childhood experiences (ACE) and psychopathology in a prospective longitudinal cohort study: the Avon Longitudinal Study of Parents and Children (ALSPAC). The overarching goal of this project is to elucidate key psychosocial pathways that underpin the intergenerational transmission of risk for childhood adversity (ACE, psychopathology, inflammation). The identification of such pathways would be of great clinical utility: targeted interventions early on could provide preventative strategies to limit these transgenerational cycles.

Background:

Childhood maltreatment is a major public health issue. Currently, over 50,000 children in England are on the child protection register (Department for Education, 2011). The National Society for Prevention of Cruelty to Children (NSPCC) identifies childhood maltreatment as any exposure to physical abuse, sexual abuse, physical neglect, emotional neglect or domestic violence. For research purposes, the term "adverse childhood experiences" (ACE), "victimisation" or "trauma" has been applied in a more generic manner to refer to such forms of maltreatment, as well as to other negative childhood experiences such as peer bullying and exposure to major traumatic life events. For the purpose of this proposal we refer to ACE as a means to encapsulate all such types of detrimental experiences.

ACE have repeatedly been shown to be associated with severe psychiatric illness in adulthood and adolescence, such as depression, psychosis and personality disorders (Fisher et al. 2012; McLaughlin et al. 2012; Nanni et al. 2012; Reed et al. 2013) as well as adulthood inflammation (Danese et al 2007, 2008). There is also a robust relationship between offspring exposure to maternal prenatal stress in utero and later psychopathology (O'Connor et al. 2002; Pawlby et al. 2009; Hay et al. 2010; Rice et al. 2010). Moreover, in our recent work we have demonstrated a strong association between an offspring's exposure to intrauterine stress (maternal depression) and their increased likelihood to experience ACE in middle childhood (Pawlby et al. 2011). Similar associations have since been reported in other samples, specifically the ALSPAC cohort, whereby offspring exposed to maternal depression/anxiety in utero were found to be at an increased risk for peer victimisation in middle childhood (Lereya et al. 2012). These data suggest two important points: i) exposure to depression in utero and ACE are likely part of the same putative pathway that links early life insults with an increased risk for persistent psychiatric disorders, and ii) exposure to maternal prenatal stress is a key risk factor for ACE.

ACE tend to be correlated across generations. Indeed, in both US and UK samples - namely the ALSPAC cohort - a mother's history of maltreatment in her own childhood predicts an increased probability for her offspring to be exposed to maltreatment (Sidebotham et al. 2006; Berlin et al. 2011). In our own sample - the South London Child Development Study (Sharp et al. 1995) - we have recently demonstrated the synergistic effects of maternal prenatal stress on the intergenerational transmission of ACE and psychopathology (Plant et al. 2013). Our findings indicate that maternal history of ACE and depression during pregnancy are key risk factors that interact, whereby the occurrence of both insults results in the greatest risk for offspring being exposed to childhood maltreatment and subsequent adolescent disruptive behaviour disorders. This data suggests that prenatal stress is a key risk factor for the intergenerational transmission of ACE and its sequelae. Whilst investigations into the intergenerational transmission of maltreatment have been conducted previously in the ALSPAC sample (see Sidebotham et al. 2001, 2006), to our knowledge, there has been no direct test of the impact of offspring exposure to maternal stress in utero on the transgenerational transmission of ACE and psychopathology. We thus propose to test this putative pathway for the intergenerational transmission of ACE and psychopathology in the ALSPAC sample, which will allow for a more robust and dynamic investigation of this model and its intricacies that were not so permitted in our existing analyses given our smaller size (n = 125).

B2014 - Suicide attempt and self harm and its association with adolescent sexuality A UK community based study - 09/05/2013

Aims and Objectives:

To determine whether there is an association with minority sexual orientation in adolescence and self-harm or suicide attempt.

B2013 - Understanding the wider context of the development of basic skills - 10/05/2013

We are about to apply for an ESRC Research Centre Grant, which will fund a cross-institutional (international) research centre for three years, with Coventry University acting as a 'hub' for collaborative working across the other centre sites. We would like to include ALSPAC as one of the national sites in this networked research centre, and cost into the project the price of one data analyst, to be employed by and based at ALSPAC for the three years that the Centre is funded (if the application is successful). This would enable us to identify research questions and specific hypotheses as a team and then ask the ALSPAC statistian to create and clean the data file and conduct the analysis agreed by the research team, with the statistian's input into this process too. This individual would be named as a coauthor on all outputs which draw on his/her work (i.e. all the activity associated with this specific work package within the centre). Broadly, we are interested in modelling the developmental relationships between key variables of interest, with a view to understanding some of the wider factors which appear to impact on children's school attainment, and their basic skills (reading, writing and mathematical abilities) in particular.

B2012 - Estimating features of trajectories in the diurnal BP of adolescents - 09/05/2013

Background: In many epidemiological scenarios, understanding change is crucial. Repeated measures (or longitudinal) data are one of the pillars of this understanding. Cohort studies and randomised controlled trails produce such data since a group of individuals are followed over time with repeated measurement of key exposure(s) or outcome(s). A plethora of methods exist for modelling such data, with mixed or multi-level models being at the forefront. However there is a lack of approaches capable of estimating features of trajectories borne out of such data. To accurately estimate a feature (such as the minimum or maximum of a trajectory) requires a descriptive approach not restricted by parametric assumptions. Furthermore, many features of a trend can only be extracted through derivative estimation. For example, derivative estimates are needed to obtain the maximum rate of change of a biological process or the time at first decline of a biomarker.

There is a strong positive association of systolic and diastolic blood pressure (SBP and DBP) across most of their distribution with increased cardiovascular disease risk. Higher SBP and DBP measured in adolescence and early adulthood are associated with increased coronary heart disease and stroke risk with magnitudes of association that are similar to those seen when blood pressure is measured in middle-life.

Blood pressure varies, by up to 20%, over the day (with lower levels during rest and in particular in deep sleep) and in response to different stimuli, one of which is physical activity. Variability in blood pressure across the day, and the magnitude of the difference between day- and night-time blood pressure have been proposed as independent cardiovascular risk factors over and above the mean level of blood pressure. Relatively little is known about these patterns and their correlates in healthy adolescents.

Aim: The aim of this proposal is to develop methods to accurately extract features of diurnal BP for individuals and for the sample. These may then be used to investigate associations with outcomes.

Hypothesis: Specific features of diurnal SBP and DBP trajectories in adolescents are associated with cardiovascular risk factors

Exposure: Extracted features of diurnal SBP and DBP. Linear mixed models are one commonly used approach for modelling continuous repeated measures. These allow separate modelling of the variability between members of the cohort and the variability within individuals. To handle non-linear trajectories over time, alterations to the linear mixed model are available, such as transforming the outcome, allowing for polynomial trends of the outcome over time (fractional polynomials) or allowing the outcome trend to change in different segments of time (regression splines). These can be useful if statistical inference is of primary concern. At the other end of the spectrum, when the question of interest is to describe the trend over time, these simple alterations can prevent goodness of fit because of the restrictions of a fully parametric model. In particular, when interest lies in identifying a feature of repeated measurements, a fully parametric model is not sufficiently flexible to obtain reliable estimates.

Flexible methods which borrow from the fields of mixed models and non-parametric smoothing come under the umbrella of functional data analysis (FDA). FDA encompasses the various modelling methods for these non-linear repeated measures data. Unfortunately, in the situation where measurement times are irregular across individuals, many methods under the umbrella of FDA become inefficient. In epidemiology such data are common since measurement often occurs within routine GP visits. Three approaches to modelling non-linear irregular repeated measures data have been identified, namely semiparametric mixed models, P-Spline mixed models and Principal components Analysis through Conditional Expectation (PACE). These have not been used to their full potential in the epidemiological literature.

In a range of disciplines it is often the case that the derivative, or rate of change, of observed data is of primary interest. In the situation where data are observed over time, the first derivative will correspond to velocity, the second to acceleration. In a LMM the rate of change is, by definition, constant for both the individual and cohort. Where the LMM contains a complex polynomial of time, this polynomial can be differentiated to give the rate of change of the biomarker at any timepoint, both on average and for each individual. When non-linear methods such as P-Splines are used, it can be difficult to obtain derivative estimates and their standard error analytically. Derivative estimation is a difficult problem for several reasons. Firstly, with no observations for derivatives, testing goodness of fit does not exist. Secondly, modelling the change of a variable over time is more sensitive to measurement error and outliers than modelling observed data. Third, standard errors can be difficult to obtain since many approaches use numerical methods to estimate the derivative as a by-product. However, derivative estimates can be very useful. For instance, when a first derivative estimate of a biomarker over time is below zero, the process is declining. Using the standard error to create variability bands, we obtain an analogous confidence interval comparison for evidence of decline. Derivative estimates allow us to obtain features of trend such as the maximum/minimum velocity or acceleration. These have been used in physiology as a marker for endurance and in child growth as a marker for puberty. Derivative estimates and their standard errors have yet to be obtained for several approaches to longitudinal data.

Outcome: Cardiovascular risk factors

Confounders: Age, sex, socio-economic status, smoking status, weight, height, fat mass, physical activity.

B2011 - Rural/urban differences in dietary intake in a UK cohort of children - 09/05/2013

Clear differences in dietary intake have been reported in residents of urban compared to rural areas. This has been frequently reported in developing countries (Bowen et al, 2012) but also in the USA and Canada (Downs et al, 2012). Differences have been reported in children/adolescents as well as adults. However, little is known about any differences in the UK.

It has generally been shown that residents of rural areas have a poorer nutrient intake compared to residents of urban areas. In developed countries, the primary reason put forward to explain these differences is down to the the food environment whereby food is generally reported to be more expensive in rural communities, with less availability and variety. It is unlikely that families living in rural communities in the UK exclusively purchase food in their immediate suroundings and we hypothesise that there will be no obvious differences in dietary profile. However, differences have been reported in obesity levels in the UK in rural versus urban areas through secondary analyses of the Health Survey for Englanddary analyses of the Health Survey for nhtat dietary intake is a driverand it is possible that dietary intake is a driver in this, so warrants attention. In addition, previous studies examining areas of residence and dietary intake suffer from residual confounding; not taking into account familial factors such as socio-economic status.

Exposures:

We plan to use the Rural/Urban Definition (England and Wales), a detailed rural/urban indicator defined by the Rural Evidence Research Centre at Birkbeck College (RERC) based on 2001 Census data and will be derived from our address information. The use of this indicator will allow us to distinguish between rural and urban areas using eight categories: Urban, Town and Fringe, Village, Hamlet and Isolated Dwellings; each on two sparsity levels) to examine detailed rural and urban residential effects on dietary patterns.

Given the heavily urban-weighted spatial distribution of the ALSPAC cohort and the potential lack of geographical representation of data in more remote areas, we also request Output Area (from which the Rural/Urban Indicator is built) and Super Output Area (Lower & Middle) to permit analysis in the event of unsatisfactory statistical power at the preferred (OA) scale.

Outcomes:

At each time point (7, 10 and 13 years) we will examine differences in selected energy-adjusted macro- and micronutrients and food group intakes derived from diet diaries according to the divisons described above using t-tests/ANOVAs as appropriate and will use general linear models to adjust for a variety of potential confounding factors.

We will also examine any differences in the clusters of dietary patterns previously described (Northstone 2012). When examining effects at ages seven and thirteen, population changes will be used to assess the accuracy of using the 2001 data for earlier/later years and extrapolating data appropriately if necessary.

If possible (dependent on relevant numbers) we will determine whether any changes in rural/urban indicator lead to any changes in dietary intake over time in an attempt to infer causality.

References

Downs SM, Fraser SN, Storey KE, Forbes LE, Spence JC, Plotnikoff RC, Raine KD, Hanning RM, McCargar LJ. Geography influences dietary intake, physical acitivity and weight status of adolescents. Journal of Nutrition and Metabolism 2012; doi:10.1155/2012/816834.

Bowen L, Ebrahim S, De Stavola B, Ness A, Kinra S, Bharathi AV, Prabhakaran D, Reddy KS. Dietary Intake and Rural-Urban Migration in India: A Cross-Sectional Study. PLoS ONE 6(6):

e14822. doi:10.1371/journal.pone.0014822.

K Northstone, AD Smith, PK Newby, and P Emmett. Longitudinal comparisons of dietary patterns derived by cluster analysis in 7 to 13 year old children. Br J Nutr 2012; 15: 1-9.

B2010 - The developmental role of Behavioural and Neurobiological Dimensions in predicting Eating Disorders in adolescence/young - 08/05/2013

Eating Disorders (ED) are serious mental health disorders affecting approximately 5-10% of adults (Hudson et al., 2007; Swanson et al., 2011) and have a peak of onset in adolescence between the ages of 15-19 (Micali et al., 2013; Field et al., 2012). The etiology of ED remains poorly understood, though and interplay of genetic and environmental factors is likely to be at play. Research into the clarification of risk factors has been hampered by uncertainties about clear phenotypic distinctions across ED categories, and by a lack of integrative studies using a longitudinal approach to clarify risk for ED. This study aims to focus on how cognitive, emotional and social processes cause ED behaviors in adolescence and young adulthood in interaction with environmental factors from infancy onwards.

Cross-sectional studies have identified cognitive, emotional and social difficulties that are associated with ED.

There is cross-sectional evidence that anorexia nervosa (AN) is associated with emotional and social communication difficulties and that specific cognitive profiles characterize bulimic type disorders.

AN shares common features with anxiety (Silberg & Bulik, 2005; Micali et al, 2011); and a range of social communication deficits, including interpersonal problems and poor emotion recognition, are present in individuals with AN (Tchanturia et al., 2012; Treasure et al., 2012).

Bulimic-type ED are cross-sectionally associated with specific cognitive profiles characterized by poor attention (Dobson & Dozois, 2004; Faunce, 2002) and low inhibition (Galimberti, et al., 2012; Rosval et al., 2006).

Most of the studies cited above are cross-sectional and have often focused on one specific area of behavior or cognition.

In relation to genetic risk for ED poor replication of early candidate genes studies has led to newer approaches heralding possible successful identification of risk markers. Large genome-wide studies of psychiatric disorders have highlighted genetic similarities across disorders, indicating either poor specificity of genetic markers or poor specificity of categorical classification systems. It also remains to be determined what the role of genetic mechanisms that affect gene expression, such as epigenetic processes, is in relation to ED.

The purpose of this study is to investigate the contribution of specific Research Domain Criteria (RDoC) constructs (across behavioral/self report and biological units of analyses (genetic, epigenetic and biomarkers data)) and their interaction with environmental factors to the risk for ED behaviors (restrictive eating, excessive exercise, bingeing, purging at ages 13,14, 16, 18, 24) in a longitudinal developmental fashion. We aim to develop a risk prediction algorithm for ED behaviors that incorporates these predictors.

We propose to use data collected prospectively (and carry out a new wave of data collection) from a unique ongoing cohort study: the Avon Longitudinal Study of Parents and Children (ALSPAC), based in the United Kingdom, to investigate the prospective association of anxiety and social communication and AN-type behaviors (restrictive eating and excessive exercise); and cognitive control and attention and BN-type behaviors (bingeing, purging).

The availability of biological (blood samples and cord blood for DNA at birth, age 7/9 and 15/17 years), neuropsychological (between ages 1 and 5, 8 and 13 years), behavioral (every two years from 3 1/2 until 12 years and more detailed at 7,10 and 13 years), social (ages 1 and 5, ages 8-10, 12 years) data at repeated time points in 7,000-9,000 adolescents/young adults over a period of 20 years makes this cohort a unique resource.

We will investigate the following specific aims:

1. To determine whether anxiety and social communication difficulties:

a) are longitudinally predictive of developing AN-type behaviors (restrictive eating, excessive exercise) in adolescence/young adulthood (ages 13-24);

b) interact with life events to predict AN-type behaviors (restrictive eating, excessive exercise)

We hypothesize that high childhood anxiety and poor social communication will be predictive of restrictive eating and excessive exercise in adolescence/young adulthood; and that they will interact with childhood life events.

2. To determine whether low cognitive control and poor attention:

a) are longitudinally predictive of developing BN-type behaviors (bingeing, purging) in adolescence/young adulthood (ages 13-24);

b) interact with life events/bullying to predict bingeing and purging from ages 13 to 24.

We hypothesize that low cognitive control and poor attention will be predictive of bingeing and purging in adolescence/young adulthood; and will interact with life events/bullying.

3. To build a risk model across domains and derive a risk prediction algorithm that can be used to identify high-risk individuals.

Exploratory aim: Exploratory analyses on the effect of poor emotion recognition on restrictive eating and excessive exercise in 500 young males, using functional and structural neuroimaging will complement the above aims.

We will look at whether these patterns and associations vary by gender. We propose to use one of the largest population-based longitudinal study in the world with a long enough follow-up and data available across most units of analyses, to investigate longitudinal associations between specific constructs and ED behaviors in adolescence/young adulthood. The size of our sample and the repeat and comprehensive assessments will allow an investigation of risk for ED across specific cognitive, social and behavioral constructs and their interaction with environmental factors in a unique and cost-effective way.

Methodology

Outcomes:

ED behaviours collected at ages 13,14,16,18. A questionnaire will be included in the 24/25 clinic to assess ED. We will use the same questionnaire used at age 14.

Predictors:

This grant focuses on using dimensional behavioural/cognitive predictors recently identified in the Research Domain Criteria (RDoC) proposal (one of the strategic aims of NIMH). RDoC focuses on understanding specific neurobiological dimensional phenotypes by studying each across a series of indicators-called units of analyses (including available biomarkers, self-report measures and behavioural observation).

Data collected throughout childhood on anxiety/emotional disorders, social communication and neuropsychological tasks (constructs) will be used as predictors. Additionally we will use data on evironmental risk factors, such as life events throughout childhood and bullying/teasing as predictors.

Genetic data already collected on ALSPAC participants will be used to investigate the role of genome and epigenome across the constructs under study. In particular a polygenic risk score will be generated using results (top SNPs) from current MEGA-analyses from two consortia. Genome-wide methylation data available from ARIES will also be used.

Biomarkers, i.e. salivary cortisol at age 11/12 will also be used as predictors.

Confounders:

data collected throughout childhood on socio-demographic data. Basic demographic characteristics and an overall environmental adversities index will be constructed from mothers' questionnaire data as collected from pregnancy through to child age 11. Information on gender, ethnicity, SES, employment, education, income, housing, family type and size, mother age at birth, gestational age and birth weight will be recorded.

Child IQ collected at age 8 will also be used as a confounder.

Data analyses:

After initial dscriptive analyses across each variable a stepped approach will be used.

Firstly each construct under study will be investigated across its units of analyses using factor analysis or by deriving latent variables.

Secondly the association between hypothesised constructs and outcomes will be investiagated using univariable analyses.

Fourthly multivariable models will be applied.

In relation to aim 3. we will use a multivariable Cox proportional hazard regression backward elimination model for each outcome under study, by including variables identified in objective 1 and 2 to build a riks prediction model.

B2008 - Biomedical Research Informatics for Data Gathering and Exploitation in Systems Medicine BRIDGES - 09/05/2013

Margaret Thatcher was famous for her need for little sleep, though nobody knows with any accuracy, how little. Now we have the sensor technology to capture many such types of lifecourse data in real-time, to passively stream those data directly to databases, and to connect 'research,' 'health' and 'clinical' data seamlessly together. This opens the potential for highly integrated systems?medicine research encompassing many disease domains in conjunction with highly multidimensional data -for example, linking data for sleep, environment, genetics, diabetes and cardiovascular health, and neuropsychiatry for an holistic approach to reearch. Such data not only encompass simple tabulatable information but also complex data types that cannot be represented in standard formats, for example, MRI, continuous monitoring/signal processing, quantitative proteomics and next-generation sequencing. Novel data types rely on emergent database technologies and as yet many different types of issues tend to confine individuals' data into isolated and lost 'pockets' - in the NHS, in research units or simply unrecorded. There might, for example, be signature relationships between sleep duration, neuroanatomy, genetic and 'omic determinants, lifecourse, and health outcomes - we need the technology and data silos to be joined up to find out.

Our proposal capitalises on unique data-orientated developments in the co-applicants' institutions and aims to integrate, structure global access, innovate real-time sampling of patient data, facilitate complex analyses across and within diseases and train a new cohort of medical informaticians to pave the way for personalised and systems medicine of the future. The institutions are already engaged with large scale multilevel data (e.g. MRC Centres in Bristol and Cardiff; ALSPAC and 1958 birth cohort in Bristol; diabetes collections in Exeter; BRU's in Leicester) and technological developments in the vanguard for database integration, access and analysis challenges. They also have large scale funding for sensor technology development (EPSRC - Bristol and collaborators), for omics integration (EU - Leicester), for graduate training in complexity (EPSRC) and analysis bioinformatics (MRC), for integrated biostats/bioinformatics (BBU - Cardiff) and importantly, for splicing or searching biomedical data types together flexibly and securely (e.g. BRISSKit, SHRINE, DataSHIELD - Bristol and Leicester). The deep complementarities between the co-applicant centres, form the basis of the proposal's workpackages which work toward seamless streaming, integration and analysis of data for biomedical research driven by the context of our specific health and disease studies.

B2005 - A comparison of twin and singleton data for early life characteristic - 23/04/2013

Aims/Hypothesis:

Twin data are valuable for quantifying genetic and environmental contributions to phenotypes, including both disease risk (e.g. type 2 diabetes) as well as quantitative traits (e.g. body mass index). However, twins can differ from singletons insofar as they tend to be born earlier (37 weeks rather than 40 weeks), and smaller (lower birth weight). The extent to which twins differ from singletons on a range of other early life characteristics (e.g. adiposity, growth, appetite and illness) is unclear. It is important to establish the extent to which twin data are comparable to singleton data, in order to ensure that results derived from twin studies may be generalisable to singletons.

The primary aim of this project is to establish the extent to which twins are similar to singletons on a variety of early life characteristics, by comparing twin data from two UK-based paediatric cohorts (the Twins Early Development Study, and Gemini - Health and Development in Twins), with singleton data from a number of large UK-based cohorts including ALSPAC. We hypothesize that twins will not differ from singletons on early life characteristics, thereby supporting the generalisability of findings from twin studies.

Our secondary aim is to test if the relationship between different early life characteristics is the same for twins and singletons.

Exposure variable:

We do not have exposure variables as such, as we are comparing summary statistics across different cohorts. 'Twinness' or 'singleton' (captured by the cohorts themselves) will be the primary 'exposures' of interest.

Outcome variables:

Our primary interest is anthropometric data. Primarily, we will compare anthropometric data from the singletons in ALSPAC to twin data from the Gemini cohort (at a number of different age points from birth to 5 years) and the Twins Early Development Study (TEDS) (at 7, 10, 11 and 12 years).

In addition to anthropometric variables, we will be comparing the twins and the singletons on appetitive data. In the Gemini cohort we have data from the Baby Eating Behaviour Questionnaire (BEBQ) and the Child Eating Behaviour Questionnaire (CEBQ) and would be looking for a comparator measure for appetite within ALSPAC. We also hope to compare feeding behaviour; encompassing breast versus bottle feeding to ascertain, for example, whether having multiple babies would make breast feeding more difficult. Other variables that we will examine are illness (to establish if the shorter gestational period of twins effects their general health in the early years of their life), infant temperament, physical activity and sleep.

One of the primary interests of the Gemini Study is to understand the predictors of weight gain in early life. As such, we have established relationships between appetite and weight, and sleep and weight, using the twin data. We will therefore examine if the magnitude of the association between appetite and weight, and between sleep and weight is the same for twins and singletons.

We are also planning to compare our twin data to singleton data from the Cambridge Baby Growth Study cohort and the Millennium Cohort Study.

Confounding variables:

When making comparisons between the cohorts we will take account of gestational age, postnatal age, gender, parental age at birth, parental health, ethnicity, and sociodemographic information.

B2003 - Sexual orientation and problem drinking in adolescence - 22/04/2013

Aims:

1. To establish whether sexual orientation (at 15) is associated with problem drinking in late adolescence;

2. To assess evidence that any link between sexual orientation and problem drinking in late adolescence may be mediated by high levels of depressed mood and/or anxiety;

3. To test whether there are gender-specific differences (females vs. males);

4. To establish the prevalence of substance use (i.e., tobacco and illicit substances) in non-heterosexual vs. heterosexual adolescents.

Adolescent alcohol use represents a main public health concern as it causes short and long-term health problems and antisocial behaviour, which can lead to self-harm or harm to others (Coleman & Carter, 2005). Alcohol use is widespread in the UK where 88% of 15 year-olds report having drunk alcohol in the past 12 months and 1% of 14-16 year olds drink nearly every day.

Adolescents who identify themselves as gay, lesbian or bisexual (i.e. sexual minority adolescents) are at increased risk of involvement in problem drinking compared to their heterosexual counterparts, with studies reporting earlier age of onset of alcohol use, more frequent and heavier (i.e., binge) drinking, and more alcohol-related problems than heterosexuals (Bergmark, 1999; Corliss et al., 2008). Although there is evidence of differences in risk of problem drinking between males and females from a sexual minority background, the pattern remains unclear. Some studies have observed more alcohol problems among females than males while others have observed the opposite pattern (Ziyadeh et al., 2007).

Evidence also shows that sexual minority adolescents experience more mental health issues (i.e., depression and anxiety) than their heterosexual peers (Fergusson, Horwood & Beautrais, 1999; Hatzenbueller et al., 2008). Greater levels of anxiety and depressive symptoms may be elicited by gay-related stressors, such as the stress of coming out (Elze, 2002; Hatzenbueller et al., 2008). Symptoms of depression and anxiety have been found to predict elevated drinking and alcohol-related problems among non-heterosexual youth. However, to our knowledge, no study has attempted to establish whether these risk factors may explain the developmental relationship between sexual orientation and drinking. Our study aims to fill this gap by assessing whether the relationship between sexual orientation and problem drinking is explained by internalising disorders. We will also include risk factors of problem drinking, identified in the general population, in order to establish if they can further help us to understand this relationship. The risk factors we intend to use are school satisfaction, relationships with friends and parents, parental monitoring and alcohol attitudes (Sareceno et al., 2010).

Few studies also identified greater substance use and misuse among sexual minorities although less research has been dedicated to tobacco and illicit drug use in this sub-group (Hefferman, 1998). Thus, our final aim is to assess substance use prevalence in the non-heterosexual group compared to their heterosexual counterparts.

Hypotheses:

1. Adolescents who identify as not heterosexual report an earlier onset age of alcohol use and greater problem drinking in later adolescences;

2. We expect that the relationship between sexual orientation and problem drinking may be stronger for those experiencing internalising disorders;

3. There are gender-specific differences in these patterns. Although there is evidence in the general population that rates of depression are higher in female than male adolescents (Thapar et al., 2012), the findings for non-heterosexual adolescents are unclear. Thus, these analyses will be exploratory in nature

4. We expect higher engagement with other substances among non-heterosexual individuals.

Exposure variable(s): Sexual orientation assessed as sexual identity and also as sexual behaviour (i.e., gender of sexual partner); depressive and anxiety symptoms experienced by the teenager; relationship within the family members; parental monitoring; relationships with peers; school satisfaction; attitudes to alcohols

Outcome variable(s): Alcohol use: age of onset; drinking patterns and alcohol-related problems. Tobacco and illicit drug use.

Covariates: Family socio-economic status (SES); parental alcohol and substance use; parental depression; sensitivity to alcohol; conduct problems (i.e., Strengths and Difficulties Questionnaire)

Analyses:

We will conduct preliminary correlations and univariate regression models between sexual orientation and problem drinking as well as substance misuse to examine the association at baseline (i.e., age 15; cross-sectional data). Moreover, we will use structural equation modelling (SEM) to assess these relationships over time while controlling for relevant covariates (e.g., family SES, parental depression and alcohol misuse). Finally, we will use SEM to test the effects of theorised moderators and mediators (i.e., depressed mood and anxiety) on this association and assess whether they explain the direction and/or strength of the relationship. The model will also be adjusted for variables which have been identified as risk factors for both alcohol and substance misuse to assess whether they further explain this mechanism (e.g., relationship with parents and peers; attitudes to alcohol). We will conduct Multiple Imputation to account for missing data.

B2002 - Role of selected endocrine disrupting chemicals on sex-hormone levels at age 15 girls enrolled in the ALSPAC study - 22/04/2013

Plasma levels of testosterone and sex hormone-binding globulin are associated with risk of diabetes. Several cross-sectional studies have reported positive associations between exposures to endocrine disrupting chemicals (EDCs) with BMI or insulin resistance. There are no longitudinal studies, however, exploring associations of gestational concentrations of EDCs during pregnancy with endogenous sex hormones known to predict obesity. For this proposal we want to use data on concentrations of sex hormones and insulin resistance generated by Hany Lashen on a sample of girls at age 15 to explore associations with EDCs.

The goals of this proposal are to explore feasibility of testing study associations with current data and development of future studies on this topic.

B2001 - Effects of vitamin B12 intake during pregnancy on offspring cognitive ability - 22/04/2013

Background: Vitamin B12 is an essential nutrient and it is required in one-carbon metabolism, the biochemical pathway that leads to DNA methylation. Maternal vitamin B12 and more generally the one-carbon metabolism are associated with neurodevelopment although the evidence is scarce (e.g. Bhate et al., 2008, Bonilla et al., 2012). Maternal vitamin B12 status seems to affect offspring's DNA methylation (McKay et al., 2012) suggesting a role for DNA methylation in the association between vitamin B12 and neruocognitive development.

Aim: To examine the causal association between vitamin B12 during pregnancy and offspring cognitive development, using genetic variants previously associated with one-carbon metabolism as proxies for vitamin B12 in a two-way Mendelian Randomization study. To assess the role of DNA methylation as a mediator in the association.

Hypotheses: We hypothesize that alleles which increase the levels of vitamin B12 during pregnancy will be associated with better cognitive performance. We hypothesize that DNA methylation mediates this association.

Exposure variables: Maternal and offspring genotypes for polymorphisms associated with vitamin B12 status and DNA methylation. Maternal vitamin B12 intake during pregnancy and cord blood levels.

Outcome variables: SCDC, WISC, WASI, CCC, DAWBA conduct problems.

Confounders and mediators: Maternal education, social class, age at delivery, parity, smoking during pregnancy, alcohol and folate assumption during pregnancy, infections during pregnancy. Child's date of birth, birth weight, sex, gestational age. Breastfeeding duration. Child's DNA methylation status.

Bhate V, Deshpande S, Bhat D, Joshi N, Ladkat R, Watve S, Fall C, de Jager CA, Refsum H, and Yajnik C. Vitamin B12 status of pregnant Indian women and cognitive function in their 9-year-old children. Food Nutr Bull. (2008) 29: 249-254.

Bonilla C, Lawlor DA, Taylor AE, Gunnell DJ, Ben-Shlomo Y, Ness AR, Timpson NJ, St Pourcain B, Ring SM, Emmett PM, Smith AD, Refsum H, Pennell CE, Brion MJ, Smith GD, Lewis SJ. Vitamin B-12 status during pregnancy and child's IQ at age 8: a Mendelian randomization study in the Avon longitudinal study of parents and children. PLoS One. (2012) 7:e51084. doi: 10.1371/journal.pone.0051084.

McKay JA, Groom A, Potter C, Coneyworth LJ, Ford D, Mathers JC, Relton CL. Genetic and non-genetic influences during pregnancy on infant global and site specific DNA methylation: role for folate gene variants and vitamin B12. PLoS One. (2012) 7:e33290. doi: 10.1371/journal.pone.0033290.

B2000 - Effects of pubertal timing on childrens bullying behaviour and mental health - 15/04/2013

Aim:

To investigate whether pubertal timing has an impact on bullying and victimisation at school for males and females and whether the relationship between peer victimisation and mental health problems (such as depression symptoms, psychosis symptoms, anxiety or self-harming behaviour) would be exacerbated by early maturation (girls) or late maturation (boys).

Hypotheses:

1) Early-maturing girls will be more likely to be victimised.

Outcome Variables:

Bullying status groups according to child, mother and teacher report at ages 8 to 18.

Exposure Variables:

Puberty measures from 8 years to 17 years

Confounding variables:

Demographics: gender, ethnicity, family social and economic status, home ownership;

Family factors: domestic violence and harsh parenting, maternal mental health status, child abuse and maltreatment;

Psychological factors: any mental health problems using DAWBA, internalizing and externalizing problems using SDQ, depression using SMFQ and MFQ;

Individual factors: sex, IQ, sexual relationships

2) Late-maturing boys will be more likely to be victimised.

Outcome, exposure and confounding variables:

Listed as above.

3) Off-time puberty will mediate/moderate the relationship between bullying involvement (at ages 8, 10 and 12) and menteal health problems (ie.depression, psychotic experiences, anxiety and self-harm) and sexual relationships.

Outcome, exposure and confounding variables:

Listed as above.

Outcome:

Depression, psychotic experiences and anxiety at 18 years and self-harming behaviour at 16.5 years and sexual relationship in adolescence.

Analysis:

Logistic regression analysis, multiple mediation model and structural equation modelling will be used to test the hypotheses. Given the potential impact of attrition on the findings, the data may be weighted for each part of the analysis. A logistic regression approach to weighting will be employed with bullying data available versus not available specified as the dependent variable and factors likely to predict attrition (e.g., gender, ethnicity, parental social class, family environment) included as independent variables and predicted probabilities (pprob) obtained. The inverse probability weight will then be calculated as 1/pprob.

B1549 - Association of maternal smoking and tooth eruption in ALSPAC - 11/04/2013

In a recent study we looked at the relationship between tooth eruption and adolescent anthropometric measures in ALSPAC. We found primary tooth eruption to be associated with height and weight at 17 years (unpublished Fatemifar et al. 2013). To gain a better understanding of factors effecting tooth development we believe that it is also important to understand exposures that may alter the timing of eruption and subsequently number of primary teeth at childhood. Smoking during pregnancy is known to reduce fetal development (1). We therefore hypothesise there will be relationship between maternal smoking during pregnancy and timing of tooth eruption.

Aims:

We aim to investigate the relationship between maternal smoking and primary tooth eruption. In doing so we need to take into account any confounders and mediators. We then aim to use a variant in a known nicotine receptor to conduct some instrumental variable analysis, in which we look at the relationship between maternal smoking and primary tooth eruption using the nicotine receptor variant as an instrument for maternal smoking.

Exposure variables:

Maternal Smoking

Paternal Smoking

Outcome variables:

Age at first tooth (15 months)

Number of teeth (15 months)

Confounding variables:

Birth weight

Maternal Education

Breast Feeding

Gestational Age

Maternal Age

Parity

1. Jaakkola,J.J.K. and Gissler,M. (2004) Maternal smoking in pregnancy, fetal development, and childhood asthma. American journal of public health, 94, 136-40.

B1548 - Identifying common genetic variants and putative genes associated with facial attractiveness - 11/04/2013

Facial attractiveness plays a crucial role in a variety of human interactions, including human mate choice. People prefer to date and marry facially attractive individuals. The preference for more attractive partners is warranted from an evolutionary perspective, given that facially attractive individuals have higher reproductive success than their less attractive counterparts and facial attractiveness is generally thought to indicate genetic quality in terms of disease resistance. People are also more likely to ascribe positive personality attributes to form same-sex appliances, employ and even vote for facially attractive individuals. Despite historical beliefs, facial attractiveness is not merely an arbitrary cultural convention. People from different cultures show strong agreement in what is considered facially attractive. Even young infants who have not been exposed to cultural norms, prefer to look at faces that adults describe as facially attractive. Previous studies have identified several facial cues (eg sexual dimorphism and symmetry) and hormones (eg testosterone and cortisol) that play a role in facial attractiveness. Yet despite the high estimated heritability of facial attractiveness, very few studeis have accessed the genetic variation underlying facial attractiveness. To our knowledge, only the human leukocyte antigen (HLA) genes have been investigated as candidate genes for facial attractiveness. Roberts et al found that HLA heterozygous men (ie men that have differenc copies of the HLA genes) were considered more attractive than HLA homozygous men (ie men that have similar copies of the HLA genes). Follow up studies have replicated this association in male, but not female subjects. Recent studies have shown that genome wide association (GWA) studies can successfully identify common genetic variants and genes which regulate quantitative heritable traits such as height and facial morphology. GWA studies therefore provide a more robust approach to identifying common genetic variants that are associated with facial attractiveness compared to candidate gene approaches that have been used for HLA).

The primary aimof this study is to identify common genetic variants, and ultimately putative genes, that are associated with facial attractiveness using GWA methodologies. We specifically chose the ALSPAC dataset because it is, to our knowledge, the largest dataset with both facial images and GWA data. To accomplish this aim, 3D facial images obtained from the ALSPAC image set will be standardised for size and orientation. 30 (15 male) caucasian students from the United Kingdom (UK) will rate all the images for attractiveness on a seven point Likert scale over eight one-hour sessions (rate calculated from previous work). 30 raters are sufficient to produce an accurate measure of facial attractiveness. We request permission to have the images rated at the Perception Lab, University of St Andrew's (UK), because of the well-established image rating facilities, large participation pool and streamlined workflow; images are rated in the UK to reduce cross-cultural variation in attractiveness judgements. Attractiveness ratings will be averaged for each image. The ALSPAC team have cleaned and imputed a GWA study dataset consisting of 8365 individuals with genotype calls for ~2.5 million common variants spread across the genome. We will use this resource to conduct a 2 stage (discovery and replication) genome-wide association study. Initially the discovery phase will include analysing ~5000 individuals that have both genotypic data and facial images. Power analysis (PowerGwas/QT version 1.0) indicate a sample size of 5000 is adequate to provide 80% statistical power to detect single nucleotide polymorphisms (SNPs) that explain as little as 0.8% of the variance in facial attractiveness. The association between each of the ~2.5 million SNPs (exposure variables) and facial attractiveness (outcome variable) will be independently tested in the ALSPAC cohort using linear additive regression, while controlling for pubertal development. SNP associations that exceed the standard significance threshold for genome-wide significance (pless than 5 x 10-8), will be identified and replicated independently in additional cohorts, making up the second replication phase for the GWA study. To determine which genes (and pathways) are most likely associated with facial attractiveness we will conduct a range of post-hoc analyses including (a) assigning SNPs to genes, (b) epistasis modelling and (c) pathway analyses. Briefly, multiple genes are ascribed to each SNP and these genes are then prioritised using epistasis modelling and pathway analysis, allowing us to further identify which biological processes regulate facial attractiveness. In addition, we will calculate a more accurate heritability estimate of facial attractiveness; do a GCTA analysis to estimate the amount of phenotypic variance in attractiveness common SNPs explains; test the relationship between admixture and attractiveness; test the relationship between genome-wide heterozygosity and attractiveness using the ~2000 ALSPAC individuals who have whole genome sequencing data; and test the association between previously imputed classical HLA alleles and facial attractiveness separately for males and females. Based on previous work we predict that HLA alleles will be associated with male, but not female attractiveness. All GWA analyses will be conducted at the University of Bristol.

The second aimis to determine the association between health measures (exposure variables) and facial attractiveness (outcome variable). The health measures will be divided into prenatal risk factors (eg parental age, presence of gestational diabetes) and childhood health measures (eg body mass index, blood pressure and self-reported health). Facial attractiveness is generally assumed to serve as a 'health certificate', but studies testing this assumption mostly utilise a few self-reported health measures and small sample size (~N=40-200). The size and quality of the ALSPAC dataset, especially the wide range of physiological measurements, provides us with the ideal opportunity to test the association between health indices and facial attractiveness in male and female faces respectively. Based on previous research and work currently under review, we predict that facial attractiveness will be significantly associated with health measures, but more so for male than for female subjects.

The third aimis to determine whether SNPs associated with facial attractiveness are also associated with other traits proposed to indicate overall quality, specifically increased height, body mass index (BMI) within the health BMI range, increased sexual dimorphism (eg facial masculinity/femininity) and facial symmetry. To do so we will calculate morphometric or perceptual measures of sexual dimorphism and facial symmetry before testing the relationship between allelic scores of SNPs for facial attractiveness and these traits.

B1547 - DGKK variants and fetal growth - 11/04/2013

DGKK was the main gene found to be associated with hypospadias in a genome-wide association study (GWAS) (van der Zanden et al., 2011), which we replicated in a further study (Carmichael et al., 2013). Given that DGKK is expressed in the placenta (we know little else about it), and hypospadias is associated with fetal growth retardation (Carmichael et al., 2012), we hypothesized that DGKK variants would be associated with fetal growth. Preliminary data among 930 non-malformed, male, population-based controls that were part of our DGKK-hypospadias study suggest that DGKK variants are associated with increased risk of low birthweight (less than 2500 gm) among term infants (37 or more weeks gestation). However, the sample size was relatively limited (only 20 subjects were term and low birthweight). ALSPAC offers an excellent opportunity to examine this hypothesis in more depth and in a much larger sample (approximately 7,500 subjects).

Our hypothesis is that DGKK is associated with fetal growth. The aim of the proposed analysis is to examine the association of fetal growth with infant genetic variants (SNPs) in DGKK that were included in the Illumina 317 genotyping (GWAS) panel, which has been run on ALSPAC samples. Parameters reflecting fetal growth, as well exclusion criteria for genotyping data, will largely follow methods developed for use of ALSPAC data for the meta-analysis of GWAS data on fetal growth by Freathy et al. (2010). That is, we will examine the association of birthweight standardized to z scores adjusted for gestational age, as a continuous measure and as a dichotomy (ie, less than 10th percentile versus higher), and we will examine birth length, head circumference and ponderal index, all among singleton term infants. The Freathy et al. study did not examine growth among preterm infants, but we propose to also examine the association of the DGKK variants with preterm delivery and with birthweight adjusted for gestational age among infants born preterm. All analyses will be stratified by infant sex since DGKK is on the X chromosome. Potential covariates to consider inclue maternal age, parity, prepregnancy body mass index, smoking, and education (as a marker of socioeconomic status). We will restrict analyses to singletons.

References

Carmichael SL, Mohammed N, Ma C, Iovannisci D, Choudhry S, Baskin LS, Witte JS, Shaw GM, Lammer EJ. Diacylglycerol kinase K variants impact hypospadias in a California study population. J Urol 2013;189:305-11.

Carmichael SL, Shaw GM, Lammer EJ. Environmental and genetic contributors to hypospadias: a review of the epidemiologic evidence. Birth Defects Res A Clin Mol Teratol 2012;94:499-510.

Freathy RM, Mook-Kanamori DO, Sovio U, Prokopenko I, Timpson NJ, et al. Variants in ADCY5 and near CCNL1 are associated with fetal growth and birth weight. Nat Genet 2010;42:430-5.

van der Zanden LF, van Rooij IA, Feitz WF, Knight J, Donders AR, et al. Common variants in DGKK are strongly associated with risk of hypospadias. Nat Genet. 2011;43:48-50.

B1546 - Social inequalities in allostatic load in childhood - 28/03/2013

Background:

Social inequalities in health, with people experiencing progressively worse health with increasing deprivation, are present throughout the world. Inequalities in health are not limited to mortality and life expectancy, with the incidence of physical and mental conditions being higher for individuals with lower socioeconomic position (SEP), including most cancers, heart disease, diabetes, depression and multimorbidity. However, the pathways, and particularly the underlying biological processes, linking poorer SEP and ill health are not well understood. Understanding the causal links between SEP and health are essential if inequalities are to be reduced in the UK and elsewhere.

Given the wide range of conditions that vary by SEP, it has been proposed that there are some common biological pathways in how SEP can 'get under the skin'. Through the exposure to environmental, psychosocial and behavioural factors that SEP results in, the body is put under demands that it can adapt to in the short-term (normal system regulation). However, if these exposures persist, dysregulation can occur. The 'wear and tear' on the body that will occur over long spells of such dysregulation is typically irreversible, eventually increasing the risks of poor health and functioning.

Cumulative physiological burden and dysregulation that occurs across multiple physiological systems throughout the lifecourse can be captured using the concept of allostatic load. The most widely used construct of allostatic load has been developed by Seeman and colleagues, where it is conceptualised using biomarker measures across an array of systems including the cardiovascular, metabolic and inflammatory systems. Allostatic load has been shown to predict the risk of major health outcomes including heart disease and all-cause mortality. Importantly, many of the individual components of allostatic load are not risk predictors for the same health outcomes associated with allostatic load. Assessing these biomarkers together as allostatic load helps us to understand the synergistic nature of the physiological burden on the body imposed by exposure to damaging environmental stressors. To date, there has been consistent (albeit small in number) evidence for lower SEP to be associated with higher allostatic load. Given the associations identified between SEP and allostatic load, and allostatic load and health, it is hypothesised that allostatic load is a mediator in the pathway between SEP and health. However, we are missing evidence for how SEP and allostatic load are associated throughout the lifecourse, how these associations can differ over time and place and if allostatic load is indeed a link between SEP and health. If allostatic load is a predictor of health, it would be expected that similar patterns of inequality would be seen in allostatic load as those seen with life expectancy and diseases like CHD. Greater knowledge on the relationship between SEP and allostatic load (and subsequent risk prediction of ill health) could be important for targeting interventions aimed at reducing inequalities in health that will have the broadest impact across the population. Understanding how the relationship between SEP and allostatic load differs according to factors such as age, gender and geographical location could be an important step in ensuring that these interventions are targeted correctly and efficiently.

Preliminary work:

I have recently led on a study paper looking at the relationship between SEP over the lifecourse and allostatic load (to be submitted April 2013). This study used a structured modelling approach comparing various theoretical models of the influence of SEP on health across the lifecourse that encompass the accumulation of risk, critical/sensitive periods and social mobility models. We found that the accumulation model of lifecourse SEP had the best model fit for the association with allostatic load in men and women aged approximately 35, 55 and 75 from the West of Scotland Twenty-07 Study (although the results were less convincing at older ages). However, the results also indicated that childhood was a particularly important time-point for the link between SEP and allostatic load. Since March 2013 I have also been leading on a study investigating some of the potential mediators (behavioural, psychosocial and material factors) between SEP and allostatic load using the Twenty-07 Study. This work has been funded by a six-month MRC Centenary Award.

Aims:

The overall aim of the fellowship is to examine if allostatic load, as a measure of cumulative physiological burden, is a mediator in the association between lower SEP and poorer health outcomes, including physical and mental health and mortality. The specific aim of the project using ALSPAC data is to examine allostatic load inequalities by SEP in children. Very little evidence exists in the development of allostatic load in childhood and its association with SEP, although there is good evidence for social patterning in adolescence. In addition, our preliminary work above has indicated the importance of childhood as a possible critical period in the development of adult allostatic load. Other data on childhood circumstances will also help answer if any patterning is driven by factors such as disease in infancy.

Hypotheses:

Lower SEP (based on a latent parental SEP construct) will be associated with higher allostatic load scores in children aged 9 from the ALSPAC study. This association will be partly mediated by disease in infancy and poorer conditions at birth (e.g. low birth weight, small for gestational age).

Exposure variables:

Parental SEP (education, income, social class, housing tenure, financial difficulties and area deprivation)

Outcome variables:

Allostatic load - a score produced from several bookmarkers (blood pressure, pulse rate, cholesterol, glycated haemoglobin (diabetes marker), waist-hip ratio, C - reactive protein (inflammation marker) and IL-6 (inflammation marker))

Confounding variables:

Sex, disease, birth weight, gestational age, ethnicity

Please note, any data provided will be stored on secure drive spaces at SPHSU, which only I have access to.

B1545 - The Changing Nature of Lone Parenthood and its consequences - 28/03/2013

Research Aims

The study will focus on four inter-related research questions.

1. Who becomes a lone-parent and what are the consequences?

How does lone-parenthood today differ from the past when it was relatively rare? Are lone-parents an increasingly (or decreasingly) "selected" group of the population? How might we expect lone-parents families to fare (in terms of employment, income and poverty) had they not become lone-parents?

2. How long does lone-parenthood last and what is the nature of parents' relationships before and after periods of lone-parenthood?

Most mothers who become lone-parents at the time of their child's birth will have partnered by the time their child is five years old, whilst many married / cohabiting relationships will founder resulting in lone-parenthood for older children. How have these patterns evolved? Do they offer important information for the variation in children's experiences?

3. Are lone-parents becoming more heterogeneous?

Is lone-parenthood becoming increasingly polarized, as has been found in US, with some mothers managing to maintain their incomes through work and maintenance while others fare poorly? Or is lone-parenthood a dominant characteristic leading to poor outcomes for parents and children regardless of background? What are the longer term consequences of lone-parenthood for mothers - does it leave a long term scar even after re-partnering or children leaving home?

4. How does lone-parenthood influence children's outcomes and has this changed over time?

How does family structure, including lone-parenthood and re-partnering (step-parenthood), influence children's outcomes? How does this map onto the patterns in the variation in lone-parenthood described in the preceding questions? To what extent does the background of lone-parents (e.g. age, education) matter in determining children's outcomes? And how does lone-parenthood affect children's social mobility?

Estimation Techniques (Exposure and Outcome Variables)

The analysis will use simple descriptive statistics and panel data techniques to address the research questions set out above. Our first step will be to examine lone-parent status across all data sets. Family status will be defined at the child's birth, at early school age (around age 6), end of primary school (age 11) and end of compulsory schooling (age 16). Re-partnering will be treated as a separate status to intact partnerships from birth. Much of our analysis will focus on lone mothers, who constitute over 90 percent of the lone parent population, although we will also examine lone fathers as a single distinct category where sample sizes allow.

The data will allow us to provide a description of the growth of lone-parenthood over time and across the cohorts. It will also allow us to measure duration of lone-parenthood for children at various ages in the birth cohorts. To do this we will add information of the duration of the relationship prior to the birth to form a typology of lone-parenthood by age of child, duration of lone-parenthood and stability of surrounding relationships. This typology will then be mapped across the cohorts and changes over time will be compared as well as onto child outcomes at ages 6, 11 and 16 to gauge the size of educational deficits at each age for children in or have moved through lone-parent families into re-partnered families. This can also be extended to adult economic and social outcomes, including marriage, fertility and lone-parenthood. So we will assess patterns on social mobility for children growing up in lone-parent families for the early cohorts.

As we are particularly interested in the diversity of experience of lone-parenthood an important question is whether lone-parenthood is more damaging to women's economic position depending on their route into lone-parenthood. We will investigate the influence of education and labour market experience on outcomes for lone-parents; routes into lone-parenthood (including past relationship histories, age of children on becoming a one parent and labour market attachment) and the duration of lone-parenthood. In addition, as paid work has increasingly become the "social norm" for women, has a greater divide developed between lone-parents with strong labour market attachment and earnings and will examine how lone-motherhood has changed in response to increased female labour market opportunities. We will use regression based approaches to condition on observable differences prior to lone-parenthood but it is difficult to also predict what the effects of extremely unhappy relationships would have had if families remained intact. So a number of approaches can be undertaken, each with strengths and weaknesses so as to give as robust a picture as possible. As the data are longitudinal this will allow the use of "fixed effects" estimators, or their equivalents in forms other than linear regression, to further condition out unobservable characteristics of parents and children. Propensity score matching can be used to remove observable differences in socio-economic origins between lone-parent and couple families (including step-parent families), and also to match families by duration of relationships.

The data on children will provide insights into the relationship between the components of our typology and the test scores, so that we can identify which elements of the lone-parent typology appear to lower test scores. We will use regression based approaches to condition on observable differences. In particular we would envisage using propensity score matching to remove observable differences in socio-economic origins between lone-parent and couple families. For those children where lone-parenthood occurs after age 6 or so, and so a pre-lone-parenthood observation of test scores is available a value added model structure will be employed.

B1544 - Evaluation of a child-parent screening approach to identify people with famillal hypercholesterolaemia in ALSPAC - 28/03/2013

AIMS

Familial hypercholesterolaemia (FH) is one of the commonest inherited disorders affecting about 1 in every 500 people in theUK. The condition causes an increase in the "bad" form of blood cholesterol (LDL-cholesterol) which places affected people at much higher risk of suffering heart attacks or angina, or requiring by-pass operations. About 1 in 2 men with FH suffer a heart problem by age 50, and 1 in 3 women suffer a heart problem by age 60. Some sufferers are recognised as having the condition either because they have evidence of fat deposits in the skin or eyes, suffer a heart attack at a very young age, come from a high-risk family, or are found to have an extremely high level of blood cholesterol when they have a blood test (often for an unrelated reason). However, of the 110,000 sufferers thought to exist in theUK, only about 15% are aware that they have the condition.

Statin drugs reduce the blood level of LDL-cholesterol and the risk of heart disease and are a safe and effective preventative intervention in people with FH. There is therefore interest in developing a national screening strategy to detect people with FH early in order that they can receive statins in order to reduce death and disability from heart disease in this group.

B1543 - Prevalence and co-morbidities of specific language impairment SLI in middle childhood - 28/03/2013

Aims

(1) To determine the prevalence and detection of specific language impairment (SLI) in middle childhood.

(2) To identify the most common comorbid deficits associated with SLI in the educational, social, emotional and behavioural domains.

(3) To examine the association between key factors (e.g., language abilities, gender) and educational, social, emotional and behavioural outcomes in typical (non-SLI) children and children with SLI.

(4) To raise awareness of SLI in middle childhood and develop knowledge and understanding of SLI as children approach the primary-secondary school transfer.

Hypotheses

(1) SLI is a developmental condition and is subject to changes over time. We hypothesise that the prevalence of SLI amongst children in middle childhood in the ALSPAC sample would be beween 5 and 10%, with boys showing a higher prevalence than girls.

(2)SLI is associated with a range of comorbidities: deficit in pragmatic language skills, difficulties in literacy, numeracy and science learning, and a higher prevalence of emotional, behavioual and peer problems compared with their typically developing (TD) peers.

(3) Children with SLI, however, are just as likely as their TD peers to display prosocial behaviour.

Exposure variables

- Expressive language skills

- Receptive language skills

- Performance and verbal IQ

- Speech problem and speech therapy attendance

- Education provision and special education needs (SEN)

- Milestones in understandng and talking; speech and language development

- Gender

Outcome variables

- Conduct problems

- Hyperactivity

- Emotional symptoms

- Peer relations

- Prosocial behaviour

- General behaviour or personality problems

- Pragmatic language skills

- Reading skills

- Educational attainment in English, maths and science

Confounding variables

- Family history of speech and language problems

- Medical problems (epiliepsy)

- Developmental milestones and difficulties, eg fine and gross motor skills, social development, developmental delay, diagnosis of autism/ASD.

- Hearing impairment

- Number of other children in family

- Number of people living in the household

- First language

- Maternal education

- Parental employment

- Family income

- Age

- Ethnicity

B1542 - Associations between changes in DNA methylation and changes in adioposity - 28/03/2013

The role of epigenetic modifications in obesity is poorly understood. Some associations between DNA methylation in cord blood and BMI in later childhood have been demonstrated, but the causality of these associations requires further investigation. Any causal relationships between epigenetic modifications and obesity could operate in either direction - DNA methylation may alter transcriptional regulation and hence affect obesity, or alternatively obesity may lead to changes in DNA methylation. We propose to study this by examining the associations between changes in DNA methylation and changes in adiposity in the Avon Longitudinal Study of Parents and Children (ALSPAC).

The associations between changes in adiposity and changes in epigenetic modifications will be assessed using measurements of adiposity and DNA methylation at birth and ages 7 and 15/17 years. Adiposity will be assessed by weight and height at all ages, and by DXA-assessed fat mass at 7 and 15/17 years. The associations will be investigated in multiple ways in order to compare methodological approaches to investigating changes in methylation. We will:

1. Identify the 100 methylation sites that change the most between each pair of sequential time points, and assess whether change in methylation at these sites is associated with change in adiposity

2. Perform principal components analysis (PCA) of changes in all 450k methylation sites to identify patterns of change in methylation, and relate the scores from these principal components to changes in adiposity

3. Perform partial least squares (PLS) analyses - a method that has similarities to PCA. PCA identifies combinations of variables that explain the greatest proportion of variance in those variables. In contrast, PLS identifies combinations of variables which explain the greatest proportion of variance in an outcome (in this case change in adiposity)

4. Perform latent class analysis of changes in methylation and relate these to change in adiposity

If any associations between changes in DNA methylation and changes in adiposity are identified, we will use a genetic risk score for obesity as an instrument for obesity changes, and perform a Mendelian Randomisation analysis to assess the direction of causality.

B1541 - Childhood body size and growth and later risk of haemorrhagic stroke - 28/03/2013

AIM

The aim of this Ph.D.-study is to investigate associations between birth weight, childhood body mass index (BMI), height and growth in weight and height, respectively, and the risk of hemorrhagic stroke later in life. Moreover the question of which biological parameters that underlie the observations made when examining the associations between these particular anthropometric parameters and later risk of hemorrhagic stroke, will also be investigated. As associations between the mentioned anthropometric parameters in childhood and cardiovascular disease (CVD) have been found, and as CVD shares many risk factors with hemorrhagic stroke, it is plausible that associations exist here as well. Thus, low birth weight, high and/or low BMI, height and accelerated gain in weight and/or in height are possible risk factors for hemorrhagic stroke.

BACKGROUND AND SIGNIFICANCE

Stroke causes 9% of all deaths around the world and is the second most common cause of death after ischemic heart disease. Stroke is also a major cause of disability worldwide and consumes about 2-4% of total health-care costs, and in industrialised countries it accounts for more than 4% of direct health-care costs. Approximately 10-15% of all strokes are caused by intracerebral hemorrhage.

Well-established risk factors for hemorrhagic stroke are arterial hypertension, anticoagulant usage, cerebral aneurysms, age, family history of strokes and excessive alcohol intake. Smoking, diabetes, high cholesterol, obesity, and a sedentary lifestyle are risk factors for all types of strokes. The identified risk factors for stroke only explain about 60% of the attributable risk, whereas more than 90% of ischemic heart disease is explained by identifiable risk factors.

The most important of the risk factors for hemorrhagic stroke is arterial hypertension, as it induces degenerative vascular changes that can result in ruptured vessels or micro-aneurysms leading to intracerebral hemorrhage. Excessive use of alcohol is thought to increase the risk of intracerebral hemorrhage by impairing coagulation and directly affecting the integrity of cerebral vessels. High cholesterol levels are known to cause atherosclerosis and thus increase the risk of thrombo-embolic (ischemic) stroke. The vascular degeneration caused by atherosclerosis is, however, likely to increase the risk of rupture and thereby the risk of hemorrhagic stroke. In contrast, some Asian studies have found that low cholesterol levels are associated with the risk of hemorrhagic stroke, suggesting that it causes the arterial wall to weaken and small intra-parenchymal cerebral arteries to subsequently rupture.

Furthermore, it has been found that greater BMI or relative weight in adulthood is strongly associated with the risk of total and ischemic stroke. A J-shaped association between adult BMI and hemorrhagic stroke has been found, thus low and high BMI values increase the risk. Other studies have examined different measures of body size: e.g. adult waist-to-hip ratio and found associations with both ischemic and hemorrhagic stroke. Height is thought to be a surrogate marker of early life and childhood conditions. In studies that have investigated the association between adult height and risk of hemorrhagic stroke an inverse relationship has been found.

Although risk factors for hemorrhagic stroke have been found in adulthood, would it not be better if they could be detected already in childhood? There is evidence that at least a part of the risk may originate in utero as studies consistently find that low birth weight is associated with an increased risk of hemorrhagic stroke. Studies investigating if there are risk factors in childhood, however, are lacking. Childhood BMI, childhood height and growth in height are associated with risk of coronary heart disease (CHD) in adults, and it is therefore likely that these factors also are associated with the risk of hemorrhagic stroke. Despite the plausibility of the associations, few studies have investigated how childhood body size is associated with hemorrhagic stroke. Results from the studies that have are inconsistent, and this is likely due to the low numbers of cases included (less than 100 per study). Therefore, the proposed research will address a gap in the knowledge of childhood body size and growth and its later health consequences.

PROJECT DESCRIPTION

This Ph.D project will be based on data from two epidemiological cohorts. The large Copenhagen School Health Records Register (CSHRR) will serve to investigate the birth weight and childhood anthropometry in relation to risk of hemorrhagic stroke. By using the very detailed data from the smaller Avon Longitudinal Study of Parents and Children (ALSPAC) it will be possible to investigate what biological associations that underlie such particular feature of birth-weight childhood-anthropometry association with later stroke risk. The studies are described in below.

THE CSHRR STUDIES

The CSHRR is an electronic database of information from health examinations on 372.636 schoolchildren who attended school in the capital city of Denmark from 1936 to 2005. The CSHRR contains virtually every school child that attended school in Copenhagen. The children were given full health examinations annually. Essential personal information and dates along with birth weight and height and weight measurements have been computerized.

The CSHRR contains a unique personal identification number, assigned by the Danish Civil Registration System (CRS), for 329,968 (88.5%) of the children. Via the CRS number, the cohort has been linked to the National Cause of Death Register (NCDR) and the National Hospital Discharge Register (NHDR). The size and the prospective and serial measurements of body size along with the age structure of the cohort, where many members have reached middle age, make the CSHRR well suited for studying diseases that occur later in life, such as hemorrhagic stroke.

Therefore, using the CSHRR, the following hypotheses will be investigated:

* Low birth weight increases the risk of hemorrhagic stroke

* High and/or low BMI in childhood increases the risk of hemorrhagic stroke

* Accelerated weight gain increases the risk of hemorrhagic stroke

* Short height in childhood increases the risk of hemorrhagic stroke

* Accelerated growth in height increases the risk of hemorrhagic stroke

Childhood will be defined as 7 to 13 years of age as these are the ages of children in the CSHRR. There are 3.458 cases of hemorrhagic stroke among the cohort members, however these numbers will increase as this is from an older linkage to the NCDR and the NHDR. Furthermore, a sub-set of the CSHRR will be augmented by the use of data from the Danish National Indicator Project (DNIP) that now contains detailed information on prior medical history, diagnostic methods (i.e. CT or MR scannings and severity by the Scandinavian Stroke Scale) and supplemental test, interventions and treatment during hospitalization on more than 4000 cases of hemorrhagic stroke after year 2001. Since other studies on this subject have had less than 100 cases of hemorrhagic stroke, results from this study will contribute to what is known in this area of research. However, an important issue is that the methods used to diagnose hemorrhagic stroke have changed during the given period due to the technical development and implementation of CT scannings in the 1990s. Since hemorrhagic stroke in most cases appear late in life, and given the age structure of the CSHRR, only a small number of cases in this cohort will have had the diagnosis made solely on the basis of a clinical examination.

The proposed research will be conducted at the Institute of Preventive Medicine. The group that will supervise the Ph.D. project has extensive experience in the area of researching long-term health consequences of childhood body size, has a successful history of collaboration, and is skilled in the statistical techniques required. The proposed research is feasible, as the data resource has been used for similar types of projects. With the support of the team, the proposed research is achievable within the timeframe of the Ph.D.

Statistical methods: Associations between birth weight, BMI and height at each age and hemorrhagic stroke will be investigated using Cox regression. Growth will be investigated using the life course analysis technique. Analyses will be conducted separately for men and women. Additionally, analyses will be conducted with the inclusion of birth weight to see if this changes the observed associations. Interactions between birth weight and body size in childhood will be investigated. The assumptions of the Cox regression model will be assessed as will the linearity of the associations. Sensitivity analyses will be conducted to examine the effect of diagnostic changes for hemorrhagic strokes.

Ethical aspects: The Danish Data Protection Agency has approved the use of the CSHRR for these studies

THE ALSPAC STUDY

The ALSPAC resource has a richness of detail that is incredibly valuable as it contains genetic and biological samples collected at multiple time points ranging from the prenatal period through to adolescence and young adulthood of the subjects, thus allowing the assessment of developmental trajectories and critical periods of development. The study recruited 14,541 pregnant women who resided in the former Avon Health Authority area of southwest England with an expected date of delivery between April 1991 and December 1992, resulting in a total birth cohort of 14,062 live births of whom 13,970 were alive at 1 year of age. These children have been followed, initially with questionnaires throughout childhood, and at regular annual clinic visits since the age of 7 years. The UK Medical Research Council, the Wellcome Trust, and the University of Bristol provide core support for ALSPAC, and there have been more than 850 articles published by February 2013; details of these can be found on the ALSPAC study website (enter the website here).

Information on weight and height, puberty, social background medical history for parents and grant parents and exposure to passive smoking, as well as health care examinations, multiple blood samples (including blood lipids) and cardiovascular health parameters (such as blood pressure and pulse rate, intima-media thickness, pulse wave, flow-mediated dilation and scan of the carotid arteries) is available for more than 5000 children.

Using information from ALSPAC, the current study will investigate the hypothesis:

* Childhood body composition and growth are associated with biological risk factors for hemorrhagic stroke

The proposed research will investigate these factors in the ALSPAC-children using the collected data and blood samples. Information from records of preceding measurements of height and weight, including birth weight will be used. Associations between body size and the known risk factors for hemorrhagic stroke such as hypertension, family history of stroke and diabetes will be examined. Associations with blood pressure will be investigated as well. Furthermore, associations of body size with the blood lipid-profile will be investigated. The study will examine both known and also more uncertain risk factors as the lipid profile will, in addition to the traditionally examined lipids like low density lipoprotein (LDL), total cholesterol, triglyceride and high density lipoprotein (HDL), include apolipoprotein B and apolipoprotein A-I which have been found to provide more useful information on the risk cardiovascular disease in adults than traditional lipids do. Also IGF-I levels, which have been hypothesized to promote structural integrity of cerebral arteries and thereby offering protection from hemorrhagic stroke, will also be examined.

It will thus be possible to investigate how different anthropometric parameters are biologically mediated to hemorrhagic stroke.

Statistical methods:

Longitudinal modelling of the relations between rates and patterns of growth in body weight and height from birth through adolescence and the pertinent potential biological mediators of the asscociation between birth-weight-childhood antropometrics and stroke risk will be carried out in collaboration with statisticians with particualr expertise in this type of analyses in Bristol and Copenhagen

Ethical aspects: Approval for the study was obtained from the ALSPAC ethics and law committee, and written informed consent and assent was obtained from both the parent or guardian and the child.

FUTURE ASPECTS

This PhD. study will, with the possible findings of childhood risk factors of hemorrhagic stroke, provide leads for future research aimed at targeted prevention already in childhood and clinical research within the areas of vascular disease.

B1540 - GWAS meta-analysis on childrens sleep problems - 28/03/2013

AIM:

To study the genetic basis of sleep problems in children (Caucasian ancestry only).

HYPOTHESES:

A GWAS meta-analysis on children's sleep problems will provide a powerful tool to reveal novel pathways and enhance our understanding on the architecture of these problems.

Family based and twin studies reveal high genetic heritability of sleep problems but so far, little evidence exists on particular genes and related pathways.

EXPOSURE VARIABLES:

No.

OUTCOME VARIABLES:

-Child Behavior Checklist (CBCL) : Scale Sleep Problems.

-Any other instrument with 3 or more comparable items to the above scale.

CONFOUNDING VARIABLES

- age, gender

B1539 - Joint effect of patterns of infant weight gain and breastfeeding on the risk of body mass index and obesity in childhood - 28/03/2013

Although the potential protective effect of breastfeeding on obesity has been studies extensively, the causal role is still discussed. In a previous analysis of the Avon Longitudinal Study of Parents and Children (ALSPAC) conducted by Dr. John J. Reilly and colleagues, weight gain in the first 12 months was associated with an increased risk of obesity at 7 years also after adjustment for a wide range of potential confounding factors, whereas an apparent protective effect of breastfeeding was reversed after adjustment (BMJ 2005).

It has been suggested that the observed association between longer duration of breastfeeding and lower risk of obesity might be explained by reverse causality. The concern is that more rapid weight gain in infancy induces breastfeeding cessation, and that the faster weight gain itself entrains later obesity. Only few studies have had sufficient data to model this bidirectional relationship and they show heterogeneous results. We propose to model the relation between weight and breastfeeding in infancy and the joint effect on obesity with relevant statistical methods, namely the g-computation formula that can account for the proposed bidirectional relation between infant weight gain and breastfeeding.

The research questions of this proposal are:

1) To investigate whether infant weight and weight gain predicts subsequent infant feeding.

2) To investigate the joint effect of patterns of infant weight gain and breastfeeding on body mass index and risk of obesity through childhood

Exposure: infant feeding at several occasions (breastfeeding, bottle feeding and complementary feeding)

Outcomes: child anthropometrics from birth through childhood

Covariates: maternal education, paternal education, family income, occupational social class, maternal age at childbirth, parity, maternal size, maternal smoking, sex of the child and gestational age.

B1538 - Genome-wide association study of deodorant usage - 28/03/2013

Background

The identification of genes involved in human behaviour is challenging. Genome-wide association studies (GWAS) have shown evidence of genetic contribution in relation to human traits including smoking behaviour and suicidal behaviour (http://www.genome.gov/gwastudies/). We have recently published a study showing a strong (P less than 10^-20) association between rs17822931, a functional SNP located in the ABCC11 gene, and deodorant usage (Rodriguez et al., 2013). A detailed analysis in ALSPAC showed a 5-fold over-representation of AA homozygous in categories of never using deodorant or using it unfrequently. Previous studies offer a biological basis for this association, since there are clear-cut differences in secretion of odour precursors dependent on rs17822931 genotype.

Two remarkable findings in relation to the behaviour of axillary deodorant use were that nearly 80% of European genetically non-odorous still use deodorant, whereas one in 20 individuals genetically odorous did not use it. This opens the possibility of a more complex scenario to explain the genetic basis of this human behaviour. To explore this possibility, an analysis of association at the whole genome level would therefore be required. However, a genome-wide analysis of genetic factors associated with deodorant usage has not been performed to date.

Aim

To conduct a (GWAS) in relation to deodorant usage in ALSPAC

Approach

We will perform a standard GWAS using genome-wide SNP data and phenotypic data already available in ALSPAC. Our proposal does not require the generation of new additional data.

Reference

Rodriguez S, Steer CD, Farrow A, Golding J, Day IN. 2013. Dependence of Deodorant Usage on ABCC11 Genotype: Scope for Personalized Genetics in Personal Hygiene. J Invest Dermatol. 2013 Jan 17. doi: 10.1038/jid.2012.480.

B1537 - The genetics of wound healing Collection of scar phenotypes following common insult and their genetic analysis - 29/04/2013

Where adult tissue is damaged, a complex repair process is taking place involving regeneration and acute phase immunological response. Unlike embryonic tissues, adult repair always leads to the formation of a fibrotic scar where the wound has healed, which ultimately can disable proper tissue function [1]. In recent years, research was able to link several genes to the event of scar formation . Knockdown of Ostepontin (OPN) in mice for example resulted in reduced granulation tissue formation and scarring [2]. It also has been indicated that TGF-beta1 in conjunction with Connective tissue growth factor (CTGF) is promoting scar formation [3]. Most of this data comes from mouse model studies, in humans however, less is known.

BCG injections were routinely given in schools since the 1960s (up until 2005) and lead to a charateristic scar, which individually differs in size and character. Before injection, a skin test is performed to test for exsiting Tuberculosis antibodies. If the test is negative, BCG injections are given [4,5]. In the age group of ALSPAC mothers, up to 70% were immunised each year during childhood, making it a great read-out for assessing population wide scarring outcomes.

By collecting information about different levels of BCG scarring outcomes in ASLPAC mothers by telephone interviews and combining this data with genome data we hope to perform a genomewide associaiton study (and possible rare variant analysis) for scar type. For ethical approval this research proposal will be submitted to ALEC. Please find attached documents summarising the infornation and SOP to be summarised and used during the course of proposed telephone interviews. These are in the process of development before submission to ALEC.

Analysis plan:

(i) develop cover letter, info sheet, protocol and consent form for the BCG scar study for use within a telephone interview

(ii) submitt proposal to ALEC for ethical approval

(iii) collect phenotypic data - coordinated effort with Kate Sherlock and tele-contact team

(iv) submit data for processing by ALSPAC team

(v) unite both genetic and phenotypic data to undertake tests of association

between genetic variation and phenotypic characterisation.

(vi) test selected genes plus surrounding regions locally for variant associated with scarring outcome

Genetic analysis will be supported by Nic Timpson.

1. Stramer, B.M., R. Mori, and P. Martin, The inflammation-fibrosis link? A Jekyll and Hyde role for blood cells during wound repair. J Invest Dermatol, 2007. 127(5): p. 1009-17.

2. Mori, R., T.J. Shaw, and P. Martin, Molecular mechanisms linking wound inflammation and fibrosis: knockdown of osteopontin leads to rapid repair and reduced scarring. J Exp Med, 2008. 205(1): p. 43-51.

3. Shi-Wen, X., A. Leask, and D. Abraham, Regulation and function of connective tissue growth factor/CCN2 in tissue repair, scarring and fibrosis. Cytokine Growth Factor Rev, 2008. 19(2): p. 133-44.

4. NHS (1996) Immunisation against infectious disease - The green book 1996 edition.

5. Shaaban, M. A., Abdul Ati, M., Bahr, G. M., Standford, J. L., Lockwood, D. N. and McManus, I. C., Revaccination with BCG: its effects on skin tests in Kuwaiti senior school children. Eur Respir J, 1990. 3(2): 187-91.

B1536 - The association of ADHD symptoms in childhood to self-harm in adolescence - 09/05/2013

Aims: To investigate the relationship between ADHD and self-harm, in order to see if self-harm can be considered to be a risk factor, and to explore any possible gender effects.

Hypothesis: That self-harm will be more prevalent in individuals with ADHD, particularly in females with ADHD, compared to controls with ADHD.

Method

We propose to obtain participants from the Avon Longitudinal Study of Parents and Children (ALSPAC) which is an ongoing population-based study investigating a wide range of environmental and other influences on the health and development of children. Of the core cohort of 13,988 infants, 10% were randomly selected to be examined in more detail encompassing 10 examinations between 4 months and 5 years - the Children in Focus (CiF) clinics.

Outcome Variables

Diagnostic information (ADHD diagnosis) will be derived from the Development and Well-being Assessment (DAWBA) which was administered to all children remaining in the CiF cohort at 91 months of age (7 years 9 months). All children who were given a diagnosis of ADHD using the DAWBA will be included in the clinical experimental group (currently unknown figure). There will be a sex and age-matched control group. The number in this control group will be twice the amount in the clinical/experimental group.

We are interested in seeking data on self harm in the questionnaire at 16 years 6 months for all individuals that we have DAWBA information on (Section L: Deliberate self-harm, p. 39-43). Can be downloaded from the ALSPAC site: http://www.bristol.ac.uk/alspac/researchers/resources-available/data-det...

Confounding Variables

Associations between diagnosis of ADHD as a predictor for self-harm will be calculated using Chi square analysis. We will control for potential confounders in a logistical regression analysis exploring ADHD and self-harm: presence of learning difficulties and behavioural problems (DSM-IV items on Oppositional Defiant Disorder (ODD); anxiety, social class (of parents); gender and substance abuse. Both ODD and learning difficulties will be evaluated since both have significant impact on functioning and frequently co-occur with ADHD, however they are relatively unexplored as a potential confounding factor in ADHD studies.

B1535 - Comparison of methods to relate GWG to child BMI at age 7 - 28/03/2013

There is increasing emphasis in medical research on fetal and childhood antecedents of chronic disease risk, and how these interact with other exposures throughout the lifecourse to influence later-life conditions (1). Answering questions about the relative importance of speed, magnitude and timing of growth, behaviour and health status for longer-term outcomes requires appropriate analyses of longitudinal data. For example, to understand how maternal weight gain during pregnancy (gestational weight gain, GWG) influences later cardiovascular disease risk for the child, we might seek to describe relationships between GWG and BMI at age 7, and how any relationships are mediated through birthweight and changes in weight during childhood.

Analysis of lifecourse data poses several statistical problems (2). Analysis of a repeated outcome must account for dependencies between multiple observations on the same person: methods to do this (e.g. multilevel models, (3) (4)) are now widely available in standard statistical software packages (e.g. Stata (5)). Within-individual variation may vary over time (e.g. absolute measurement error in weight will be larger in later childhood than at birth) and there will usually be dropout due to non-response, death, illness, emigration, etc. Where several repeated measures are used as exposures in one regression model for a later-life outcome, standard regression models may be affected by their multicolinearity. Disentangling the genuine associations between GWG, birth weight and later outcomes is important; a negative correlation between birth weight and later cardiovascular risk would imply a public health focus on increasing average birth weight, whereas if the relationship were largely between subsequent growth and later cardiovascular risk, this would imply a focus on minimising excess weight gain in children (6).

We consider methods for relating growth (exemplified here by GWG) to later outcomes (here, BMI at age 7). Methods to be used include: SITAR (7); multivariate multilevel growth models (8); latent class models (9); mediation models (10)including structural equation models (11) and lifecourse models (12). We propose to use the associations between GWG, birthweight, childhood growth and BMI at age 7 in ALSPAC as an example dataset on which to compare these statistical methods.

B1533 - FLG genotyping in ALSPAC children - 14/03/2013

Proposal submitted to the MRC centenary award (presided over by George Davey Smith):

Filaggrin (FLG) genotyping to enable FLG+/- stratified analysis to identify FLG*SNP interactions in eczema.

Lavinia Paternoster (PI)

Filaggrin null mutations have been established as a major risk factor for eczema. Several low frequency loss-of-function mutations have been identified which result in skin barrier defects and are associated with increased risk of ichthyosis, eczema and asthma. Originally two mutations (R501X and 2282del4) were identified and used in genetic association studies. However, recently published data on a European population shows that whilst using these two mutations will classify ~13% of the population as FLG mutation carriers, including a further two loss of function mutations (R2447X and S3247X) will classify an additional ~4% of the population as carriers.

We recently carried out a large-scale GWAS meta-analysis within the EAGLE consortium, where we identified three novel loci for atopic dermatitis. Two of these variants were located near genes that play a role in epidermal differentiation and proliferation (OVOL1 and ACTL9), whilst one was in KIF3A within a cytokine cluster of genes with previous evidence of immune-related and inflammatory functions (including associations with asthma and psoriasis). These findings highlight the importance of both skin-barrier and immune related genes in the aetiology of eczema. We hypothesise that there are likely to be important interactions between these two pathways, in that genetic variants within inflammatory/immune-related genes might only predispose to eczema if there is also dysfunction in skin barrier pathways. Due to the large number of tests carried out, analyses often lack power to detect interactions between genetic variants, but we plan to focus on interactions between FLG and known eczema and atopy variants.

Proposed Analysis: We propose genotyping the 4 FLG null mutations in the EAGLE cohorts and then carry out FLG+/- stratified analyses for the known eczema (and other atopy) hits to identify interactions between each SNP and FLG. Each cohort will carry out the analyses and provide summary data to Bristol for meta-analysis.

Pilot results: In ALSPAC we have already genotyped two of the four FLG variants (i.e. R501X and 2282del4). Preliminary analyses show evidence for an interaction between FLG and one of the known eczema hits (rs2897442, in KIF3A), showing an association only in those individuals with a FLG mutation (FLG+ OR=1.75, 95%CI 1.22 to 2.50, p=0.002 compared to FLG- OR=1.08, 95%CI 0.96 to 1.21, p=0.212; interaction p-value =0.014). We also find some evidence for an interaction between atopy SNP rs2252226 (FCER1A) and FLG, with this SNP also only showing association amongst individuals with a FLG mutation (FLG+ OR=1.50, 95%CI 1.11 to 1.98, p=0.008 compared to FLG- OR=0.96, 95%CI 0.87 to 1.07, p=0.475; interaction p-value=0.005). This gene also has a role in immune response.

It is expected that genotyping the additional two FLG variants in ALSPAC will increase power to detect interaction (by improving classification of people into FLG+ and FLG- strata). We also plan to use the other EAGLE cohorts to replicate this finding and carry out a meta-analysis of all FLG*known atopy hit interactions.

This resource will subsequently be used to carry out a genome-wide test for FLG interactions amongst the EAGLE cohorts and could be used in the analysis of other conditions, such as asthma. More thorough genotyping of the FLG mutations will also enable us to investigate properly whether the GWAS signal seen in this region can be completely explained by known FLG mutations.

B1532 - Limb Length in Children An Epidemiological Study of Growth in Northern Europeans - 18/03/2013

Aim:

To assess change of leg length over time in the skeletally imature population, inorder to accuratley assess growth remaining when planning epiphyseodesis.

B1531 - Metabolomic analysis of the affects of the rs174575 FADS2 polymorphism - 14/03/2013

AIMS

This study aims to use mass spectrometry (MS) to identify differences in metabolites between individuals who are homozygous for either the major or minor allele of FADS2. Using MS to identify metabolites will enable a snapshot of the physiological state to be captured and compared between genotypes.

HYPOTHESES

The FADS genotypes have been implicated in a range of outcomes including cardiovascular and metaboloic disease risk, neurological conditions and IQ. FADS2 is a delta 6 fatty acid desaturase involved in the synthesis of omega-6 and omega-3 fatty acids. It is thought that the enzyme from the FADS2 minor allele is less effective at producing derivatives of the fatty acid pathway and thereby there is an increase in precursors left un-metabolised. This infers that the metabolic profile will differ between FADS2 genotypes. PLS regression will be used to examine the metabolites most associated with variation in the outcome (the phenotype or genotype).

EXPOSURE VARIABLE

rs174575 FADS2 polymorphism either individuals homozygous for the major allele (CC) or homozygous for the minor allele (GG)

OUTCOME VARIABLE

Mass spectra from QStar XL QqTOF Mass spectrometer

CONFOUNDING VARIABLES

Age, gender, lean mass, fat mass. The main purpose of the project is to pilot MS methodology, additional variables may be added at a later date.

B1530 - The interplay between fetal growth and ischemia-hypoxia regulated genetic variability in the development of ADHD - 14/03/2013

Association between fetal growth and ADHD. Low birth weight (less than 2500 grams) is a well-established risk factor for ADHD (Nigg et al., 2010). Across prospective case-control studies LBW cases are at approximately 2-times increased risk to developing ADHD or clinically significant ADHD symptoms (e.g., Breslau et al., 1996). Other fetal growth phenotypes such as small for gestational age, ponderal index, and head circumference at birth are also associated with ADHD symptomtatology (Indredavik et al., 2004; Lahti et al., 2006; Heinonen et al., 2011). The relationship between reduced fetal growth and prematurity exists after controlling for a variety of confounding child factors including: child sex, season of birth or duration of breast feeding (Elgen, Sommerfelt, & Markestad, 2003; Horwood, Mogridge, & Darlow, 1998); or by parental factors including: marital status, age, maternal education, paternal education, maternal stress, parental psychopathology, substance abuse, maternal smoking, or parental nurturance (Breslau et al., 1996; Elgen et al., 2003; Horwood et al., 1998; Indredavik et al., 2004; Linnet et al., 2006; Zubrick et al., 2000). Furthermore, evidence suggests that there is a dose-response relationship between birth weight and child behavioral problems (van Os et al., 2001; Wichers et al., 2002; see Wilens et al., 2006 for null findings), including ADHD (Boulet et al., 2009). Given the association between fetal growth and ADHD has been examined primarily in prospective case-control studies, it is necessary to utilize population birth cohorts to further understand the nature of the relationship across the full spectrum of fetal growth and ADHD symptom severity.

Fetal growth and ADHD neurodevelopmental risk. Growth restricted infants have reductions in overall white and gray matter compared to normally grown infants (Brown et al., 2009; Larroque et al., 2003; Tolsa et al., 2004). Such reductions relate to poorer performance on early measures of attention, negative neurodevelopmental outcomes (Peterson et al., 2003; Tolsa et al., 2004) and are consistent with findings in ADHD samples (Filipek et al., 1997; Kates et al., 2002; Mostofsky et al., 2002; Overmeyer et al., 2001). In addition to between group findings, neuroanatomical abnormalities, such as parenchymal lesions or ventricular enlargement, predict increased risk for ADHD within a LBW cohort (Whitaker et al., 1997; Whitaker et al., 2011). Together, these findings suggest that youth who have experienced restricted fetal growth, tend to display neurodevelopmental abnormalities which are functionally related to ADHD symptomatology and consistent with findings in ADHD samples.

Restricted fetal growth as a proxy for an ADHD environmental pathogen(s). Evidence from twin studies suggest that environmental factors that underlie fetal growth, increase vulnerability for ADHD and that this relationship is not confounded by genetic factors (Groen-Blokhuis et al., 2011). This suggests that restricted fetal growth is a proxy for a constellation of prenatal environmental risk factors which restrict fetal growth and are implicated in the complex pathophysiology of ADHD. Genetic factors, however, cannot be discounted and likely play an important role in modifying the relationship between fetal growth and vulnerability for ADHD.

Prenatal ischemia-hypoxia as a possible common pathway linking prenatal environmental risk with ADHD. Suboptimal maternal-placental-fetal nutrient transport is a main determinant of restricted fetal growth (Ghidini, 1996). Thus, prenatal ischemia-hypoxia is believed to underlie restricted fetal growth in the majority of cases, especially within well-nourished populations (Henriksen & Clausen, 2002). This suggests that prenatal ischemia-hypoxia may represent a common prenatal pathway which alters neurodevelopment (Schimdt-Kastner et al., 2012) and subsequent vulnerability for ADHD. For example, both prospective and retrospective case-control studies have shown that ADHD is associated with ischemia-hypoxia related obstetric complications (Pineda et al., 2007; Getahun et al., 2013). Furthermore, low neonatal cerebral blood flow is associated with greater dopamine receptor availability and increased ADHD-related executive functioning deficits (Lou et al., 2004). These findings suggest that prenatal ischemia-hypoxia and related neurodevelopmental and cerebral vascular sequelae may represent an early developmental pathway to ADHD.

Developmental Origins of Health and Disease Hypothesis. The Developmental Origins of Health and Disease hypothesis (DOHaD; Gluckman & Hanson, 2004) provides a framework to conceptualize how genetic and early environmental factors interact to confer vulnerability for ADHD. For example, neurodevelopmental delays or neurodevelopmental disruptions, which covary with restricted fetal growth, may result from a limited supply of nutrients and oxygen in utero. Within individuals exposed to prenatal ischemia-hypoxia vulnerability for ADHD may then be moderated by fetal and maternal genotype. Aberrant epigenetic regulation of gene expression is believed to mediate the relationship between gene x environment interaction with an observed phenotype. Therefore, to further understand developmental mechanisms linking prenatal ischemia-hypoxia with increased vulnerability for ADHD, it is essential to examine variation in both the epigenome and trascriptome.

In our previous research, we have showed that fetal growth moderates the relationship between genetic variants in ischemia-hypoxia regulated (IHR) neurotrophic and kynurenine genes and ADHD symptom severity (Smith et al., In preparation). This study included a limited number of candidate genes that are regulated by prenatal ischemia-hypoxia (Schmidt-Kastner et al., 2012). Therefore, there is a need to more comprehensively examine how IHR genes alter vulnerability for ADHD within a population birth cohort. Therefore, this project aims to leverage the size and scope of the ALSPAC database, along with an IHR gene database curated by Dr. Schmidt-Kastner (see Schmidt-Kastner, 2012) to examine the interplay between fetal growth, IHR genetic variation, and vulnerability for ADHD. The IHR gene database will include 388 genes that: 1) are up- or down-regulated in response to prenatal ischemia-hypoxia in microarray studies of the rodent brain; and 2) are either regulated by hypoxia inducible factor 1 or 2 (HIF-1; HIF-2 ) which regulate the cellular response to hypoxia or have a vascular function.

Summary. Although restricted fetal growth is a well-established risk factor for ADHD (Nigg et al., 2010), little is known about biological mechanisms that underlie the relationship between restricted fetal growth and ADHD. Therefore, the current proposal aims to explore the role of ischemia-hypoxia pathway (as indexed by IHR genetic and epigenetic variation) as an underlying mechanism linking restricted fetal growth and vulnerability for ADHD.

Aim 1. Estimate theproportion of genetic covariance between fetal growth and ADHD symptom severity that can be accounted for by genome-wide SNPs and separately within IHR SNPs using genome-wide complex trait analysis (GCTA; Lee et al., 2012).

Aim1.1. Examine the relationships betweenmeasured fetal and maternal SNPs within IHR genes on ADHD symptom severity, as well as pleiotropic relationships between IHR SNPs on both fetal growth and ADHD symptom severity (Hartley et al., 2012).

Maternal and fetal SNPs that have pleiotropic associations with ADHD symptom severity and fetal will inform gene-environment interaction models in Aim 2.

Aim 2. Model the interactive effects of IHR genetic variants (identified in Aim 1.1) and fetal growth on child ADHD symptoms.

Aim 3. Characterize the role of DNA methylation of CpG sites at birth within child IHR genes (identified in Aim 1.1) in mediating the relationship between fetal growth and ADHD symptom severity.

Aim 4. Examine the interrelationships between fetal growth, methylation profiles of IHR genes, ischemia-hypoxia gene expression and ADHD symptom severity.

Overall Hypothesis: These aims will examine the overall hypothesis that IHR genetic and epigenetic variability will partially explain the relationship between restricted fetal growth and increased ADHD symptom severity.

Exposure Variables: Fetal growth based on gestational age (birthweight, head circumference, crown-heel length) and ischemia-hypoxia related obstetric complications may be examined on a secondary basis (e.g., preeclampsia).

Outcome Variables: ADHD symptom severity is the primary outcome measure. From the ALSPAC site, ADHD (via parent report) is assessed multiple times with the DAWBA (ages 7, 10, 14) and SDQ (ages4, 7, 8, 10, 12, 13, and 17) providing a longitudinal measure of the primary outcome.

Genetic Determinants: Maternal and Child genome-wide data to be used in GCTA analysis. Child DNA Methylation Data at birth and 7 or 9 years of age. SNPs and CpG islands within IHR genes will be utilized in Aims 2 and 3. RNA expression data of IHR genes will be used in Aim 4. NOTE: IHR gene database (in consultation with Dr. Schmidt-Kastner) and results from Aim 1 analysis will be used to guide analyses in Aim 2, 3, and 4.

Confounding Variables: Placental weight, maternal blood pressure, hypertension during pregnancy, maternal smoking during pregnancy, prenatal alcohol use, socioeconomic status and pregnancy, delivery and neonatal health/complications.

B1529 - Investigating the link between umbilical cord PUFAs and maternal and child genotypes - a genome wide approach - 28/02/2013

AIM: To investigate whether fetal cord plasma fatty acid levels are determined by fetal fatty acid conversion

HYPOTHESIS: We hypothesise that variants across the genome, both maternal and child, will be associated with fetal fatty acid levels.

VARIABLES: Levels of cord blood fatty acids will be the outcome variable, while imputed genotype (both maternal and child) will be the exposure. Additional potential confounders will include dietary data and gender of the child.

Previous research investigated the influence of maternal and child FADS genotypes on the levels of long chain polyunsaturated fatty acids (LC-PUFAs) present in umbilical cord venous plasma (Lattka et al., 2012). These levels were used as an indicator of fetal fatty acid supply during pregnancy and the paper suggested that fetal LC-PUFA levels are partly determined by fetal fatty acid conversion.

We propose to extend this to a genome-wide analysis of the maternal and child genotypes on cord blood fatty acids. Additionally, we plan to carry out a secondary analysis on plasma fatty acids levels collected in the children at age 7.

References:

Lattka, E., B. Koletzko, et al. (2012). "Umbilical cord PUFA are determined by maternal and child fatty acid desaturase (FADS) genetic variants in the Avon Longitudinal Study of Parents and Children (ALSPAC)." British Journal of Nutrition FirstView: 1-15.

B1528 - Does increased bone turnover explain the link between cardiovascular disease and osteoporosis - 18/03/2013

Aims

This project will, which will form the basis of an Arthritis Research UK Clinical Research Fellowship for Anupama Nandagudi, will use the mother participants in ALSPAC to investigate whether increased bone turnover explains the link between CVD and osteoporosis:-

(i) Using a cross sectional design, we will confirm that carotid intimal thickness (cIMT) is associated with hip BMD, as measured in the first mothers' clinic comprising predominantly premenopausal women, independently of shared risk factors.

(ii) We will investigate whether cIMT is related to bone turnover, as assessed by beta-CTX measured on blood samples obtained at the same time funded by this fellowship, and whether any association observed explains that between cIMT and hip BMD as described in (i).

(iii) Using a prospective design, we will determine whether cIMT is related to pQCT parameters as assessed at the distal and mid radius in the second mothers' clinic two years later. In particular, we will determine whether these associations involve phenotypes suggestive of increased bone resorption, and if so, whether these relationships are explained by associations with beta-CTX as described in (ii).

(iv) Whether shared genetic risk factors also contribute to the relationship between CVD and osteoporosis will be examined as follows:-

a. We will investigate whether genetic markers for cIMT as identified in recent GWA studies are also related to hip BMD, pQCT variables and/or beta-CTX.

b. We will determine whether genetic markers for bone phenotypes identified in recent GWA studies are also associated with cIMT.

c. We will determine whether associations between cIMT and bone outcomes observed above are explained by shared genetic risk factors which we identify.

d. Whether associations between cIMT, bone phenotypes and genetic factors which we find can be replicated in other populations with equivalent genotypic and phenotypic data will be investigated based on other cohorts (eg Young Finns, Twins UK).

Hypothesis

Prevalent subclinical CVD predicts future fractures and bone loss (1). As well as shared risk factors, this may reflect common pathological mechanisms such as increased bone turnover, which is the subject of the present proposal

Exposure variable

Subclinical CVD as reflected by cIMT as measured at the first mothers' clinic

Outcome Variables

Hip BMD (first mothers' clinic)

Beta-CTX (first mothers' clinic)

Trabecular BMD, as measured by pQCT at the distal radius (second mothers' clinic)

Cortical bone parameters, as measured by pQCT at the mid-radius (second mothers' clinic)

Confounders

Lifestyle risk factors (smoking, HRT use, physical activity, alcohol)

Constitutional risk factors (BP, BMI, fat mass (including intramuscular fat mass as measured by pQCT), age of menopause)

Blood measures (CRP, IL-6, LDL, VLDL, HDL, leptin, adiponectin)

References

(1) Uyl D, Nurmohamed MT, van Tuyl LHD, Raterman HG, Lems WF 2010 (Sub)clinical cardiovascular disease is associated with increased bone loss and fracture risk; A systematic review of the association between cardiovascular disease and osteoporosis. Arthritis Research and Therapy 13 (1) Article Number: R5.

B1527 - Contributions of genetic and environmental factors to muscle density - 18/03/2013

Background

There is increasing interest in the contribution of sarcopenia to frailty and ageing, but research in this area is hampered by the lack of accurate non-invasive measures of muscle function. Though a number of assessments related to muscle function are available, including tests of muscle strength, and functional assessments such as timed chair raise and 'get-up-and-go', objective imaging-based techniques are very limited. Measurement of lean mass, for example by DXA scanning, provides one potential option, based on evidence that this is related to muscle strength and physical activity. However, the overall amount of muscle provides limited information as to its function, suggesting the need for other imaging modalities. One such candidate is pQCT-based measurement of muscle density. However, rather than muscle function, it may be that this primarily provides a measure of intramuscular fat. Consistent with this suggestion, we recently reported a relatively strong inverse correlation between muscle density and total body fat mass (1). A similar relationship was reported between muscle density and insulin levels, consistent with the fact that intramuscular fat deposition is thought to represent an initial step in the development of insulin resistance.

Aims

In the present proposal, we aim to address the hypothesis that muscle density as measured by pQCT provides useful information about muscle function, which is independent of estimates of fat mass/insulin resistance. This will be investigated by examining whether muscle density (adjusted for fat mass) is related to relevant environmental factors such as physical activity, or to genetic factors unrelated to obesity (this research programme will also link in with a parallel project involving Celia Gregson using the Hertfordshire cohort, intended to examine relationships between equivalent pQCT-derived measured of muscle density and findings from muscle biopsies).

Methods

Outcome variables:

Muscle density and cross sectional area as measured by tibial pQCT at 15.5 and 17.5 clinic visits.

Exposures:

Moderate and/or vigorous physical activity, based on Actigraph measures at age 15.5 years, as previously used to examine relationships with other pQCT-derived variables at age 15.5 (2).

High impact activity, based on Newtest monitors at age 17.5 years, as previously used to examine relationships with other pQCT variables at age 17.5 (K Deere et al, JCEM, In Press).

Genome-wide genetic markers, imputed to the latest version of hapmap, as used in our recent GWAS studies of other pQCT parameters in our pQCT consortium (3) (discovery cohorts: ALSPAC, GOOD, Young Finns; replication cohorts: Mr Os, Hertfordshire, EMAS; second meta-analysis centre: University of Gothenberg).

Confounders: age, gender, height, weight, subcutaneous fat area (pQCT), lean mass, fat mass.

1. Sayers A, Lawlor DA, Sattar N, Tobias JH. The association between insulin levels and cortical bone: findings from a cross-sectional analysis of pQCT parameters in adolescents. J Bone Miner Res. 2012;27(3):610-8. Epub 2011/11/19.

2. Sayers A, Mattocks C, Deere K, Ness A, Riddoch C, Tobias JH. Habitual levels of vigorous, but not moderate or light, physical activity is positively related to cortical bone mass in adolescents J Clin Endocrinol Metab. 2011;In Press.

3. Paternoster L, Lorentzon M, Vandenput L, Karlsson MK, Ljunggren O, Kindmark A, et al. Genome-wide association meta-analysis of cortical bone mineral density unravels allelic heterogeneity at the RANKL locus and potential pleiotropic effects on bone. PLoS Genet. 2010;6(11):e1001217.

B1526 - Using Mendelian randomization to investigate the impact of maternal smoking during pregnancy on offspring obesity - 06/03/2013

Aim

To investigate whether smoking during pregnancy is causally associated with offspring dietary fat intake and obesity using a Mendelian randomization approach.

Hypotheses

There is strong observational evidence that maternal smoking during pregnancy is associated with higher adiposity in offspring. (1) It has also been suggested that prenatal tobacco exposure may lead to alteration of amygdala volume in the brain in utero, leading to changes in dietary fat intake and subsequent obesity.(2)

However, there is little robust evidence to suggest that the maternal smoking- offspring obesity association is causal and it is likely to be at least partly confounded by sociodemographic and lifestyle factors. Recent analyses in ALSPAC, comparing the associations of maternal and paternal smoking during pregnancy on offspring trajectories of height and adiposity demonstrated that whilst maternal smoking was likely to be causally associated with smaller birth length and adiposity in infancy, there was little evidence for causal effects on height and adiposity after 2 years.(3)

Mendelian randomisation analyses will allow further exploration of whether the maternal smoking offspring obesity and dietary fat intake associations are causal. Genetic variants in the CHRNA5-A3-B4 gene cluster (rs16969968/rs1051730) are robustly associated with smoking heaviness and to a lesser extent, smoking cessation. (4) These can be used as proxies for smoking behaviour during pregnancy in Mendelian randomisation analyses to investigate whether smoking during pregnancy is causally associated with outcomes in offspring. Within the ALSPAC cohort, the minor alleles of rs16969968/rs1051730 have been shown to be associated with increased heaviness of smoking in women who continued to smoke during pregnancy and reduced ability to quit smoking among women who smoked prior to pregnancy.(5)

We propose to investigate the associations of rs16969968/rs1051730 with trajectories of offspring BMI and trajectories of offspring dietary energy and fat intake, which have previously been developed in ALSPAC using random effects models. In these random effects models, age is the exposure and height, weight or adiposity (BMI or DXA-assessed fat mass) is the outcome. The SNPs will be included in the random effects models with an interaction parameter between the SNP and age, such that different mean trajectories are estimated for levels of the SNP. If an association between the SNPs and growth trajectories is observed, we will take this forward to a formal Mendelian Randomization analysis using two stage IV analysis.

Exposure variables

Mother

Genotype for rs1051730/rs16969968

Outcome variables

Child

Height (birth to 17 years)

Weight (birth to 17 years)

DXA scans (9 -17 years)

Dietary measures of fat intake (3 to 13 years)

Confounding variables

Age

Sex

1. Oken E, Levitan EB, Gillman MW. Maternal smoking during pregnancy and child overweight: systematic review and meta-analysis. International journal of obesity 2008;32:201-10.

2. Haghighi A, Schwartz DH, Abrahamowicz M et al. Prenatal Exposure to Maternal Cigarette Smoking, Amygdala Volume, and Fat Intake in Adolescence. JAMA Psychiatry 2013;70:98-105.

3. Howe LD, Matijasevich A, Tilling K et al. Maternal smoking during pregnancy and offspring trajectories of height and adiposity: comparing maternal and paternal associations. International journal of epidemiology 2012;41:722-32.

4. Munafo MR, Timofeeva MN, Morris RW et al. Association between genetic variants on chromosome 15q25 locus and objective measures of tobacco exposure. Journal of the National Cancer Institute 2012;104:740-8.

5. Freathy RM, Ring SM, Shields B et al. A common genetic variant in the 15q24 nicotinic acetylcholine receptor gene cluster (CHRNA5-CHRNA3-CHRNB4) is associated with a reduced ability of women to quit smoking in pregnancy. Human molecular genetics 2009;18:2922-2927.

B1525 - GWAS of diarrhoea during first years of life - 18/03/2013

Background and hypothesis:

Diarrhoea, as defined by the World Health Organization (WHO), is the passage of loose stool by an individual, at least three times a day, or more frequently than normal. It usually lasts less than 7 days and it can course with or without fever and vomiting. It is most commonly caused by intestinal infection that is transmitted faecal-orally, and infants and pre-school children have higher risk of infection. Children up to age 3 have an average of one to two episodes per year, with peak incidence between the ages of 6 and 23 months.

In the first 5 years of life, approximately 70% of diarrhoea cases are caused by viruses (40% Rotaviruses and 30% others such as Noroviruses and Adenoviruses), 20% by bacteria (Campylobacter spp, Yersinia spp, Salmonella spp, Shigella spp or pathogenic Escherichia coli) and 5% by parasites (Lamblia spp, Cryptosporidia spp or Entamoeba histolytica).

Infection depends on the pathogen strain and on the host genetic background. Heritability for early childhood diarrhoea in Brazil has been estimated in 54%. Histo-blood group antigens (HBGAs) are genetically determined glycoconjugates present in mucosal secretions, epithelia and on red blood cells, and are recognized as susceptibility and cell attachment factors for gastric pathogens like Helicobacter pylori, Noroviruses and Rotavirus.

We performed a preliminary GWAS on diarrhoea in INMA (N=700 children, diarrhoea yes/no during the first year of life based on questionnaire data), and among the top hits (p value ~ 10.E-06), we identified SNPs on one of the HBGA genes.

Aim:

We aim to to perform a genome-wide association (GWA) study meta-analysis on diarrhoea during first years of life.

Exposure variables:

-GWAS data imputed with 1000G project

Outcome variables:

-Diarrhea with or without doctor visit, interview or doctor diagnosis at age 1-1.5y

-Diarrhea with or without doctor visit, inerview or doctor diagnosis at age 2-2.5y

-Diarrhea with doctor visit, interview or doctor diagnosis at age 1-1.5y

-Diarrhea with doctor visit, interview or doctor diagnosis at age 2-2.4y

Confounding variables:

-Sex

Variables needed for exclusions:

-Preterm (less than 37 completed weeks of gestation)

-Congenital anomalies, where known (e.g. Down's syndrome, trisomy 18)

-Stillbirth

-One of sibling/twins or correction

-Non-European ancestry

Maybe in further steps other covariates will be needed (breastfeeding, day care attendance, siblings at birth...)

B1524 - Replication of Parent of Origin Effects in the North Finland Birth Cohort - 28/02/2013

The aim of this proposal is to replicate findings of a parent-offspring effect for BMI and height found in the Northern Finish Birth Cohort. Fourteen SNPs will be tested against either BMI or height (listed below).

The following SNPs will be tested for replication

Trait Chrom MarkerName (Or best proxy)

BMI 14 rs11160659

BMI 2 rs13013988

BMI 15 rs1345919

BMI 12 rs1718123

BMI 2 rs197088

BMI 17 rs208015

BMI 10 rs2358844

BMI 8 rs2471083

BMI 12 rs2904508

BMI 20 rs3092611

BMI 13 rs4883723

BMI 10 rs945491

Height 11 rs831630

Height 4 rs1277313

B1523 - MRC UNITE Programme 4 Using Genetics to Identify Causal Pathways that Influence Bone Related Phenotypes in Children and Young Adults - 28/02/2013

Aims:

(i) Identify genetic determinants of bone related phenotypes, in particular those affecting bone acquisition and growth, using a combination of cutting edge genetic technologies, high resolution phenotypes, and established and novel analytical approaches

(ii) Identify common and rare genetic variants that influence molecular phenotypes (methylation, expression, and the metabolome), and use these variants as well as allelic scores that index them, to identify potentially modifiable biomarkers that affect BMD, high bone mass and osteoporosis (i.e. "mining the phenome using allelic scores")

(iii) Utilize the MR approach and extensions of this methodology to determine whether the associations identified in (ii) are likely to represent causal relationships and to formally quantify these relationships through instrumental variables analyses

B1522 - Mining the phenome using allelic scores A new framework to dissect the biological basis of Ankylosing Spondylitis - 14/02/2013

The aim of this proposal is to specify formulae for allelic scores that index levels of expression, methylation and the metabolome and subsequently construct these scores in a large sample of AS cases and controls with GWAS data, and test to see whether the scores correlate with affection status, potentially identifying interesting biological pathways.

This analysis involves two distinct stages:(i) Genome-wide association analysis of genome-wide methylation, expression and metabolomic data. This will involve association analysis of both common and low frequency variants derived from genome-wide SNP chip platforms (Illumina 550K or 660K) and low density genome-wide sequencing, as well as imputed variants from the thousand genomes and UK10K projects. Because of computational constraints associated with the extremely large number of phenotypes modelled, statistical analysis will proceed using SNPTEST on a cleaned set of 8365 unrelated individuals of confirmed British ancestry. (ii) Construction of allelic scores to serve as genetic proxies for these molecular variables. I will investigate how allelic scores can best be constructed using a variety of approaches from simple weighted counts of strongly associated variants, to genome-wide allelic scores- an approach which I have pioneered in the context of individual risk prediction, to more sophisticated methods involving machine learning and lasso regression. The predictive validity of these measures will be assessed by cross validation, and/or using them to predict the same outcome in cohorts with similar data (e.g. TwinsUK in the case of genome-wide expression; Kettunen et al. (2012) in the case of metabolomic data). Please note, that this part of the project is pretty much identical to that proposed in MRC Unite Programme 4. Once the formulae for generating allelic scores has been validated, these scores will be derived and correlated with a large sample AS cases and controls with GWAS data.

B1521 - The impact of adolescent sleep disorders upon neurocognitive function and the development of chronic pain conditions - 14/02/2013

The impact of adolescent sleep disorders upon neurocognitive function and the development of chronic pain conditions.

Childhood and adolescence is a critical period for developing homeostatic sleep-wake patterns. There is a growing body of evidence to suggest that childhood sleep problems may precipitate difficulties in later life. For example, sleep restriction in children can result in memory and verbal function deficits (Randazzo et al, 1998). Objective actigraphy monitoring also indicates that children (between ages 9 and 12) with higher levels of sleep fragmentation show diminished neurocognitive function on tests such as the continuous performance test and symbol digit substitution (Sadeh, Gruber and Raviv, 2002). Furthermore, Gregory et al (2009) found that sleep problems at ages 5 and 9 could predict neuropsychological deficits at age 13; specifically, tasks requiring a high demand of mental flexibility and working memory. Similar deficits in attentional capacity, memory and cognitive function have also been found in children with sleep-related breathing disorders (Blunden, Lushington and Kennedy, 2001; Beebe, 2006; Lewin et al, 2002). Overall, these studies highlight the importance of managing sleep disorders in childhood.

Pain is an interruptive but adaptive stimulus alerting us to potential threat or danger. Chronic pain patients, however, find it difficult to disengage from the constant threat of pain. Therefore, it is common for pain-related cognitive biases to develop as patients become increasingly vigilant to pain stimuli. Such maladaptive attention processes can unfortunately, prolong pain states. Neuropsychological complaints are common amongst chronic pain patients (Hart et al, 2001) and are assumed to stem from the attention-demanding interference of pain. It may be that pre-existing neuropsychological impairments can precipitate the transition from acute to chronic pain disorders however. If childhood sleep disorders can result in diminished neurocognitive capacity, this may induce a cognitive vulnerability wherein attention towards pain will already be enhanced due to problems with distraction and inhibition.

Psychosocial measures such as depression and negative beliefs about pain have been shown to increase one's probability of transitioning from an acute to a chronic pain condition (Casey, Greenburg et al, 2008; Pincus, Burton, Vogel and Field, 2002). Whether neuropsychological factors pose a risk for the development of chronic pain has yet to be addressed. If such risk factors are identified, early psychological interventions could be critical in preventing the development of certain pain conditions.

Aim and Objectives

To consider whether sleep problems in childhood and adolescence impact upon neurocognitive function and the subsequent development of chronic pain disorders. Using regression methods, results from the study will highlight whether poor sleep in adolescence will contribute increased rates of chronic pain conditions in later life.

It is expected that those with higher incidences of sleep problems will show reduced neurocognitive function. Links between these diminished functions and the development of chronic pain conditions will then be explored.

Hypotheses

Poor sleep will be associated with an increased level of chronic pain reports. Poor sleep will also result in diminished neurocognitive function. The association between sleep and chronic pain will attenuate after the control of neurocognitive function.

Exposure Variables

Early life/adolescent sleep problems

Outcome Variables

Chronic pain condition (y/n)?

Confounding Variables

Gender, socio-economic status, depression, neurocognitive function.

B1520 - Blood pressure effects on cognitive function and academic attainment in children - 28/02/2013

Aims

To better understand how blood pressure (BP) is related to cognitive function and academic attainment in childhood. More specifically, to investigate: (a) the relationship between BP and cognitive function (ages 4, 5, 9, 10, 11, 13 and 15 years) and academic attainment (reception, year 2, year 6, year 9 and year 11) in children, (b) the association between parental hypertension (HT) and cognitive functioning and academic attainment in offspring, (c) the contribution of vascular health (flow-mediated dilatation and pulse wave velocity) to BP-related cognitive functioning and academic attainment, (d) the impact of BP in pregnancy on offspring cognitive performance and academic attainment (e) how these four risk factors (i.e., children's BP, parental history of HT, vascular health and BP in pregnancy) jointly relate to cognitive performance and academic attainment, (f) if these potential risk factors predict future as well as current cognitive functioning and academic attainment.

Hypotheses

a) Paediatric BP will be inversely related to cognitive performance and academic attainment, after controlling for potential confounders.

b) Children with one or more parents diagnosed with HT will be more likely to show poorer cognitive performance and academic attainment than those without a parental history, after controlling for potential confounders.

c) Poorer vascular health (as measured by flow-mediated dilatation and pulse wave velocity) will confer additional risk, compared to elevated BP and parental history of HT, for reduced cognitive performance and academic attainment.

d) Higher maternal BP during pregnancy will be related to reduced cognitive performance and academic attainment in offspring, after controlling for potential confounders.

e) Parental history of HT, higher maternal BP during pregnancy and poorer vascular health will each confer greater risk for poorer cognitive performance and academic attainment than when paediatric BP is considered in isolation.

f) Risk for HT (based on elevated paediatric BP and/or parental history of HT) will be related to cognitive performance and academic attainment both cross-sectionally and longitudinally.

Exposure variables

a) Paediatric BP at ages 4-15: valid measurements of BP taken and expressed as BP percentiles accounting for age, sex, and height. All children with will be included in analyses.

b) Parental HT status: Based on latest evidence of a HT diagnosis (ideally verified by antihypertensive medication) and may review latest BP measurements if necessary. Latest evidence of diabetes diagnosis will highlight secondary HT.

c) Vascular measures: Brachial artery flow-mediated dilatation and pulse wave velocity.

d) Maternal BP in pregnancy and gestational HT.

e) HT Risk: based on paediatric BP (elevated BP >=90th BP Percentile) and parental history for HT (scored as presence of 2, 1, or 0 risk factors).

Outcome variables

a) Cognitive performance: including the following: (i) Aged 4: IQ (WPPSI- R) measures and short-term memory (digit span), (ii) Aged 5: short-term memory (digit span, non-word repetition, initial consonant recognition), (iii) Aged 9: maths and reading ability, (iv)Aged 10: working memory (counting span task) and inhibition (stop signal task), (v) Aged 11: attention (TEACh), (vi) Aged 13: CDR executive function tasks (simple RT, choice RT, digit vigilance), and (vii) Aged 15: WASI measures and inhibition (stop signal task).

b) Perception of ability: including (i) mother's perception of child's ability, (ii) child's perception of school ability/performance, reading and maths ability, (iii) teacher's perception of child's ability.

c) Academic attainment : including (i) External data for Entry and Key stage 1-4, (ii) Pupil Level Annual School Census, and (iii) Key stage 3 grades and qualifications.

To minimise confounding, the following variables form the basis of exclusion or statistical control as they are known to affect one or more of the exposure or outcome variables:

Covariates

a) Study child measures, including : (i) core variables: birth weight, sex, gestation, parity, (ii) age at clinic visit or school assessment, (iii) alcohol consumption, (iv) smoking habits, (v) pubertal development and menstruation (vi) body mass index, (vii) head circumference at 6 months, (viii) clinic anxiety: heart rate and tester rating where possible, (ix) depression, and (x) blood lead level.

b) Parent/caregiver measures (depending on the analysis it might be more applicable to use biological or caregivers information, if different), including: (i) core variables: Mothers age at delivery, ethnicity, parity, marital status, housing tenure, maternal and paternal social class in pregnancy, maternal education during pregnancy, smoking in pregnancy), (ii) mothers alcohol consumption during pregnancy, (iii) mothers and fathers/partners current/most recent occupation, (iv) mothers and fathers/partners current/most recent education, (v) father/partner living with study child, (vi) female caregiver is biological mother, (vii) current partner is biological father, (viii) household income, (ix) Mothers WASI IQ score at TF3, (x) diabetes during pregnancy, (xi) diabetes medical diagnosis in biological mother and father.

Exclusions:

a) Study child measures, including: (i) chronic health conditions (e.g., seizure disorder, obstructive sleep apnoea, chronic disease such as diabetes), (ii) prescription medication, (iii) use of illicit drugs, (iv) acute illness at time of assessment (e.g., infection), (v) demeanour inappropriate at clinic assessment, (vi) presence of special education needs and learning disabilities, (vii) attendance at non-mainstream school, (viii) presence of mental health problems/ symptoms, (ix) uncorrected visual or hearing problems or other problems that may affect cognitive/ academic performance, (x) first language not English.

b) Parent/caregiver measures, including: (i) illicit drug use during pregnancy, (ii) excessive alcohol consumption during pregnancy, (iii) HT status information from both biological parents not available (only for analyses using parental history of HT).

B1519 - Obstetric complications Immune Activation and Schizophrenia Susceptibility - 28/02/2013

The overall goal of this proposal is to advance current understanding regarding the mechanisms that mediate how second trimester maternal infection and peri-natal hypoxia may increase SZ susceptibility. The specific aims of this study are to leverage the unique strengths of the ALSPAC so as to test the inter-relationships between obstetric complications, serum immune biomarkers and phenotypic features of SZ (i.e. childhood behavioral disinhibition and psychotic symptoms). Our hypothesis is that these in utero stressors activate the immune system resulting in persistently elevated serum cytokines, increased behavioral disorders and psychotic symptoms in the offspring. The primary statistical analytic approach to test these inter-relationships will use path analysis or related methods. Regression models will estimate the direct, indirect and total effects of obstetric complications and of serum immune markers on phenotypic features of SZ (psychotic symptoms and behavioral disinhibition).

Exposure variables:

? Maternal infections during pregnancy (e.g. influenza, rubella)

? Peri-natal hypoxia (e.g. umbilical cord around neck, prolonged labor, baby hypoxic requiring resuscitation); vaginal bleeding during pregnancy, placenta abruptio

? Questionnaires of mothers (32 weeks gestation and 8 weeks)

? Obstetric clinical records at time of delivery of the child

Outcome variables:

? interluekin-6 (child); C-reactive protein (child)

? IGFI (maternal); IGFII (maternal); IGFBP3 (maternal)

? Teacher ratings of child's behaviors (Child's Behaviors & Abilities questionnaire at Year 3 and The Developing Child questionnaire at Year 6)

? Mother ratings of child's behaviors (Strengths & Difficulties Questionnaire at 4 yrs, 7 yrs, more yrs?)

? Go/No-Go behavioral measures at age 17 yrs

? Psychotic symptoms (PLIKS-Q at ages 11, 13, 14 and 16 yrs)

Confounding variables:

? Low socioeconomic status

? Immunological disorders in mother or child

? History of schizophrenia in the mother.

B1518 - Automated methods for data mining of causal associations in epidemiology - 28/02/2013

This project is an extension to a mini project that was carried out last year, where we sought to identify causal associations of BMI using Mendelian randomisation. The aim is to develop a proof of principle approach to automate the process of finding causal associations.

This project will involve searching for causal phenotypic associations for BMI and other variables, in a hypothesis free manner using Mendelian Randomisation. The instrumental variables will be automatically constructed from data retrieved from an online web source.

This is a MSc Computer Science project for Arnar Bergthorsson, who will need access to ALSPAC data.

B1517 - Assessment of growth delay in children with unilateral cleft lip and/or palate - 28/02/2013

Outline:

Cleft lip and/or palate (CL/P) is a common congenital anomaly in humans. About a thousand children are born in the United Kingdom (UK) each year with some form of CL/P. Some research has indicated that weight and in particular growth including height (length) and head circumference are reduced in children with clefts when compared with controls at birth and during the first stages of their development ?ADDIN ZOTERO_ITEM CSL_CITATION{"citationID":"dKMtKsJU","properties":{"formattedCitation":"{\rtf\super1\uc0\u8211{}5\nosupersub{}}","plainCitation":"1?5"},"citationItems":[{"id":2078,"uris":["http://zotero.org/users/local/1XkiWLfQ/items/AG8DX9N5"],"uri":["http://zotero.org/users/local/1XkiWLfQ/items/AG8DX9N5"],"itemData":{"id":2078,"type":"article-journal","title":"Birthweight and gestational age of newborns with cleft lip with or without cleftpalate and with isolated cleftpalate","container-title":"The Journal of ClinicalPediatric Dentistry","page":"185-190","volume":"27","issue":"2","abstract":"Thebirth weight and gestational age of 1368 newborns with isolated cleft lip withor without cleft palate and 582 with isolated cleft palate were compared tothose of matched healthy controls. The results indicate that fetuses with oralclefts are at elevated risk of having low and very low birth weight, but not ofhaving a premature birth. Speculations on a relationship between these findingsand the presence of oral clefts arepresented.","note":"PMID: 12597694","journalAbbreviation":"JClin PediatrDent","author":[{"family":"Wyszynski","given":"DiegoF"},{"family":"Sarkozi","given":"Andrea"},{"family":"Vargha","given":"Peter"},{"family":"Czeizel","given":"AndrewE"}],"issued":{"year":2003}}},{"id":2008,"uris":["http://zotero.org/users/local/1XkiWLfQ/items/WAUWUA52"],"uri":["http://zotero.org/users/local/1XkiWLfQ/items/WAUWUA52"],"itemData":{"id":2008,"type":"article-journal","title":"Associatedmalformations in cases with oralclefts","container-title":"The Cleft Palate-CraniofacialJournal: Official Publication of the American Cleft Palate-CraniofacialAssociation","page":"41-47","volume":"37","issue":"1","abstract":"OBJECTIVE

Infantswith oral clefts (OCs) often have other associated congenital defects. Thereported incidence and the types of associated malformations vary betweendifferent studies. The purpose of this investigation was to assess theprevalence of associated malformations in a geographically definedpopulation.

METHOD

The prevalences at birth of associated malformationsin infants with OCs were collected between 1979 and 1996 on all infants born inthe area covered by the registry of congenital anomalies of Northeastern Francein 238,942 consecutive births.

RESULTS

Of the 460 cleft infants bornduring this period, 36.7% had associated malformations. Associatedmalformations were more frequent in infants who had cleft palate (46.7%) thanin infants with cleft lip and palate (36.8%) or infants with isolated cleft lip(13.6%). Malformations in the central nervous system and in the skeletal systemwere the most common other anomalies, followed by malformations in theurogenital and cardiovascular systems. Weight, length, and head circumferenceof children with OCs and multiple associated malformations were lower than incontrols, as was the weight of the placenta. Prenatal diagnosis was rarely doneby fetal ultrasonographic examination in isolated clefts. However, even inmultiple associated malformations, prenatal diagnosis by fetal ultrasonographicexamination had a low sensitivity, 31.6%.

CONCLUSION

The overallprevalence of malformations, which was one in more than three infants,emphasizes the need for a thorough investigation of infants with clefts. Aroutine screening for other malformations especially skeletal, central nervoussystem, and cardiac defects may need to be considered in infants with clefts,and genetic counseling seems warranted in most of these complicatedcases.","DOI":"10.1597/1545-1569(2000)037less than 0041:AMICWOgreater than 2.3.CO;2","note":"PMID:10670888","journalAbbreviation":"Cleft Palate Craniofac.J.","author":[{"family":"Stoll","given":"C"},{"family":"Alembik","given":"Y"},{"family":"Dott","given":"B"},{"family":"Roth","given":"MP"}],"issued":{"year":2000,"month":1}}},{"id":2089,"uris":["http://zotero.org/users/local/1XkiWLfQ/items/VXA3P79B"],"uri":["http://zotero.org/users/local/1XkiWLfQ/items/VXA3P79B"],"itemData":{"id":2089,"type":"article-journal","title":"Longitudinalstudy of growth of children with unilateral cleft-lip palate from birth to two yearsof age","container-title":"The Cleft Palate-CraniofacialJournal: Official Publication of the American Cleft Palate-CraniofacialAssociation","page":"603-609","volume":"46","issue":"6","abstract":"OBJECTIVE

Tostudy the growth of children with complete unilateral cleft lip and palate(UCLP) from birth to 2 years of age and to construct specific UCLP growthcurves.

DESIGN

Physical growth was a secondary outcome measure of aNational Institutes of Health-sponsored longitudinal, prospective clinicaltrial involving the University of Florida (United States) and the University ofS?o Paulo (Brazil).

PATIENTS

Six hundred twenty-seven children withUCLP, nonsyndromic, both genders.

METHODS

Length, weight, and headcircumference were prospectively measured for a group of children enrolled in aclinical trial. Median growth curves for the three parameters (length, weight,head circumference) were performed and compared with the median for theNational Center for Health Statistics (NCHS) curves. The median values forlength, weight, and head circumference at birth and 6, 12, 18, and 24 months ofage were plotted against NCHS median values and statistically compared at birthand 24 months.

SETTING

Hospital de Reabilita??o de AnomaliasCraniofaciais, Universidade de S?o Paulo, Bauru, Brazil(HRAC-USP).

RESULTS

At birth, children of both genders with UCLPpresented with smaller body dimensions in relation to NCHS median values, butthe results suggest a catch-up growth for length, weight, and headcircumference for girls and for weight (to some degree) and head circumferencefor boys.

CONCLUSIONS

Weight was the most compromised parameter forboth genders, followed by length and then head circumference. There was no evidenceof short stature. This study established growth curves for children withUCLP.","DOI":"10.1597/08-105.1","note":"PMID:19860503","journalAbbreviation":"Cleft Palate Craniofac.J.","author":[{"family":"Marques","given":"IlzaL"},{"family":"Nackashi","given":"JohnA"},{"family":"Borgo","given":"HiltonC"},{"family":"Martinelli","given":"AngelaP M C"},{"family":"Pegoraro-Krook","given":"MariaI"},{"family":"Williams","given":"WilliamN"},{"family":"Dutka","given":"JenifferC R"},{"family":"Seagle","given":"MichaelB"},{"family":"Souza","given":"TelmaV"},{"family":"Garla","given":"LuisA"},{"family":"Neto","given":"Jos? S M"},{"family":"Silva","given":"MarcosLN"},{"family":"Graciano","given":"MariaIG"},{"family":"Moorhead","given":"Jacquelyn"},{"family":"Piazentin-Penna","given":"S?lviaHA"},{"family":"Feniman","given":"MarizaR"},{"family":"Zimmermann","given":"MariaC"},{"family":"Bento-Gon?alves","given":"CristinaGA"},{"family":"Pimentel","given":"MariaCM"},{"family":"Boggs","given":"Steve"},{"family":"Jorge","given":"Jos?C"},{"family":"Antonelli","given":"PatrickJ"},{"family":"Shuster","given":"Jonathan"}],"issued":{"year":2009,"month":11}}},{"id":2097,"uris":["http://zotero.org/users/local/1XkiWLfQ/items/NDG4EQTB"],"uri":["http://zotero.org/users/local/1XkiWLfQ/items/NDG4EQTB"],"itemData":{"id":2097,"type":"article-journal","title":"Lineargrowth characteristics of children with cleft lip andpalate","container-title":"The Journal ofPediatrics","page":"707-711","volume":"131","issue":"5","abstract":"OBJECTIVE

Tostudy the linear growth characteristics of children with isolated cleft lip(CL), cleft palate (CP), or both (CLP) and to determine whether this populationis at risk for short stature.

STUDY DESIGN

Retrospective chart reviewidentified 324 patients with CL, CP, or CLP that displayed no additionalcongenital anomalies. Longitudinal height and growth rate analyses wereperformed on routine anthropometric measurements gathered from hospital andclinic records. One-sample t tests (p less than 0.05) of average height percentileswere performed at yearly intervals. Analysis of variance was performed onclefting subgroups.

RESULTS

From birth to 10 years of age, the averageheight of both male and female white patients is consistently near the 40thpercentile. At yearly intervals, 60% of male and 70% of female average heightsdemonstrate statistical difference from the population mean. For all patients,64% of male but only 36% of female growth rates, from 2.5 to 12 years of age, wereabove the population mean.

CONCLUSIONS

White children from birth to 10years of age with isolated CL, CP, or CLP demonstrated a mean height below thepopulation mean. These data suggest that children with isolated cleftingmanifest an intrinsic tendency toward short stature. In addition, male patientsdisplay above-average growth rates, whereas female patients displaybelow-average growth rates, from 2 to 18 years of age. The data imply thatfemale patients may be at increased risk of overall short stature, whereas malepatients may eventually obtain mean populationheight.","note":"PMID:9403650","journalAbbreviation":"J.Pediatr.","author":[{"family":"Cunningham","given":"ML"},{"family":"Jerome","given":"JT"}],"issued":{"year":1997,"month":11}}},{"id":2104,"uris":["http://zotero.org/users/local/1XkiWLfQ/items/JKPPZFQ3"],"uri":["http://zotero.org/users/local/1XkiWLfQ/items/JKPPZFQ3"],"itemData":{"id":2104,"type":"article-journal","title":"Failureto thrive in babies with cleft lip and palate","container-title":"BritishJournal of PlasticSurgery","page":"471-475","volume":"54","issue":"6","abstract":"Weestablished the frequency of failure to thrive (FTT) in children undergoingprimary cleft procedures by using growth charts and standard-deviation scores.Initially, 147 babies with cleft lip and/or palate undergoing 186 primarylip-and-palate repairs were studied between 1993 and 1996. Rates of FTT werecategorised according to cleft type. There was an increasing rate of FTT from32% for unilateral cleft lip and palate to 38% for bilateral cleft lip andpalate to 49% for cleft palate. There was a high incidence of FTT in palatalclefts, especially if these were associated with a syndrome or anomaly (P=0.001). The incidence of FTT with the Pierre Robin sequence was 100%. In viewof the high rates of FTT, two changes were instituted: a feeding-support nursewas appointed to supervise and monitor patients at risk and all patients withthe Pierre Robin sequence had supervised airway management. Thereafter, theincidence of FTT was prospectively studied in 68 babies undergoing 84 primaryprocedures between 1997 and 1999. There was a decrease in the incidence of FTTin comparison with the earlier cohort (9% for unilateral cleft lip and palate,20% for bilateral cleft lip and palate, 26% for cleft palate). There was asignificant decrease in the incidence of FTT in the group with the Pierre Robinsequence, from 100% to 40%. As a result of the provision of a feeding-supportnurse and airway management of patients with the Pierre Robin sequence, theincidence of FTT was reduced and the audit loopclosed.","DOI":"10.1054/bjps.2001.3618","note":"PMID:11513506","journalAbbreviation":"Br J Plast Surg","author":[{"family":"Pandya","given":"AN"},{"family":"Boorman","given":"JG"}],"issued":{"year":2001,"month":9}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"}1-5. The evidence though is not entirely clear ?ADDIN ZOTERO_ITEM CSL_CITATION{"citationID":"GTTgUF2u","properties":{"formattedCitation":"{\rtf\super 6, 7\nosupersub{}}","plainCitation":"6,7"},"citationItems":[{"id":2071,"uris":["http://zotero.org/users/local/1XkiWLfQ/items/5852FGUE"],"uri":["http://zotero.org/users/local/1XkiWLfQ/items/5852FGUE"],"itemData":{"id":2071,"type":"article-journal","title":"Evaluationof growth in patients with isolated cleft lip and/or cleftpalate","container-title":"Pediatrics","page":"e543-549","volume":"125","issue":"3","abstract":"OBJECTIVE

Thepurpose of the study was to evaluate the growth of patients with isolated cleftlip (CL), with or without cleft palate (CP), or CP during the first few yearsof life.

METHODS

A retrospective analysis of data from birth to 5 yearsfor 307 patients with isolated CL/CP or CP alone who were seen in a largecraniofacial center between 1980 and 2007 was performed. We analyzed growthpatterns and feeding interventions. Anthropometric values were plotted onto2000 Centers for Disease Control and Prevention charts. Longitudinal analyseswere performed to estimate age-related changes and to test whether feedinginterventions or early education influenced age-relatedchanges.

RESULTS

Including progressive weight, length, and headcircumference values, a total of 1944 data points were available. The mostfrequent diagnosis was unilateral CL with CP (165 [53.7%] of 307 cases). Nopatients experienced significant failure to thrive during the study period,although predicted weight and length percentiles for age had initial decreasesduring the first year of life, with nadirs at 5.2 and 15 months, respectively.These decreases were followed by recovery that started at approximately 12months for weight and at 20 months for length (P less than .0001). Patients who hadfeeding interventions had a significantly (P = .047) increased gain rate overtime for weight for length, compared with those who didnot.

CONCLUSIONS

In this population, there were weight and lengthdecreases during the first year of life, which were not clinically significantand were followed by statistically significant recovery. Recovery seemed to berelated to successful education and feeding interventions. Head circumferenceand weight for length started at lower percentiles but showed consistent gainovertime.","DOI":"10.1542/peds.2009-1656","note":"PMID:20142284","journalAbbreviation":"Pediatrics","author":[{"family":"Zarate","given":"YuriA"},{"family":"Martin","given":"LisaJ"},{"family":"Hopkin","given":"RobertJ"},{"family":"Bender","given":"PatriciaL"},{"family":"Zhang","given":"Xue"},{"family":"Saal","given":"HowardM"}],"issued":{"year":2010,"month":3}}},{"id":2131,"uris":["http://zotero.org/users/local/1XkiWLfQ/items/9ET5JDVA"],"uri":["http://zotero.org/users/local/1XkiWLfQ/items/9ET5JDVA"],"itemData":{"id":2131,"type":"article-journal","title":"Hospitalization,breast-milk feeding, and growth in infants with cleft palate and cleft lip andpalate born in Denmark","container-title":"The CleftPalate-Craniofacial Journal: Official Publication of the American CleftPalate-CraniofacialAssociation","page":"628-632","volume":"45","issue":"6","abstract":"OBJECTIVE

Toevaluate if the duration of postpartum hospitalization, duration of breast-milkfeeding, and growth during the first year of life in infants with cleft lip andpalate (CLP) and cleft palate (CP) are comparable to infants without facialclefts.

DESIGN

Prospective data collection using a registration chartdeveloped by the authors.

SETTING

Special health care of infants withCLP/CP born in Denmark.

PARTICIPANTS

All mature infants with CLP/CPborn in 2003 and 2004 were included. Of 165 infants, 115 participated in thestudy.

INTERVENTION

In Denmark, parents of children with CLP/CP receivecounseling. This counseling is managed by specially trained healthvisitors/nurses and is initiated at birth. The counseling seeks to supportparents' confidence in having an infant with CLP/CP and to initiate arelationship between the infant and the parents.

MAIN OUTCOMEMEASURES

Duration of postpartum hospitalization, duration of breast-milkfeeding, and weight and length at birth, 5 months of age, and 12 months ofage.

RESULTS

Hospitalization was 4 days and comparable to that ofinfants without CLP/CP. The infants with CLP/CP received breast milk but for ashorter period compared with infants without CLP/CP. Weights at birth, 5 monthsof age, and 12 months of age were identical with Danish growthreferences.

CONCLUSION

The authors find the results satisfactory andbelieve that the counseling provided by the health visitors/nurses plays a partin theresults.","DOI":"10.1597/07-007.1","note":"PMID:18956929","journalAbbreviation":"Cleft Palate Craniofac.J.","author":[{"family":"Smedegaard","given":"Lisa"},{"family":"Marxen","given":"Dorthe"},{"family":"Moes","given":"Jette"},{"family":"Glassou","given":"EvaN"},{"family":"Scientsan","given":"Cand"}],"issued":{"year":2008,"month":11}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"}6, 7. Some studies however suggested that the initial "lag period", especially around birth, is then followed by a later "catch-up" period ?ADDIN ZOTERO_ITEM CSL_CITATION{"citationID":"2e763iojj2","properties":{"formattedCitation":"{\rtf\super 3, 6\nosupersub{}}","plainCitation":"3,6"},"citationItems":[{"id":2089,"uris":["http://zotero.org/users/local/1XkiWLfQ/items/VXA3P79B"],"uri":["http://zotero.org/users/local/1XkiWLfQ/items/VXA3P79B"],"itemData":{"id":2089,"type":"article-journal","title":"Longitudinalstudy of growth of children with unilateral cleft-lip palate from birth to twoyears of age","container-title":"The CleftPalate-Craniofacial Journal: Official Publication of the American CleftPalate-CraniofacialAssociation","page":"603-609","volume":"46","issue":"6","abstract":"OBJECTIVE

Tostudy the growth of children with complete unilateral cleft lip and palate(UCLP) from birth to 2 years of age and to construct specific UCLP growthcurves.

DESIGN

Physical growth was a secondary outcome measure of aNational Institutes of Health-sponsored longitudinal, prospective clinicaltrial involving the University of Florida (United States) and the University ofS?o Paulo (Brazil).

PATIENTS

Six hundred twenty-seven children withUCLP, nonsyndromic, both genders.

METHODS

Length, weight, and headcircumference were prospectively measured for a group of children enrolled in aclinical trial. Median growth curves for the three parameters (length, weight,head circumference) were performed and compared with the median for theNational Center for Health Statistics (NCHS) curves. The median values forlength, weight, and head circumference at birth and 6, 12, 18, and 24 months ofage were plotted against NCHS median values and statistically compared at birthand 24 months.

SETTING

Hospital de Reabilita??o de AnomaliasCraniofaciais, Universidade de S?o Paulo, Bauru, Brazil(HRAC-USP).

RESULTS

At birth, children of both genders with UCLPpresented with smaller body dimensions in relation to NCHS median values, butthe results suggest a catch-up growth for length, weight, and headcircumference for girls and for weight (to some degree) and head circumferencefor boys.

CONCLUSIONS

Weight was the most compromised parameter forboth genders, followed by length and then head circumference. There was noevidence of short stature. This study established growth curves for childrenwith UCLP.","DOI":"10.1597/08-105.1","note":"PMID:19860503","journalAbbreviation":"Cleft Palate Craniofac.J.","author":[{"family":"Marques","given":"IlzaL"},{"family":"Nackashi","given":"JohnA"},{"family":"Borgo","given":"HiltonC"},{"family":"Martinelli","given":"AngelaP M C"},{"family":"Pegoraro-Krook","given":"MariaI"},{"family":"Williams","given":"WilliamN"},{"family":"Dutka","given":"JenifferC R"},{"family":"Seagle","given":"MichaelB"},{"family":"Souza","given":"TelmaV"},{"family":"Garla","given":"LuisA"},{"family":"Neto","given":"Jos? SM"},{"family":"Silva","given":"Marcos LN"},{"family":"Graciano","given":"MariaIG"},{"family":"Moorhead","given":"Jacquelyn"},{"family":"Piazentin-Penna","given":"S?lviaHA"},{"family":"Feniman","given":"MarizaR"},{"family":"Zimmermann","given":"MariaC"},{"family":"Bento-Gon?alves","given":"CristinaGA"},{"family":"Pimentel","given":"MariaCM"},{"family":"Boggs","given":"Steve"},{"family":"Jorge","given":"Jos?C"},{"family":"Antonelli","given":"PatrickJ"},{"family":"Shuster","given":"Jonathan"}],"issued":{"year":2009,"month":11}}},{"id":2071,"uris":["http://zotero.org/users/local/1XkiWLfQ/items/5852FGUE"],"uri":["http://zotero.org/users/local/1XkiWLfQ/items/5852FGUE"],"itemData":{"id":2071,"type":"article-journal","title":"Evaluationof growth in patients with isolated cleft lip and/or cleftpalate","container-title":"Pediatrics","page":"e543-549","volume":"125","issue":"3","abstract":"OBJECTIVE

Thepurpose of the study was to evaluate the growth of patients with isolated cleftlip (CL), with or without cleft palate (CP), or CP during the first few yearsof life.

METHODS

A retrospective analysis of data from birth to 5 yearsfor 307 patients with isolated CL/CP or CP alone who were seen in a largecraniofacial center between 1980 and 2007 was performed. We analyzed growthpatterns and feeding interventions. Anthropometric values were plotted onto2000 Centers for Disease Control and Prevention charts. Longitudinal analyseswere performed to estimate age-related changes and to test whether feeding interventionsor early education influenced age-related changes.

RESULTS

Includingprogressive weight, length, and head circumference values, a total of 1944 datapoints were available. The most frequent diagnosis was unilateral CL with CP(165 [53.7%] of 307 cases). No patients experienced significant failure tothrive during the study period, although predicted weight and lengthpercentiles for age had initial decreases during the first year of life, withnadirs at 5.2 and 15 months, respectively. These decreases were followed byrecovery that started at approximately 12 months for weight and at 20 monthsfor length (P less than .0001). Patients who had feeding interventions had asignificantly (P = .047) increased gain rate over time for weight for length,compared with those who did not.

CONCLUSIONS

In this population, therewere weight and length decreases during the first year of life, which were notclinically significant and were followed by statistically significant recovery.Recovery seemed to be related to successful education and feedinginterventions. Head circumference and weight for length started at lowerpercentiles but showed consistent gain overtime.","DOI":"10.1542/peds.2009-1656","note":"PMID:20142284","journalAbbreviation":"Pediatrics","author":[{"family":"Zarate","given":"YuriA"},{"family":"Martin","given":"LisaJ"},{"family":"Hopkin","given":"RobertJ"},{"family":"Bender","given":"PatriciaL"},{"family":"Zhang","given":"Xue"},{"family":"Saal","given":"HowardM"}],"issued":{"year":2010,"month":3}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"}3, 6 eliminating most of the growth differences compared with the norm at the latest by the age of 5 years ADDIN ZOTERO_ITEM CSL_CITATION{"citationID":"1m1i87p57t","properties":{"formattedCitation":"{\rtf\super6\nosupersub{}}","plainCitation":"6"},"citationItems":[{"id":2071,"uris":["http://zotero.org/users/local/1XkiWLfQ/items/5852FGUE"],"uri":["http://zotero.org/users/local/1XkiWLfQ/items/5852FGUE"],"itemData":{"id":2071,"type":"article-journal","title":"Evaluationof growth in patients with isolated cleft lip and/or cleftpalate","container-title":"Pediatrics","page":"e543-549","volume":"125","issue":"3","abstract":"OBJECTIVE

Thepurpose of the study was to evaluate the growth of patients with isolated cleftlip (CL), with or without cleft palate (CP), or CP during the first few yearsof life.

METHODS

A retrospective analysis of data from birth to 5 yearsfor 307 patients with isolated CL/CP or CP alone who were seen in a largecraniofacial center between 1980 and 2007 was performed. We analyzed growthpatterns and feeding interventions. Anthropometric values were plotted onto2000 Centers for Disease Control and Prevention charts. Longitudinal analyseswere performed to estimate age-related changes and to test whether feedinginterventions or early education influenced age-relatedchanges.

RESULTS

Including progressive weight, length, and headcircumference values, a total of 1944 data points were available. The mostfrequent diagnosis was unilateral CL with CP (165 [53.7%] of 307 cases). Nopatients experienced significant failure to thrive during the study period,although predicted weight and length percentiles for age had initial decreasesduring the first year of life, with nadirs at 5.2 and 15 months, respectively.These decreases were followed by recovery that started at approximately 12months for weight and at 20 months for length (P less than .0001). Patients who hadfeeding interventions had a significantly (P = .047) increased gain rate overtime for weight for length, compared with those who didnot.

CONCLUSIONS

In this population, there were weight and lengthdecreases during the first year of life, which were not clinically significantand were followed by statistically significant recovery. Recovery seemed to berelated to successful education and feeding interventions. Head circumferenceand weight for length started at lower percentiles but showed consistent gainovertime.","DOI":"10.1542/peds.2009-1656","note":"PMID:20142284","journalAbbreviation":"Pediatrics","author":[{"family":"Zarate","given":"YuriA"},{"family":"Martin","given":"LisaJ"},{"family":"Hopkin","given":"RobertJ"},{"family":"Bender","given":"PatriciaL"},{"family":"Zhang","given":"Xue"},{"family":"Saal","given":"HowardM"}],"issued":{"year":2010,"month":3}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"}6.

Aims: We aim to investigate whether there is still evidence for a growth delay within a sample of children with unilateral non-syndromic CL/P (Cleft Care UK) at the age of 5 years when compared with population based controls.

Methods: Using a univariate and or multivariate linear design, we will compare the risk effects of unilateral CL/P (case:control ratio 1:4) on differences in height, weight, BMI and head cirumference measured at the age of 5-7 years compared with age and sex-matched healthy children from the ALSPAC cohort, a sample which is representative of the general UK population.

Confounding issues: We are aware that secular trends in weight, length and head circumference might be associated with differences in birth years(ALSPAC: 1991/1992; Cleft Care UK: 2005/2007). However as our case sample was born ~15 years later than the control sample (ALSPAC), the hypothesis of a growth delay in CLP will, in the presence of a strong secular trend, either support the null hypothesis or show as an effect in the opposite direction (growth increase in CLP), and as such does not invalidate the proposed analyses. Furthermore, there is some evidence that secular trends with respect to adult height are largely stabilised during the last years8 in Northern Europe, and a similar trend might be expected for the UK. All analyses will be adjusted for socio-economic differences.

B1516 - Establishing the link between omega 3 fatty acids and postpartum depression using Mendelian Randomisation - 14/02/2013

AIM: To establish whether there exists a causal association between omega 3 polyunsaturated fatty acids (PUFAs) and depression

HYPOTHESIS: We hypothesise that maternal levels of omega 3 PUFAs could be a contributing factor in postnatal depression (PND)

VARIABLES: Genetic variants will be used as instrumental variables for the omega 3 PUFAs docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA). The outcome variable will be PND as measured by the Edinburgh Postnatal Depression Scale (EPDS) completed at 8 weeks postpartum.

Literature surrounding the association between PUFAs and depression reports conflicting results regarding efficacy. A number of observational studies reported in the psychiatric literature suggest that a deficiency of maternal DHA can lead to the development of major depressive disorder (MDD) during pregnancy and postpartum, whereas clinical benefits of supplementation with EPA are reported in more intervention studies (Mozurkewich et al., 2011). In an attempt to clarify the situation, meta-analyses of supplementation with omega 3 PUFAs have been performed which point to EPA, rather than DHA, being the key PUFA associated with depression (Martins et al., 2012; Freeman et al., 2006). However, these analyses may be limited due to issues including small sample sizes and heterogeneity between studies.

We plan to use Mendelian Randomisation (MR) to explore the association between maternal genotype and occurrence of postnatal depression. Genetic variants discovered through genome-wide association studies (GWAS) (Lemaitre et al., 2011; Tanaka et al., 2009) will be used as instrumental variables for the PUFAs. The use of MR should help to eliminate the issues with confounding and reverse causation to which conventional observational studies are subject.

Women completing the EPDS at 8 weeks postpartum will be classified as cases or controls depending on their score, with those scoring greater than 12 being designated as cases (Cox et al., 1987). This threshold will help to distinguish women who are likely to be suffering from a depressive illness of varying severity. Given the nutritional demands of breast feeding on the mother, we will investigate whether the effect of fatty acids differs according to the occurrence of breast-feeding. A secondary analysis will be carried out using EPDS scores at 8 months postpartum.

Participants will be excluded from the study if they experienced a stillbirth or early neo-natal death (within 27 days).

B1515 - Is complement factor H genotype associated with recognised AMD-related traits and serum inflammatory markers - 14/02/2013

Background

ALSPAC is a vital resource in the study of child development and has contributed to much influential work on the topic of child development and paediatric disease.

Age-related macular degeneration (AMD) is the most frequent cause of blindness in Europe and accounts for severe visual loss in around 25 million people worldwide.(1) It is characterised by reduction in visual acuity and contrast sensitivity with subsequent loss of central vision. There are two categories of AMD: wet (neovascular and exudative) and dry. Wet AMD accounts for 90% of blindness due to AMD (2) and if untreated results in an average loss of approximately 4 lines of visual acuity with 2 years of disease onset.(3) Timely identification and treatment of those with neovascular ARMD improves visual outcomes.(4) The economic burden of AMD in terms of direct and indirect costs is significant.(5)

A meta analysis by Chakravarthy et al in 2010 found that risk factors for AMD include major risk factors (with a strong, consistent association): increasing age, current cigarette smoking, previous cataract surgery and family history of AMD. Risk factors with a moderate and consistent association include history of cardiovascular disease, hypertension, raised plasma fibrinogen and high body mass index. Weak, inconsistent association was found between AMD and gender, ethnicity, diabetes, iris colour, history of cerebrovascular disease and serum total and HDL cholesterol and triglyceride levels.(4) The same study identified 73 potential risk factors for late age-related macular degeneration including nine genetic factors. Increased sun exposure and low dietary intake of zinc and vitamin E were also highlighted by Smith et al using data pooled from three continents.(6)

More recently the link between genetics, environment and AMD has become far better understood with the discovery of potential AMD susceptibility genes. One such gene is Complement Factor H (CFH), a variant of which is rs1061170 (T1277C, Y402H) which is characterised by substitution of histidine for tyrosine at codon 402 on the long arm of chromosome 1, region 31. This is a missense mutation, which results in altered binding of the CFH protein to sulphated polysaccharides and may contribute to the pathogenesis of AMD through complement dysregulation. In individuals of European descent the Y402H variant was found to confer a 2-fold higher risk of late AMD per copy.(7,8)In homozygous individuals, those with neovascular AMD may have a decreased treatment response, particularly to anti-VEGF agents, when compared to individuals who are homozygous for the T-allele.(9) Along with another common variant (rs1410996), Y402H is thought to explain around 17% of AMD liability.(10)

There is evidence that chronic low-grade inflammation is key in the pathogenesis of AMD.(11) Raised serum inflammatory markers have been identified as possible indicators of increased risk of developing AMD, including C-reactive protein (CRP), interleukins (IL)-2 and -6, tumour necrosis factor (TNF)-a, soluble intercellular adhesion molecule (sICAM)-1 and C3a-desArg as have raised levels of urinary pro-inflammatory cytokines, including transforming growth factor (TGF)-b1 (OR 1.24 CI 1.02-1.50; Pless than 0.031) and macrophage chemoattractant protein (MCP)-1 (OR 1.07 CI 1.02-1.12 pless than 0.008) in early AMD and MCP-1 (OR 1.10 CI 1.03-1.17 pless than 0.003) in geographic atrophy.(11,12) Linked to this is the finding of the Blue Mountains Eye study that there is reduced renal function in AMD demonstrated by decreased estimated glomerular filtration rate and creatinine clearance.(13) Urinary MCP-1 levels above median levels were 2.5 times more likely to be found in individuals who were heterozygous or homozygous for the C-allele (Y402H) (Pless than 0.040).

The study team are experienced in working with ALSPAC data and among them have a wealth of epidemiological, genetic and ophthalmological clinical experience. The existing ALSPAC data contains snps directly associated with the Complement factor H and we will therefore be able to address the research question with existing data. This is a proposal for a small pilot study of the potential association between complement factor H genotype and AMD-related traits, which will inform the direction of future work.

B1514 - Puberty and adolescence as sensitive period in the development of cardiovascular risk - 14/02/2013

Background & Aim:

Adolescence is characterised by pubertal development, changing body composition, decline in health-promoting behaviours and uptake of potentially harmful behaviours. Blood pressure (BP) increases in adolescence, and changes are observed in levels of circulating lipids, glucose and insulin. Adverse levels of BP and lipids in adolescence are associated with greater adult risk of cardiovascular diseases. Adolescence thus represents a potentially sensitive period in the development of cardiovascular risk. However, the causal mechanisms linking adolescence-related changes with cardiovascular risk are not well understood. We propose to study this in the Avon Longitudinal Study of Parents and Children. Specifically, we will assess whether pubertal development, genetic variants, adiposity and behavioural factors are associated with patterns of change in BP, lipids, glucose and insulin from 7-17 years; and explore how puberty and changes in BP, lipids, glucose and insulin are associated with cardiovascular structure and function measured at age 17.

Our key hypotheses (numbered) will each be addressed by relevant objectives (letters) as follows:

1. Age at puberty will influence the patterns of change in BP, circulating lipids, glucose and insulin across childhood and adolescence, with earlier age at puberty resulting in a more adverse cardiovascular profile

a. To assess the association between age at puberty (measured using age at peak height velocity, measures derived from height for mid-parental-height and age at menarche) with patterns of change in SBP and DBP from 7 to 17 years (measures at 7, 9, 11, 13, 15 and 17 years), and patterns of change in lipids, glucose and insulin from 9 to 17 years (measures at 9, 15 and 17 years), and gender differences in these associations

b. To test the causality of associations between age at puberty and SBP, DBP, lipids, glucose and insulin, using genetic variants related to puberty in a Mendelian Randomisation analysis

c. To assess the age at which associations between genetic variants related to puberty and trajectories of SBP, DBP, lipids, glucose and insulin become apparent, and how these associations change across childhood and adolescence.

2. Changes in adiposity will influence the patterns of change in BP, circulating lipids, glucose and insulin across childhood and adolescence

a. To assess the associations of changes in BMI (from age 7 to 17), DXA-assessed fat mass (age 9 to 17) and waist circumference (age 7 to 17) with changes in SBP, DBP, lipids, glucose and insulin across childhood and insulin (ages as in 1a above), and whether these differ between males and females

b. To assess the association of genetic variants related to BMI and waist circumference with changes in SBP, DBP, lipids, glucose and insulin across childhood and insulin

3. Modifiable behavioural risk factors will influence the patterns of change in BP, circulating lipids, glucose and insulin across childhood and adolescence

a. To investigate the associations of dietary intake (ages 7 to 13), physical activity (ages 11 to 15) and smoking (ages 9 to 17) (and changes in these across childhood and adolescence) with changes in BP, lipids, glucose and insulin (ages as in 1a above, but starting at age 11 for physical activity and age 9 for smoking)

4. Genetic variants robustly associated in adult populations with BP, lipids, glucose and insulin will exhibit stronger associations with these traits later in adolescence (after puberty) compared with in childhood and earlier adolescence

a. To assess the relationship between an allelic score of BP-related SNPs and changes in BP

b. To assess the relationship between an allelic score of lipid-related SNPs and changes in lipids

c. To assess the relationship between allelic scores for i) type II diabetes, ii) fasting glucose levels and iii) circulating insulin levels and changes in glucose and insulin

5. Age at onset of puberty will be associated with cardiovascular structure and function

a. To assess the association of age at pubertal onset with measures of cardiovascular structure and function (measures detailed in section 4) at age 17

b. To determine the associations of changes in BP, lipids, glucose and insulin across childhood and adolescence with measures of cardiovascular structure and function at age 17

c. To assess the extent to which changes in BP, lipids, glucose and insulin across childhood and adolescence mediate the relationship of age at pubertal onset with measures of cardiovascular structure and function at age 17.

Statistical analysis will mainly involve multilevel models (including multivariate multilevel models) as well as standard regression techniques.

B1513 - Do hypertensive disorders and anaemia in pregnancy increase the risk of respiratory and atopic diseases in childhood - 14/02/2013

Background:

We have previously found a negative association between umbilical cord iron concentration and early childhood eczema in ALSPAC[1], but associations between maternal anaemia and childhood atopic outcomes have not been reported. Other studies have reported that maternal hypertension in pregnancy is associated with impaired infant lung function[2] and, along with preeclampsia, with an increased risk of early childhood wheezing[3], but data are lacking on whether these conditions predict asthma and impaired lung function later in childhood. It would be interesting to know whether any effects of maternal hypertension/preeclampsia on these outcomes are mediated through lower birth weight and whether preeclampsia might explain any of the well-known birth order/parity association with atopy. Clearly, if anaemia and maternal hypertension/preeclampsia are causes of childhood asthma and atopy there may be important opportunities for primary prevention.

Aims:

To analyse the associations between maternal anaemia and hypertensive disorders of pregnancy and respiratory and atopic outcomes in the offspring.

Hypotheses:

* Anaemia is associated with increased risk of atopic disease

* Hypertension and preeclampsia are associated with increased risk of asthma and impaired lung function.

Variables needed for primary analyses:

Derived exposure variables of interest:

* Hypertensive disorder of pregnancy (gestational hypertension plus preeclampsia)

* Preeclampsia

* Gestational hypertension

* Pre-existing hypertension

* Early pregnancy Hb

Confounders and outcomes: We have all potential confounder variables with the exception of gestational weight gain. Outcomes will include asthma, hayfever, eczema, atopy and total IgE at 7 years, and lung function at 8-9 years (we have these variables too).

If we confirm associations with hypertension it might be of interest to carry out secondary analyses to explore associations with changes in blood pressure at different stages of gestation using the appropriate derived variables.

B1512 - Is the effect of maternal smoking on childhood lung function mediated by nicotine A Mendelian Randomisation approach - 14/02/2013

Aims:

To investigate the association between child (fetal) CYP2A6 genotype and lung function and interactions with reported maternal smoking.

B1511 - APOE and working memory at 17 - 14/02/2013

APOE is a gene found on chromosome 19 in humans, which encodes a protein (ApoE) which is involved in lipid transport. ApoE is the main lipid transport protein in the brain.There are 3 known variants of APOE: epsilon2, epsilon3 and epsilon4. epsilon4 is thought to be the ancestral allele of APOE(Mahley et al 2000), but in the UK population the expected frequencies of epsilon3, epsilon4 and epsilon2 are 0.78, 0.14 and 0.08 respectively.(Abdollahi et al 2006) These variants are the single of single nucleotide polymorphisms at two locations: T2060C(Cys112Arg) and C2198T (Arg158Cys).(Ensembl) The epsilon3 allele has cysteine and arginine in these two positions, the epsilon2 allele has cysteine in both and the epsilon4 allele has arginine in both.(Weisgraber et al 1981)

Possession of an e4 allele has been robustly shown to increase the risk of late onset Alzheimer's disease (Corder et al 1993). It is now known that ApoE is involved in neuronal repair, with E4 being the least efficient isoform (White et al 2001) and that APOE genotype influences outcome following head injury (Teasdale et al 1997).

Positive pleiotropy of the e4 allele has been investigated over the last 10 years with mixed results (e.g. Hubacek et al 2001, Bunce et al 2011). There is no effect of e4 on IQ (Taylor et al 2011), but several fMRI studies have been reported as showing more efficient memory activation in young adult e4 carriers (e.g. Scarmeas et al 2005). Working memory and e4 has been little studied, but there are suggestions from small imaging studies that e4 may be beneficial for working memory in young adults (Rusted et al 2013). Conversely studies of middle aged and older adults have found a deleterious effect of e4 on working memory (Reinvang et al 2010, Greenwood et al 2005)) A study of 445 people of mixed ages found no effect (Alexander et al 2007)

Defects in working memory have been reported as one of the earliest deficits seen in Alzheimer's disease (McKhann et al 1984). I therefore aim to study the relationship between APOE genotype and working memory in a large community sample of young adults.

Hypotheses

1) Null hypothesis: APOE genotype does not influence working memory performance

2) APOE genotype influences working memory performance, either positively or negatively.

Exposure Variable

APOE genotype

Outcome Variables

Working memory performance, specifically performance on the n-back test aged 18 with accuracy across the 2 and 3 back levels being the primary outcome.

Confounding Variables

In genetic studies it is often difficult to identify confounders as they have to have an independent relationship with both the genotype and the outcome of interest. Head injury outcome is known to be associated with APOE genotype and such injuries can have a wide range of adverse neuropsychological effects. APOE genotype is known to influence LDL levels. I would like to use this as a proxy means of checking genotyping accuracy as is routinely done in this field. Higher LDL levels have also been linked to increased cognitive problems in later life. I would like to investigate a number of other variables likely to modify working memory performance to see if they have any effect on my results.

B1510 - Children of parents with depression DANVA as a predictor of child psychopathology - 14/02/2013

Depression is one of the most commonly occuring mental illnesses, with a lifetime prevalence of 9.4%

(Kessler, 2012). The World Health Organization has ranked depression among the top 4 leading causes of

disability worldwide (WHO, 2008). Rates of depression also appear to be universally higher for women

than men, with women being roughly at 2 times greater risk of developing depression than males

(Kessler, 2003; Weissman & Klerman, 1977). This sex difference has been attributed to differences in

seeking out rewarding behaviours (Ryba & Hopko, 2012), response toward emotionally salient stimuli

(Bradley, Codispoti, Sabatinelli, & Lang, 2001) and differences in underlying neurocircuitry including the

inferior frontal gyrus and left amygdala (Stevens & Hamann, 2012). Children of parents diagnosed with

major depressive disorder (MDD) are also 2-3 times more likely to develop depression (Johnstone,

Lawrie, & Cosway, 2002; Lieb, Isensee, Hofler, & Wittchen, 2002; Weissman et al., 2006) and 2-3 times

more likely to develop other anxiety or behavioural disorders (Lieb et al., 2002; Mars et al., 2012;

Weissman et al., 2006). This risk suggests the influence of either familial genetic loading or

environmental factors. The most commonly reported risk allele is a low-expressing variant of the

serotonin transporter gene (5HTTLPR) (for more information please see appendix 1b).

Maternal behaviours towards their own children can also be affected by depression. Mothers become less

emotionally responsive to their infants as a result of depression and this has noticable effects on the longterm

behavioural and social outcome of the offspring. In infancy, these children are more likely to show

avoidance or disorganized attachment behaviours (to strange situation tasks) (Madigan, Moran, &

Schuengel, 2007; Martins & Gaffan, 2000) and higher rates of internalizing/ externalizing behavioural

problems (Garai et al., 2009) than children of non-depressed mothers. Children of depressed mothers have

poorer scores on the Child Behavioural Checklist (CBCL) when children were exposed to maternal

depression during their first year of life (Bagner, Pettit, Lewinsohn, & Seeley, 2010). They also show

lower scores on the Peabody picture vocabulary test; a measure of verbal fluency (Brennan et al., 2000),

lower scores on the Rey Auditory Verbal Learning task; a measure of declarative recall memory (Mannie,

Barnes, Bristow, Harmer, & Cowen, 2009), but, executive functioning does not seem to be affected by

parental depression (Micco et al., 2009). However, emotional labeling deficits remain the most commonly

reported deficit among offspring of depressed parents, suggesting difficulties in the emotional processing

network is part of the core psychopathology among at-risk children.

The purpose of this study is to determine the extent to which childhood emotional face labeling ability

mediates risk for depression (by having one or more parent with depression) and the psychiatric outcome

in adolescence. We predict that errors in emotional labeling (measured at 8 years of age) in childhood will

be significantly associated with (1) exposure to maternal depression in childhood, and (2) depression or

other psychiatric effects in adolescence. We predict this emotional face labeling ability will account for

part of the measured association between maternal depression severity and youth depression in

adolescence. Furthermore, we predict that the child's genetic risk for depression (identified by the lowexpressing

serotonin allele status) will be a moderator between maternal depression exposure and their

emotional face labeling ability. We predict that short allele status in the children will increase the effect of

exposure to maternal depression and this effect with be seen as greater difficulty on the

B1509 - GWAS meta-analysis on sleep duration - 14/02/2013

Aims: Humans sleep a third of their life and adequate sleep duration is an important factor in preventing metabolic and psychiatric disorders.

Two GWAS studies in adults have suggested that genetic factors may influence the sleepiness and circadian rhythms. Allembrandt et al. (2011) conducted high-density genome-wide association studies for sleep duration in seven European populations and identified an intronic variant (rs11046205; P=3.99 * 10(-8)) in the ABCC9 gene that explains Approximately 5% of the variation in sleep duration. RNA interference knockdown experiments of the conserved ABCC9 homologue in Drosophila neurons renders flies to sleep less during the first 3 h of the night. ABCC9 encodes an ATP-sensitive potassium channel subunit (SUR2), serving as a sensor of intracellular energy metabolism. Similarity the linkage analysis of sleep by Gottlieb et al. (2007) revealed a linkage peak close to the gene PROK2. Its product is the precursor of prokineticin 2, which is highly expressed in the suprachiasmatic nucleus, regulated by the circadian molecular clock, and believed to be an important output molecule from the suprachiasmatic nucleus, coordinating and transmitting the behavioural circadian rhythm to multiple brain regions (Cheng et al. (2002); Li et al. (2006).

Little is known about the genetic underpinnings sleepiness at distinct childhood growth phases. Through a large-scale meta-analysis of GWAS data for sleep duration, our main aim is to identify genetic mechanisms that underlie sleep duration during childhood.

Hypotheses: We hypothesize that a meta-analysis of GWAS data can identify genetic factors associated with sleep duration.

Outcome variable: Sleep duration during day (night + naps)

Exposure variables: Genetic variants as identified by GWAS genotyping and imputing (1000 Genome Project, release March 2012)

Confounding variables: sex, age, BMI

B1508 - Investigation on the mediating role of methylation in lipid pathways - 15/02/2013

Aims

To identify methylation variation mediating lipid pathways.

B1507 - Integrative systems analysis of omics data for outcome prediction and identification of molecular pathways - 15/02/2013

Aims

1. Development and application of Multiple Kernel Learning (MKL) approaches to the prediction of common outcomes using high density omics data

2. Identification of molecular "modules" and pathways by integrative analysis of high density omics data.

B1506 - Alcohol consumption and cardiovascular health in adolescents - 14/02/2013

Title:

Alcohol consumption and cardiovascular health in adolescents

The question whether alcohol is protective or a risk factor for cardiovascular disease in adolescents and, if so, where the threshold might be, remains largely unanswered. There are interesting similar behavioural patterns regarding excessive alcohol consumption and overindulgence in eating that leads to obesity, the mechanisms of which are relatively unknown. Marc Schuckit and co-workers have shown that the drinking pattern and level of response to alcohol have values in predicting future heavy drinking and alcohol problems in earlier studies of the ALSPAC cohort (Schuckit & Smith, 2008) as well as other populations (Schuckit & Smith, 2011). Both excessive alcohol consumption and obesity are well- known risk factors for developing cardiovascular disease (Juonala et al., 2009), (Romelsjo, Allebeck, Andreasson, & Leifman, 2012), but the mechanisms and interactions are not easy to investigate in an adult population where the damage is already well established.

Regarding the possibility of a common genetic origin of disease for obesity and alcoholism, there have been few studies with different results. Closely connected to obesity, the FTO rs9939609 genotype has been investigated for association with measures of alcohol consumption, but with inconsistent results (Sobczyk-Kopciol et al., 2011). There are to our knowledge no studies in children, when the epigenetic influence might be less muddled, and therefore present a truer picture of these associations.

Similarly, we know of no previous prospective studies of alcohol consumption and its influence on cardiovascular health, or the connection to obesity, in adolescents of both genders.

Aim:

The ALSPAC - study has investigated cardiovascular risk factors, adiposity, alcohol consumption, a low sensitivity to alcohol (a risk factor for heavy drinking), drinking patterns and drug in children at the ages 9-12 and 17-20.

In the present study our aim is to study cross-sectionally and longitudinally whether alcohol consumption is associated with cardiovascular changes in young healthy adults.

Hypotheses:

We hypothesise that:

1. Alcohol consumption affects cardiovascular risk factors and vascular phenotype:

- cross- sectionally at age 17-20

- with detectable thresholds of alcohol consumption for increased cardiovascular risk or deleterious vascular phenotypes

- with detectable gender differences

We also hypothesise that an earlier onset of alcohol consumption (ages 9-17) relate to the cardiovascular measurements more closely than alcohol quantities and frequencies alone

2. There is an additive effect of alcohol and obesity on cardiovascular risk and vascular phenotype, in the sense that alcohol consumption have an additive relationship to the cardiovascular risk development or adverse vascular phenotype in obese children.

3. That alcohol consumption and obesity are related as measures of common behavioural origins, and that obesity is associated with the sensitivity (i.e., the level of response) to alcohol or alcohol consumption:

- at age 12 or 17 (cross- sectional)

- obesity at age 12 predicts the level of response to alcohol at age 17

- obesity at age 12 predicts the alcohol consumption at age 17

- alcohol consumption at age 12 predicts the development of obesity at age 17

4. That the genetic predisposition to obesity is augmented by alcohol consumption in young.

Exposure variables will be: alcohol intake, level of response to alcohol, duration of alcohol intake, obesity genes.

Outcome variables will be : Cardiovascular measurements: PWV, FMD, brachial distensibility, blood flow, IMT, carotid distensibility, blood pressure and heart rate. Biochemical measurements: IL-6, CRP, Adiponectin, Leptin, Cholesterol, Non-fasting triglyceride. Obesity outcome: BMI, Fat mass.

Confunding variables are: age, gender, heart rate, height, weight, smoking, exercise, medical history, drugs intake.

B1505 - Study of Learning Ability Development and Genes - 28/02/2013

Project outline:

Study of Learning Ability, Development and Genes

Background

Intellectual disability (ID) in childhood is common with a prevalence rate of around 2.6% (Emerson, 2003). Children with ID have substantially higher rates of persistent comorbid psychiatric disorders (ADHD, ASD, Conduct Disorders, Anxiety Disorders), around 4-7 times higher than the general population (e.g., Einfeld et al., 2006; Emerson, 2003; Emerson & Hatton, 2007; Emerson & Einfeld, 2010). The most strongly associated childhood diagnoses are ADHD (odds ratio=10 compared with non-ID controls) and autistic spectrum disorder (ASD; odds ratio=75; Emerson, 2003). Comorbid psychopathology in children with ID is important because it increases parent stress more than the severity of ID, raises the cost of care and has a long term impact on adult outcomes (Herring et al., 2006).

The majority of children with mild-moderate ID have no clearly identifiable cause for their ID (Einfeld et al., 2006). Although multiple common gene variants, comorbid neurological illness and psychosocial disadvantage contribute to the aetiology, there is growing evidence that the rate of subtle chromosomal anomalies (deletions and duplications), known as copy number variants (CNVs), is elevated in those with previously unexplained ID (Girirajan, et al., 2010; Ropers, 2008; Sagoo et al., 2009). As a result of this work, some UK clinical genetics services are offering array CGH diagnostic services and a recent consensus statement recommends using chromosomal microarrays in the first tier of investigating developmental delay (Miller et al., 2010).

In a recently completed study of ADHD (Williams et al., 2010) we found a significantly elevated rate of CNVs in those with ID + ADHD (36%) than amongst controls (7%) or those with ADHD alone (11%). This is actually a higher CNV rate than previously reported for idiopathic ID (around 10%-12% for significant CNVs) and leads us to postulate that in individuals with idiopathic ID, the presence of large, rare CNVs in ID is clinically important because it might increase the risk of comorbid neuropsychiatric disorder. We now propose to explicitly examine whether the presence of large, rare CNVs in children with idiopathic ID is associated with a broad range of psychopathology (not ADHD only).

Aims

* To investigate in children with mild/moderate Intellectual Disability (IQ test score less than 70) whether subtle chromosomal anomalies (CNVs) are associated with;

- The presence of psychopathlogy

- Higher levels of ADHD and autism scores

- Higher levels of aggression

- Lower levels of adaptive functioning

As such the primary outcome measures is the child's psychopathology and the main predictor is the presence of a Copy Number Variant (CNV).

Hypotheses

Children with Intellectual Disability and CNVs will have higher rates of psychopathology and lower levels of functioning

.

B1504 - Exploring genetic association between schizophrenia and dimension-specific psychotic experiences in adolescence - 14/02/2013

The current project is an initial step aimed at uncovering genetic aetiology of psychotic experiences in a population based study of adolescents. The aims of the current study are three-fold. First, to examine potential associations between previously identified and reviewed Schizophrenia associating single nucleotide polymorphisms (SNPs) and dimension-specific psychotic experiences in a community based sample, using Twin Early Development Study (TEDS;Oliver & Plomin, 2006) data. Psychotic experiences are measured in TEDS using a quantitative dimension-specific Psychotic Experiences Questionnaire. Second, to create a gene score made up of previously identified risk alleles and to test for associations with psychotic experiences. Third, to replicate significant associations found in stage one of the analyses using Avon Longitudinal Study of Parents and Children (ALSPAC) sample.

It is hypothesised that some of the previously identified Schizophrenia associating SNPs will be also associating with the dimension-specific psychotic experiences. It is further expected that there will be an association between the polygenic scores and psychotic experiences. Finally, it is hypothesised that any statistically significant findings made using TEDS sample will be then replicated using ALSPAC.

The study will employ allelic and genotypic association analysis between SNPs of interest and psychotic-like symptoms as well as polygenic risk analysis. Sex, age and SES will be treated as potential covariates.

B1503 - Mapping and assessing TP53-associated linkage disequilibrium blocks in cancer reproductive traits and viral infections - 31/01/2013

The general focus of the work to be carried out is to understand the importance of the TP53 gene and its product (p53 protein) to several aspects of human health and disease (comprehensively available in the ALSPAC cohort database), including cancer, reproductive traits (such as pregnancy loss and success of assited reproduction) and viral infections. The p53 protein is essentially a transcription factor that is well-understood to play crucial roles in cancer. This protein mediates the response to DNA damage signals by activating cellular pathways that result in senescence or apoptosis. Mutations in the coding region of TP53 have been found in approximately 50% of all human cancers (although this can vary considerably depending on the cancer type), thus being a hallmark of tumourigenesis. More recently, p53 has been evidenced to participate of other biological contexts, including skin colour, embryo implantation to the uterus, metabolic disorders, ageing and viral infections.

Germline genomic variations (mainly Single Nucleotide polymorphism - SNPs) in TP53 have thus been extensively studied as an attempt to identify genetic markers of cancer predisposition, which would represent a contribution to the clinical field. SNPs are, in general, low-penetrance genetic variations that depend on complex interactions with other genetic profiles and environmental factors to be associated with a certain phenotype or disease. Considering that SNPs that change protein primary amino acid sequence (non-synonymous SNPs - nsSNPs) tend to have more prominent effects on protein function than synonymous or non-coding SNPs (although the relevance of these two last have been evidenced in the context of mRNA expression, splicing or translation), the majority of the currently available association studies has given attention to TP53 nsSNPs. Although there is a considerable amount of nsSNPs reported for TP53, the current work focus is on four of them, which may be considered the best validated: P47S, R72P, V217M and G360A. The two first nsSNPs have been substantially evidenced to functionally impact p53 function (p53 transactivation activity and apoptosis efficiency, respectively) and have been associated with cancer risk, while the remaining two currently lack such association findings. Interestingly, both these nsSNPs have functional experiments suggesting they might be important in cancer (V217M is located in the DNA binding domain of p53 and G360A has been evidenced to impact the transactivation of some p53-interacting proteins).

The notion that the association between a SNP and a phenotype is complex and the experimental evidences for assuming V217M and G360 SNPs might have significant impacts on p53 function, the current project proposes the investigation of TP53 haplotypes (set of SNPs on a single chromosome that are statistically associated) regarding the four nsSNPs described, as well as linkage disequilibrium (LD) blocks (which are composed of genetic loci that do not - in a statistical sense - do not segregate randomly) with SNPs in other genes. For instance, the association of TP53 R72P SNP and response to UV exposure (and, consequently, associations with tanning and skin cancer) are dependent on SNPs in the MC1R gene (a typical epistatic effect).

Studies of this nature are particularly suitable for large population cohorts such as ALSPAC, since the tendency of reducing the number of individuals per genetic subgroup when analyzing haplotypes would not result in insufficient statistical power. Moreover, there are comprehensive data available regarding ALSPAC mothers health, which is invaluable for the present study. Since TP53 R72P SNP is well-established to be associated with skin color, ALSPAC data is also of interest because it has little ethnic admixture, reducing bias. In this topic, the large and high-quality characterization of the sample (including massive data at the genetic level) allows the construction and assessment of LD blocks with high accuracy, converging information of different pathways at the genetic level.

The aims of the project can be divided in: 1) Identify haplotype and LD blocks involving the nsSNPs of interest. 2) Investigate possible associations of these blocks with different disease traits available for ALSPAC cohort. 3) Investigate possible interactions of TP53 nsSNPs with SNPs in LD with them regarding the associations of the latter with traits currently not described as affected by TP53. 4) Understand how TP53-associated SNPs interact with each other in order to provide substantial insights related to the genetics of complex traits. ((5) With a possibel amendment, extend analyses to other variants collected in ALSPAC (from GWAS/sequence data) across the TP53 locus).

B1502 - Variations in wound healing loci and their association with injury and scar related outcomes in the ALSPAC cohort - 31/01/2013

Where adult tissue is damaged, a complex repair process is taking place involving regeneration and acute phase immunological response. Unlike embryonic tissues, adult repair always leads to the formation of a fibrotic scar where the wound has healed, which ultimately can disable proper tissue function [1]. In recent years, research was able to link several genes to the event of scar formation . Knockdown of Ostepontin (OPN) in mice for example resulted in reduced granulation tissue formation and scarring [2]. It also has been indicated that TGF-beta1 in conjunction with Connective tissue growth factor (CTGF) is promoting scar formation [3]. Most of this data comes from mouse model studies, in humans however, less is known.

Using ALSPAC data we want to perform both a candidate driven analysis and a non-hypothesis driven GWAS (the latter being determined by the sample sizes generated from available phenotypic data) comparing individuals involved in an accident developing a scar compared to individuals involved in an accident who did not develop a scar. Where possible, we will attempt to assess differing types of scar

tissue and healing related phenotype, however this will again be contingent upon available phenotypic data).

Analysis plan:

(i) assess the depth of data pertinent to scarring phenotypes and establish cases

control series according to differential scarring patterns.

(ii) perform bioinformatic work up of select genes (LIST) to establish likely

functional variants across the coding region and surrounding region.

(iii) unite both genetic and phenotypic data to undertake tests of association

between genetic variation and phenotypic characterisation.

B1501 - NUTRIMENTAL call under FP7-KBBE-2013-7 - 31/01/2013

The aim is to examine the role of life styles, social background and socioeconomic factors on the mood-nutrition reciprocal relationships using samples from countries with different diets and different levels of mental health problems. For example, Mediterranean, Scandinavian and UK or US samples have been investigated in isolation but no study has carried out a comparison of social and dietary influences on mental health in different countries. Other factors which can be examined are changes in diet-mental health relationships across different age groups, gender and socio-economic status.

The research methodology will be largely based on secondary analyses of existing databases. In some cases the diet-mental health relationships have already been examined and the novel part will be the inclusion of social influences into the analyses. However, there are also extensive new samples which can provide new information on these topics. For example, in the UK the Biobank initiative has led to the collection of relevant data from 350,000 individuals. This database is potentially available (for a small fee) to the present project.

B1500 - External validation of an algorithm to estimate overweight risk in childhood from predictors during infancy - 31/01/2013

Background:

In the United Kingdom in 2010, around three in ten boys and girls (aged 2 to 15) were classed as either overweight or obese. However, overweight and obesity rates are not currently available for the under 2s despite evidence that some infants are larger than desired. Estimates vary but it is thought that between 25% to 33% of infants gain weight rapidly during the first six months of life. Rapid weight gain during infancy is associated with obesity between 6- 8 years of age and later life. There is evidence that weight at 5 years of age is a good indicator of the future health of a child and that obesity during childhood increases the risk of adult obesity. This has a clearly measurable impact on physical and mental health, quality of life, and generates considerable direct and indirect costs. Thus, there is a compelling rationale for identifying those infants at greatest risk.

Previous work:

We have developed a risk score algorithm for overweight in childhood based on a predictor model in infants using the Millenium Cohort Study, a large British birth cohort. Stepwise logistic regression was used to determine a predictor model for childhood overweight at 3 years defined by the IOTF. A risk algorithm was developed by assigning integer values to beta-coefficients based on relative strength. Discrimination was analysed using the receiver operating characteristic (ROC) curve.The strongest predictors of overweight risk at 3 years were rapid weight gain during the first year of life, infant birth weight greater than 3.81 kg, maternal pre-pregnancy BMI from 25 kg/m^2 to 30 kg/m^2 and maternal pre-pregnancy BMI >= 30 kg/m^2. The total risk score ranged from a minimum of 0 to a maximum of 33 corresponding to a predicted risk of overweight from 5.1% to 68.8%. The c-statistic from the ROC was 0.70. While the risk algorithm has been proven to have good internal validity, we have yet to test/validate the algorithm on an external cohort.

Aim of current study:

Therefore, the aim of the current study is to determine the validity of the risk algorithm developed from the MCS using the ALSPAC data set.

Methods:

We have a developed risk equations from the MCS that we will apply to the infants in the ALSPAC cohort. We will compare the predictive risk of overweight at 3 years to the observed risk of overweight at 3 years. Discrimination will be assessed using ROC c-statistics (AUC). This will allow us to calibrate the existing risk equations if neccessary.

Key exposure variables:

Child's gender, household income, infant birth birth, infant weight gain the first year of life, maternal pre-pregnancy BMI, maternal smoking in pregnancy, infant breastfeeding status in the first year, formal childcare arrangements in the first year

Outcome variables: Child's weight at 3 years, Child's height at 3 years, Child exact age at follow-up

Final outcome:

Using those three variables, the primary clinical outcome for childhood overweight at 3 years was defined by the International Obesity Task Force sex and age-specific cut-offs corresponding to an adult BMI >= 25 kg/m^2 (Girls: 18.02 kg/m^2; Boys: 18.41 kg/m^2).

Other confounding variables for the investigation and calibration of the risk equations (We have conducted a systematic review which has informed variable selection):

Child's ethnicity, maternal marital status, maternal education, maternal employment, delivery type, maternal age, maternal alcohol consumption, maternal depression, diabetes, breastfeeding duration, formula feeding, age at introduction of solid food, infant temperment, feeding/eating, sleep, activity, SES

B1499 - Efficient estimation of causal treatment effects using genotypic data - 31/01/2013

Aims: We will investigate the optimal methods for combining multiple genetic variants to estimate the causal effects of risk factors on outcomes. This is a methodological investigation, however as an example, we will investigate the associations of height and weight and IQ, behavioural problems (hyperactivity, emotional problems, conduct problems and peer problems) and academic achievement across childhood and adolescence.

Mendelian randomization uses genetic variants as instrumental variables for modifiable risk factors.5 It has been widely applied to investigate the effects of risk factors for disease such as weight, blood pressure, cholesterol, and behavioural risk factors such as alcohol and tobacco consumption on health and socio-economic outcomes.1-4 To be valid instruments, variants must be associated with risk factors of interest, and have no direct effect on the outcome of interest. The stronger the association between the instrument and the exposure, the more statistical power and precision a Mendelian randomization analysis can achieve. One challenge in using genetic instrumental variables is that many variants only have modest effects on the risk factor of interest.6 The use of multiple variants as instruments, thereby explaining more of the variability in the risk factor,7 could therefore increase the precision of the results, improving the likelihood of being able to draw inferences from any given dataset.

Researchers have used various approaches to construct instruments, including allele scores, weighted allele scores, using each genetic variant as an independent instrument, and using generalized method of moment estimators to efficiently weight each of the variants. However, we currently do know the optimal approach for aggregating this information for Mendelian randomization analysis. Thus in this project we will investigate the optimal methods for combining multiple variants to maximise statistical power.

We will examine the effects of anthropometry on cognitive and behavioural outcomes as a motivating example. However our major objective is to develop methodologies rather than investigating any single hypotheses.

Hypotheses: What is the most efficient method for combining multiple variants into a Mendelian randomization analysis?

Exposures: Height, weight and adiposity at age 8-13, genome-wide data.

Outcomes: Academic achievement, IQ score aged 8, measures at age 13 of hyperactivity, emotional problems, conduct problems, and peer problems (from SDQ).

Potential confounding variables or descriptive data: Age, birth weight, number of younger and older siblings, income, parents' education, social class and employment status. Index of multiple deprivation of families' neighbourhood. Mothers' characteristics during pregnancy: age, locus of control, EPDS, CCEI, and teaching score.

B1498 - MSc project Validation of essential fatty acid intakes using FFQ at age 7 with plasma fatty acid measures - 31/01/2013

MSc Project for Nutritions student in School for Policy studies

We have been unable to calculate the intake of essential fatty acids from the FFQ to date due to lack of funding - this is an oportunity to obtain this useful data and partially validate it against blood fatty acid levels at age 7 years.

The student would be provided with a copy of the macro used to calculate the intake of total polyunsaturated fatty acids (PUFA) from the food frequency questionnaire completed by parents for their child age x months (7y FFQ). We would also provide a list of the foods and portion sizes used to calculate total PUFA. The student would search for data on the content of selected fatty acids, particularly Arachadonic acid and Alpha-linoleic acid (the precursors of the omega-6 and omega-3 series respectively) of the foods used. They would record the sources of all data on a spread sheet and complete the macro to enable calculation of each of these new fatty acids.

The calculation of the intake of the fatty acids from ALSPAC participants data would be carried out by Pauline Emmett so that the student would not need access to the ALSPAC dataset. Unlinked summary results would be used by the student to assess possible outliers and for their MSc write-up. The fatty acid intakes thus claculated would be correlated (by Pauline Emmett) with blood measures of these fatty acids to assess the effectiveness of the FFQ to assess these nutrients. Summary unlinked results would be returned to the student. The calculated fatty acid intake for ALSPAC 7 year olds would become available to other users at the end of this project.

B1497 - Facial dysmorphism and maternal alcohol consumption in the ALSPAC cohort - 31/01/2013

Background

Development of the face is dependent on complex interactions of genetic and environmental factors, and is also affected by maternally derived exposures. Alcohol consumption in pregnancy is an important health issue and the DOH currently advise that pregnant women or women trying to conceive should avoid drinking alcohol1.Prenatal alcohol exposure causes a continuum of effectsand is thought to be a leading cause of learning disability in the western world with between 0.2 and 2.0 cases per 1,000 live births. Some of the highest incidence levels have been identified in Eastern Europe, in indigeneous North American communities, and in the South African Cape-Coloured population.The most severe phenotype, fetal alcohol syndrome (FAS), affects face shape, growth and neurobehavior. Fetal alcohol spectrum disorders (FASD) include FAS and other pathologies arising from prenatal alcohol exposure.

The characteristic facial features believed to be due to alcohol ingestion between 10 and 20 wks of gestation include smooth philtrum, thin upper lip vermilion, long upper lip, shortened palpebral aperture width, flattened mid-face and small head circumference. The timing of maternal alcohol consumption is considered to affect the severity of facial dysmorphology and through PH's involvement in the CIFASD consortium (www.CIFASD.com), we recently reported on the link between neurofacial effects and timing of ethanol exposure in a mouse model2. In another CIFASD study, of South African children3, we used face shape to induce classification schemes and tested agreement with clinical FASD categorization: FAS, partial FAS, and HE (heavily alcohol exposed without clinically detectable facial features). The more heterogeneous phenotype of HE forced us to introduce a novel clustering technique, signature graph analysis4, which normalizes face shape and links individuals with similar facial dysmorphism. Signature graph analysis identified half of the HE group as having facial dysmorphism more FAS-like than control-like. These HE individuals performed less well on psychometric tests than HE individuals who facially were more control-like. We also demonstrated that heat map comparisons of, and animated morphs between, individual faces and matched control means revealed facial dysmorphism otherwise overlooked. Thus, visualizations and signature analysis can help pediatricians detect facial dysmorphism across the fetal alcohol spectrum, especially in non-syndromal alcohol exposed cases.

The ALSPAC database provides an opportunity for a much larger-scale investigation of associations between volume and timing of maternal alcohol consumption during pregnancy and facial dysmorphism. In addition, we wish to explore further associations between facial characteristics, cognitive impairment and psychosis

Subjects and data

There are 4747 3D facial scans captured for the 15 year old cohort and these images provide detailed facial morphology at tens of thousands of 3D surface points. The 3D scans have been landmarked and derived facial features recorded. ALSPAC has also collected information on maternal alcohol consumption through questionnaires at 12, 18 and 32 weeks of gestation as well as data regarding the drinking consumption of the parents. In addition, quantity of maternal alcohol intake data is available related to the timing of fetal development: before pregnancy, first trimester of pregnancy, and at around the time the baby was first felt to move. The dataset identified above will need to be extracted and sent to both Peter Hammond and Stephen Richmond.

B1495 - The evolution and development of aggression in humans and other animals - 15/02/2013

GENERAL BACKGROUND

Aggression and violence are issues of global concern, identified by the World Health Organisation as a leading cause of death among young people and exerting considerable strain on individuals and society. Extensive research effort has been directed at understanding both the evolutionary origins of aggression and the factors affecting its development, but these two lines of research have proceeded largely independently. Developmental studies (mainly on humans) neglect how aggressive behaviour is shaped by evolutionary forces; while evolutionary studies (mainly on other animals) focus on fully developed,

adult behaviour and ignore how that behaviour develops during early life. This divergent approach

severely limits the conclusions we can draw about the root causes of aggressive behaviour. For a fuller

understanding of aggression, we urgently need an integrated approach in which developmental changes

in behaviour are seen as an outcome of evolved mechanisms organising behavioural development. My proposed project using the ALSPAC data forms part of a larger programme of research (5-year ERC Consolidator Grant application) aimed at understanding the evolution of developmental trajectories of aggression in humans and other animals.

AIMS

I plan to combine evolutionary theory with data on behavioural development to understand how natural selection has influenced developmental trajectories and how these interact with early life conditions to shape behaviour. Using the ALSPAC data, I will test some general predictions derived from a series of models of aggressive behaviour, in which individuals are uncertain of their own strength but can learn about this through their social experiences (see Fawcett & Johnstone 2010, Proc. R. Soc. B 277, 1427-1434). To refine the models and generate more specific predictions, I will incorporate data on patterns of physical development (growth in body size, strength etc.) and age-structuring of interactions in an attempt to explain age-dependent patterns of play fighting and aggressive behaviour. The underlying assumption of this work is that children learn about their physical capabilities through interactions with their peers.

HYPOTHESES

(i) In early childhood, there is little or no correlation between aggressive behaviour and proxies of physical strength.

(ii) As children mature, a positive correlation develops (at least in boys) between aggressive behaviour and proxies of physical strength: children (or at least boys) who are physically stronger than their peers tend to display higher levels of aggression.

(iii) As children mature, overall levels of aggression decline. The decline is more rapid for children (or at least boys) who are physically weaker than their peers.

(iv) Levels of aggression during adolescence are related to the timing of growth spurts: aggression increases immediately after growth spurts, particularly for those who undergo growth spurts earlier.

(v) There is a hump-shaped relationship between the age to which boys continue to playfight and their level of aggression later in life; boys who stop playfighting earlier show either a high or a low level of aggression, whereas those who continue to playfight until a later age show intermediate aggression.

EXPOSURE VARIABLE(S)

None.

OUTCOME VARIABLE(S)

Levels of aggression in interactions with peers, both in terms of play fighting and genuine fighting. Assessed through questionnaire responses about the tendency to start fights, hit/kick/bite other children, etc.

CONFOUNDING VARIABLE(S)

In the longitudinal analyses I wish to conduct, the principal confounding variables are age and collinear measurements of body size, such as height, weight and BMI. To deal with this issue I will centre the body size measurements around the mean for each age group, and compute residuals from the regression of weight on height. I will also need to control for the effects of socioeconomic status, fatness (obesity) levels and peer victimisation.

METHODOLOGY

To take account of the repeated-measures design inherent in longitudinal datasets, I will use multilevel models (Bryk & Raudenbush, 1992) with a first-order autoregressive error structure (Goldstein et al., 1994). This statistical approach retains individual-specific measures of growth and behaviour and therefore uses all of the available longitudinal information.

B1494 - The development of aggregation methods for rare variant analysis - 14/02/2013

Aim: To apply a range of statistical methods involving the aggregtion of genetic variant data. We intend to undertake this with the aid f pathway analysis and weighing the analysis with prior biological information.

Hypothesis: Pathway analysis and prior biological information can improve the performance of analytical methods involving the aggrevation of rare genetic variants.

Exposure variables: We would like to carry out the project with as much data as possible as this will give us the maximum amount of statistical power for our analysis. Therefore we would like all available genotype data from the ALSPAC cohort for genetics vriants with MAFless than = 0.05 if possible.

Outcome variables: We would also like access to the phenotype data mentioned in Section 8. If possible we would also like to perform a hypothesis free analysis using a wide range of phenotypes. It would therefore be ideal to have direct access to the R drive which I've had experience with on a previous project.

Confounding variables: As we will be looking a the effects of aggregated genetics variant scores on individual phenotypes on interest we will not have to consider possible confounding phenotype variables.

Project Background:

Currently there are few analytical approche that provide the necessary power to efficiently analyse rare variant data (ie variants with MAFless than 0.05) and therefore there needs to be an emphasis on the development of new methods. Our aim is to conduct an overview of the existing methods which aggragate rare variant data together and then to apply more novels measures to develop improved methods with greater statistical power,. In order to achieve this we owuld like to request access to all the ALSPAC genotype data for genetic variants with a minor allele frequency of 0.05 or les. Although we have some phenotypes i particular that we are interested in, we would also like to be able to undertake a hypothesis free analysis of cardiovascular phenotypes if possible.

B1493 - Utilising population-based collections from the UK to identify genetic risk factors for idiopathic scoliosis - 31/01/2013

Aims

We aim to carry out the first population-based genome wide association studies for the presence of scoliosis using white European populations, and to investigate whether similar genetic associations are seen in different ethnic groups. In addition, by utilising resources already available from ALSPAC we will carry out preliminary functional investigations on any identified genetic loci.

To utilise the genetic data already collected to investigate the genetic contributions to scoliosis we will

1. Investigate if the SNP rs11190870 is associated with the presence of scoliosis

2. Perform GWAS in ALSPAC

3. Meta-analysis of GWAS from ALSPAC and Twins-UK

4. Evaluate if identified novel SNPs are likely to have biological relevance bioinformatically and by utilising gene expression, DNA methylation and metabolomic data

5. Continue to develop a model to predict the progression of scoliosis

Methods 1: GWAS

Only those common genotypic variants with a minor allele frequency greater than 5% will be studied. Only SNPs which passed an exact test of Hardy-Weinberg equilibrium are considered for analysis. Association analysis will be performed using logistic regression models based on log additive models, adjusting for age, gender and other appropriate variables. We will assess genome-wide data for associations with scoliosis in ALSPAC alone, setting genome-wide significance at P<=5x10-8.

Methods 2: Power

The power of our GWAS depends on the minor allele frequency of SNPs, the likely size of effect and our cut-off for defining scoliosis. Given the two previous genome-wide studies have found an effect size of 1.56 and 1.85, and the rs11190870 has an allele frequency of 0.437 in ALSPAC, we have reasonable power to detect de novo effects of a comparable magnitude to those previously published.

Methods 3: Meta-analysis

We will perform a meta-analysis of the ALSPAC and Twins-UK GWAS. Prior to meta-analysis, poorly imputed SNPs and those with an allele frequencyless than 5% will be excluded. Inverse variance fixed-effects meta-analyses will be undertaken using METAL. Genomic control corrections will be applied before reporting SNPs which reach genome-wide significance (Pless than 1x10-5) for further investigation.

Methods 4: Replication

We will select signal loci (+/-500mb) with the greatest evidence for association with the risk of scoliosis for replication within data from Japanese and Hong-Kong case-control studies that have GWAS data already available. Population linkage disequilibrium (LD) will be taken into account and where possible used to aid fine mapping. The Chinese Hong Kong disease cohort will then be genotyped for our top 10 SNP hits. Associations between SNPs and scoliosis will then be analysed as described above. We will then repeat the meta-analysis based on all five cohorts.

Methods 5: Bioinformatics

We will use all existing knowledge to analyze our identified SNPs in order to establish its status as a potential functional variant for scoliosis. A bioinformatic approach will be taken to help identify which gene the signal is in, and its likely functional networks. The potential impact of coding variation will be assesed with a series of predictive approaches including SIFT and PolyPhen and we will also followup non-coding functional elements recently annotated by the ENCODE consortium. This will generate prioritised lists of variants for further functional examination in future research projects.

Methods 6: Integrated use of available expression, methylation and metabolomic data

We will examine the impact of our identified SNPs on patterns of protein expression in cell lines, in DNA methylation and through examination of detailed banks of metabolomic data. Along with a sub-set of ALSPAC and Twins-UK samples with transformed multi-tissue specific expression data, the BBSRC-funded ARIES study provides an opportunity to examine the likely effect of our identified SNPs on methylation, as a potential mechanism of gene-environment interaction. This will allow us to extend our primary goal and to begin to unpick the contributing nature of genetic loci to scoliosis risk in a unique study environment.

Exposure variables

Common genotypic variants genotyped using the Illumina HumanHap550 platform.

Outcome variable

Scoliosis (yes/no as a binary variable) identified by the DSM at aged 9 and 15, will be defined as those with a curve >=10degrees, as this has substantial repeatability (Kappa of 0.74). Sensitivity analyses will be carried out using a lower cut-off of >=6degrees to define scoliosis, as the DSM underestimates curve size by approximately 40%, although this lower cut-off has only moderate repeatability (Kappa of 0.56). In addition, we will explore the use of angle size as a continuous variable.

Confounding and other variables

Age and gender

Gene expression data

DNA methylation data

Metabolomic data

B1492 - Explaining risk for suicidal behaviour in adolescent offspring of depressed parents - 31/01/2013

AIMS

(1) Examine in detail the longitudinal association between maternal and paternal depression and the course of offspring suicidal behaviour.

(2) Assess the extent to which prior child psychopathology accounts for excess risk of suicidal behaviour in offspring of depressed parents relative to offspring of non-depressed parents.

(3) Assess the extent to which other hypothesised mediating mechanisms (such as family factors, peer problems and other child factors) account for excess risk of suicidal behaviour in offspring of depressed parents and to examine how these factors interact with child psychopathology.

(4) Where possible, use repeated measures to test the direction of effects for identified mediating mechanisms and adolescent suicidality.

B1491 - Life course socioeconomic patterning of dental health in ALSPAC - 06/02/2013

Aims: Describe the socioeconomic patterning of dental health trajectories, in terms of changes in number

of decayed, missing and filled primary and permanent teeth, from birth to young adulthood, in the

ALSPAC cohort.

Analyze whether changes in dental health in this period is related to socioeconomic background, in terms

of parental socioeconomic data, and to suspected adverse early exposures antenatal and postnatal, and

finally to individual characteristics from birth to young adulthood.

Hypotheses:

a) Early adverse exposures both antenatal and postnatal have causal relations to dental health

trajectories.

b) Expected relations between socioeconomic position of parents and dental health trajectories of

their offspring can be explained by overrepresentation of early adverse exposures in low socioeconomic

groups.

c) Dental health trajectories from birth to young adulthood also relate to various individual

characteristics. For instance individual level of education, health behaviors and awareness, and general

health.

d) Social mobility will affect the level of dental health as young adult.

Outcome variables: Number of decayed, missing and filled primary and permanent teeth (dmft

and DMFT) from children in focus obtained from clinical examinations at 31,43 and 61 months.

Combined with appropriate outcome measures from questionnaires antenatal to age 17.

2. Main exposure variables: Life course socioeconomic position

- Parental Socio-economic position: Educational level of parents, marital status, housing tenure,

income level, car ownership

- Child's Individual socio-economic position: Educational level, labour market association

3. Other exposure/mediating/confounding factors:

Antenatal:

- Parents health status: Comorbidity such as diabetes, psychological disorders etc.

- Maternal health awareness: Dietary habits, smoking habits (both parents), level of physical

activity, BMI, use of dental health care system, medication

Postnatal:

- Parents health status: Comorbidity

- Parents health awareness: Breastfeeding characteristics, dietary habits, smoking habits, use of

dental health care system

- Individual dental hygiene

- Individual health behavior and awareness: Dietary habits, smoking habits, physical activity level,

BMI

- Individual general health: Birth weight, Comorbidity

- Individual social network: Level of support from family and friends

B1490 - Educational attainment and BMI bidrectional assessment of causal relationships using Mendelian randomisation - 17/01/2013

he aim of this miniproject is to look for relationships between educational attainment and BMI and assess causality between them using Mendelian randomisation. This will involve:

- Generating educational attainment (EA) scores derived from genotypic associations with EA from an independent study (carried out as part of the Social Science Genetics Association Consortium) and genotypic dosage information within ALSPAC data.

- Assessing the performance of a series of genotype based scores of EA in terms of their predictive ability for KS3 SATS results (and IQ) and their performance as potential instruments for EA within Mendelian randomisation frameworks.

- Undertaking both observational assessment and Mendelian randomisation analysis of relationships between EA and child BMI.

- Generating similar genetic scores for BMI (initially derived from the 32 most predictive loci taken from Speliotes et al, 2010) and undertake the same analyses as above, but in a bidirectional manner.

In order to perform these analyses, we will require access to ALSPAC genetic (I already have access via the alspac-shared directory on BlueCrystal) data and a series of key phenotypes outlined in the table earlier in this form.

Reference:

Speliotes et al (2010) Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index. Nature Genetics. 42 (11). pp. 937-948.

B1489 - Associations between primary care measures and psychosis-like symptoms in the ALSPAC birth cohort - 17/01/2013

Aim:

The aim of this research is to identify if associations are present between PLIKS, recorded within ALSPAC, and primary health care measures, taken from GPRD.

B1488 - Maternal alcohol use during pregnancy and offspring growth trajectories - 17/01/2013

Maternal alcohol drinking during pregnancy and offspring trajectories of height, weight and head circumference

In Denmark, United Kingdom, Australia and Ireland it has been estimated that between 37% and 81% of fetuses are exposed to alcohol in pregnancy (1-5). While the hazards of heavy alcohol consumption in pregnancy on birth outcomes including preterm birth and birth weight are well recognized, the effects of moderate-low levels of alcohol drinking in pregnancy are less clear both at birth and in particular longitudinally. The association between alcohol use during pregnancy and postnatal growth throughout childhood is not well established. Studies which focus on postnatal growth are a priority (6, 7) if consensus on safe alcohol recommendations for pregnant women is to be reached.

Aim : To investigate whether different patterns of alcohol use during pregnancy adversely affect height, weight and head circumference between birth and 10 years

Objective #1 Recent work conducted using the ALSPAC data investigated maternal smoking during pregnancy and offspring trajectories of height and adiposity up to age 10 (8). We propose to replicate the approach taken in this analysis in an investigation of the associations between different levels of alcohol consumption during pregnancy and height, weight and head circumference trajectories between birth and age 10 years.

Briefly, we will estimate the association between maternal drinking during pregnancy (any versus none and by dose) and trajectories of height, weight and head circumference that have previously been developed using multilevel models by Laura Howe and Andrew Smith. In keeping with Lewis and colleagues' recent categorisation of alcohol use in pregnancy (9) moderate alcohol consumption will be defined as equal to 1-6 drinks on average per week during pregnancy, heavy consumption will be defined as consumption of greater than 6 drinks per day and binge drinkers will be classified as women who report consuming more than 4 units of alcohol at 18 and 32 weeks of pregnancy. This classification will be examined with reference to the growth trajectories of women who abstained from alcohol during pregnancy.

Covariates adjusted for will include maternal age, ethnicity, maternal education, household occupational class, parity, maternal height, paternal height, maternal BMI, smoking during pregnancy, and other key variables. We will also consider drug use as a potential confounder, but this has a very low prevalence, so we will investigate whether or not it is possible/appropriate to include in analyses.

Objective #2 Residual confounding is often a significant limitation in studies of fetal alcohol exposure and infant outcomes. The relationship between alcohol use during pregnancy and growth outcomes at birth could be confounded by shared familial characteristics as has been suggested for the relationship between smoking during pregnancy and growth (8). For this part of the analysis, we will compare the associations of maternal alcohol consumption during pregnancy to the woman's partners in order to explore the presence of unmeasured confounders. This will allow us to estimate the extent to which any associations detected are likely to be the result of unmeasured genetic, socioeconomic or behavioural confounders.

Partner alcohol consumption was collected in a questionnaire sent to them at 18 weeks gestation. Partner alcohol consumption will be classified as moderate, heavy and/or binge in line with UK recommendations of no more than 21 units per week and no more than 4 units in one occasion. We will run the analysis specified in objective #1 both with mutual adjustment for partner alcohol consumption and for partner consumption alone adjusting for covariates already specified.

As a further tool for the assessment of potential unmeasured confounding, we will compare the growth trajectories of children whose mothers drink alcohol during pregnancy with those who do not drink during pregnancy but resume alcohol consumption shortly after delivery.

References

1. Colvin L, Payne J, Parsons D, Kurinczuk JJ, Bower C. Alcohol consumption during pregnancy in nonindigenous west Australian women. Alcoholism: Clinical and Experimental Research. 2007;31(2):276-84.

2. Kelly Y, Sacker A, Gray R, Kelly J, Wolke D, Quigley MA. Light drinking in pregnancy, a risk for behavioural problems and cognitive deficits at 3 years of age? International Journal of Epidemiology. 2009;38(1):129-40.

3. Bakker R, Pluimgraaff LE, Steegers EAP, Raat H, Tiemeier H, Hofman A, et al. Associations of light and moderate maternal alcohol consumption with fetal growth characteristics in different periods of pregnancy: The Generation R Study. International Journal of Epidemiology. 2010;39(3):777-89.

4. Andersen AMN, Andersen PK, Olsen J, Gronbaek M, Strandberg-Larsen K. Moderate alcohol intake during pregnancy and risk of fetal death. International Journal of Epidemiology. 2012.

5. Mullally A, Cleary BJ, Barry J, Fahey TP, Murphy DJ. Prevalence, predictors and perinatal outcomes of peri-conceptional alcohol exposure - retrospective cohort study in an urban obstetric population in Ireland. BMC Pregnancy and Childbirth. 2011;11.

6. Patra J, Bakker R, Irving H, Jaddoe V, Malini S, Rehm J. Dose-response relationship between alcohol consumption before and during pregnancy and the risks of low birthweight, preterm birth and small for gestational age (SGA)-a systematic review and meta?analyses. BJOG: An International Journal of Obstetrics & Gynaecology.

7. Henderson J, Gray R, Brocklehurst P. Systematic review of effects of low-moderate prenatal alcohol exposure on pregnancy outcome. BJOG: An International Journal of Obstetrics & Gynaecology. 2007;114(3):243-52.

8. Howe LD, Matijasevich A, Tilling K, Brion MJ, Leary SD, Smith GD, et al. Maternal smoking during pregnancy and offspring trajectories of height and adiposity: comparing maternal and paternal associations. International journal of epidemiology. 2012;41(3):722-32.

9. Lewis SJ, Zuccolo L, Smith GD, Macleod J, Rodriguez S, Draper ES, et al. Fetal Alcohol Exposure and IQ at Age 8: Evidence from a Population-Based Birth-Cohort Study. PloS one. 2012;7(11):e49407.

B1487 - BRAINEAT - 17/01/2013

There is a bidirectional relationship between the brain and nutrition. The brain influences our food

choices and, therefore, the amount of macro- and micro-nutrients entering our bodies. These nutrients

affect body composition and a variety of metabolic processes that, in turn, influence brain function and

structure. Understanding the various elements of this brain-body loop is one of the overarching goals of

the proposed research, both in terms of gaining new knowledge about the underlying processes and

applying it to enhance population health.

We will take advantage of several community-based cohorts including ALSPAC to investigate bidirectional

brain-body relationships in the context of food choices; magnetic resonance images (MRIs) of

the brain and, in most cases, of abdominal fat have been collected in these cohorts together with a wealth

of other relevant information (e.g., food recall interviews) and blood samples suitable for genetic and

metabolomics analyses.

1. Cohorts

Given the high cost of acquiring large samples with imaging-based, systems-level phenotypes, we have

brought together several cohorts in which MRI of the brain and body have been already accomplished or

funded (~8,000 participants). Three of these samples are birth cohorts (ALSPAC, Generation R, and

NFBC86), thus allowing us to use all of the longitudinal data collected so far. In addition, we will be able

to incorporate the (Canadian) Saguenay Family Study, which is unique with regards to its twogenerational

design (adolescents and their middle-aged parents) and the detailed cardiovascular and

metabolic phenotyping available in all participants (15 hours of assessments).

Using these datasets, we will ask: (1) how do inter-individual differences in the structural (and functional)

properties of the relevant neural circuits relate to food choices, such as fat or carbohydrate intake; and (2)

how do inter-individual differences in body composition (visceral fat from MRI and/or body composition

from bioimpedance) influence metabolic profiles (as determined by metabolomics) and, in turn, brain

structure and function.

2. Magnetic resonance imaging

All cohorts acquired T1-weighted images of the brain, which are well suited for the quantification of a

number of grey-matter properties (see below). Furthermore, all cohorts used MR sequences (Diffusion

Tensor Images [DTI] and/or Magnetization Transfer Images [MTI]) suitable for quantifying various

properties of white matter. Three of the cohorts (Generation-R, NFBC86, and the parent arm of the SFS)

have acquired resting-state functional MRI (fMRIrs), and one of the cohorts (ALSPAC) has acquired a

paradigm-based fMRI (viewing faces; Grosbras and Paus 2006).

Using this rich dataset, we plan to use image-processing pipelines developed and implemented at two of

the sites (Erasmus University and University of Toronto) to process these images in order to generate

quantitative phenotypes suitable for answering both questions, namely from the brain to food choices and

from metabolic profiles (and body composition) to the brain. These brain MR phenotypes include:

MRI sequence Structure and physiology

T1-weighted Volumes, thickness, folding, shape, tissue density

Diffusion tensor imaging Fractional anisotropy, mean diffusivity, track delineation

Magnetization transfer Myelination index

Resting state functional Spontaneous cerebral networks; functional connectivity

Paradigm-based functional Brain response associated with specific stimuli/tasks; functional

connectivity.

B1486 - Phthalates Asthma and Obesity in a Large Longitudinal Cohort - 17/01/2013

Asthma and obesity are two of the most common chronic and disabling conditions of childhood. While both are multifactorial (risk factors include genetics, race, socioeconomic status, diet, and physical activity), most of these risk factors are not amenable to modification or avoidance. However, environmental factors are amenable to change and are plausible contributing factors to both. Given documented rapid increases in both conditions over the past three decades, it is imperative to find ways to reduce both asthma and obesity.

Phthalates, chemicals used to produce a diverse array of consumer products including shampoos, plastic bottles and cosmetics, have been found to interact withperoxisome proliferator-activated receptors that play critical roles in lipid and carbohydrate metabolism.Di-2-ethylhexylphthalate (DEHP) is of particular concern, because mono-(2-ethylhexyl) phthalate,a DEHP metabolite,increases expression of threeperoxisome proliferator-activated receptors(PPARs) which play key roles inlipidand carbohydrate metabolism, providing biological plausibility for a role of DEHP metabolites in childhood obesity and insulin resistance. Additionally, DEHP metabolites induce the release of pro-inflammatory cytokines from lung cells, and activation of PPARs can also modulate immune response.

Investigators have found associations of exposure to plastic wall materials with the development of bronchial obstruction, persistent wheeze, cough, and phlegm in children.Prenatal exposure to butylbenzylphthalate, a high molecular weight (HMW) phthalate used in flooring, has been associated with the development of eczema in one urban longitudinal birth cohort, and a cross-sectional study has associated urinarymono-carboxyoctyl phthalate and mono-carboxynonyl phthalate with asthma.Cross-sectional studies and one longitudinal cohort study have associated lower-molecular weight phthalates with child and adolescent obesity. It is plausible that fetal vulnerability to DEHP is greater, and that this earlier life exposure is more likely to disrupt endocrine processes that maintain dietary balance, leading to obesity. Measurement of phthalates at a single timepoint in pregnancy has moderate sensitivity (56-67%) and high specificity (83-87%) for four phthalate metabolites to estimate exposure tertile over a three-month period, but past studies have been unable to assess a developmental window of vulnerability to phthalate exposure.

The Avon Longitudinal Study of Parents and Children (ALSPAC) is a longitudinal population-based birth cohort study of 14,541 UK mothers enrolled during pregnancy in 1991 and 1992, with data collected at multiple time points during pregnancy and in childhood, through review of hospital records, clinical and laboratory examination, and surveys of parents and children.This population is well-characterized with regard tosociodemographic and behavioral risk factors for obesity, and represents an efficient method to examine ubiquitous environmental chemical exposures as separate risks. We propose to analyze 1500 banked maternal urine samples from each of three trimesters of pregnancy for urinary phthalates, and assess associations with standardized measures of infant, child and adolescent body mass, allergy, and respiratory outcomes.

Aim 1. To examine whether prenatal urinary phthalate metabolites are associated with weight-for-length and Body Mass Index Z-scores in childhood, fat mass, and cardiovascular risks in the school age years and adolescence.

H1. Prenatal urinary phthalates are independently associated with increases in standardized measures of body mass and obesity in childhood, as well as increases in fat mass, adjusting for maternal, sociodemogra