Proposal summaries
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
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.
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.
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.