Proposal summaries
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.
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.
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.
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.
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.
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).
B2143 - Statistical methodology for population genetics inference from massive datasets with applications in epidemiology - 16/01/2014
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.
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.
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.
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.