Dave Evans

Associations of FTO and MC4R Variants with Obesity Traits in Indians and the Role of Rural/Urban Environment as a Possible Effect Modifier.

Few studies have investigated the association between genetic variation and obesity traits in Indian populations or the role of environmental factors as modifiers of these relationships. In the context of rapid urbanisation, resulting in significant lifestyle changes, understanding the aetiology of obesity is important. We investigated associations of FTO and MC4R variants with obesity traits in 3390 sibling pairs from four Indian cities, most of whom were discordant for current dwelling (rural or urban). The FTO variant rs9939609 predicted increased weight (0.09 Z-scores, 95% CI: 0.03, 0.15) and BMI (0.08 Z-scores, 95% CI: 0.02, 0.14). The MC4R variant rs17782313 was weakly associated with weight and hip circumference (P < .05). There was some indication that the association between FTO and weight was stronger in urban than that in rural dwellers (P for interaction = .03), but no evidence for effect modification by diet or physical activity. Further studies are needed to investigate ways in which urban environment may modify genetic risk of obesity.

International Genome-Wide Association Study Consortium Identifies Novel Loci Associated With Blood Pressure in Children and Adolescents

Background— Our aim was to identify genetic variants associated with blood pressure (BP) in childhood and adolescence. Methods and Results— Genome-wide association study data from participating European ancestry cohorts of the Early Genetics and Lifecourse Epidemiology (EAGLE) Consortium was meta-analyzed across 3 epochs; prepuberty (4–7 years), puberty (8–12 years), and postpuberty (13–20 years). Two novel loci were identified as having genome-wide associations with systolic BP across specific age epochs: rs1563894 (ITGA11, located in active H3K27Ac mark and transcription factor chromatin immunoprecipitation and 5′-C-phosphate-G-3′ methylation site) during prepuberty (P=2.86×10–8) and rs872256 during puberty (P=8.67×10–9). Several single-nucleotide polymorphism clusters were also associated with childhood BP at P<5×10–3. Using a P value threshold of <5×10–3, we found some overlap in variants across the different age epochs within our study and between several single-nucleotide polymorphisms in any of the 3 epochs and adult BP-related single-nucleotide polymorphisms. Conclusions— Our results suggest that genetic determinants of BP act from childhood, develop over the lifecourse, and show some evidence of age-specific effects.

Causal Analyses, Statistical Efficiency And Phenotypic Precision Through Recall-By-Genotype Study Design

Genome-wide association studies have been useful in identifying common genetic variants related to a variety of complex traits and diseases; however, they are often limited in their ability to inform about underlying biology. Whilst bioinformatics analyses, studies of cells, animal models and applied genetic epidemiology have provided some understanding of genetic associations or causal pathways, there is a need for new genetic studies that elucidate causal relationships and mechanisms in a cost-effective, precise and statistically efficient fashion. We discuss the motivation for and the characteristics of the Recall-by-Genotype (RbG) study design, an approach that enables genotype-directed deep-phenotyping and improvement in drawing causal inferences. Specifically, we present RbG designs using single and multiple variants and discuss the inferential properties, analytical approaches and applications of both. We consider the efficiency of the RbG approach, the likely value of RbG studies for the causal investigation of disease aetiology and the practicalities of incorporating genotypic data into population studies. Finally, we provide a catalogue of the UK-based resources for such studies, an online tool to aid the design of new RbG studies and discuss future developments of this approach.

OP03 The effect of in utero exposure to alcohol, tobacco and cannabis on educational attainment in adolescence: findings from ALSPAC, a UK cohort study

Background Alcohol, tobacco and cannabis can cross the placenta, and could have long-lasting effects on the brain of the developing foetus. We examine whether exposure to these substances is associated with educational attainment in adolescence (Key Stage 4 [KS4], aged 16 yrs), and consider whether any associations are due to an intrauterine causal mechanism. We use two main approaches: (1) a comparison of the risks associated with maternal substance use during pregnancy with the risks associated with paternal substance use at the same time, and (2) Mendelian Randomisation (MR). Methods The Avon Longitudinal Study of Parents and Children is a population-based birth cohort. Educational attainment at KS4 was determined through linkage to the National Pupil Database: capped score of eight best subjects (converted to percentage). Mothers and their partners reported use of substances during the mother’s pregnancy via questionnaire. In observational complete-case analysis (n = 6018), multilevel (child level 1, school level 2) linear models were used to examine the association between maternal and paternal substance use and KS4 attainment adjusted for potential confounders. In MR analysis, genetic markers associated with maternal alcohol (rs1229984) and tobacco (rs1051730) use were used to estimate the unconfounded effect of the exposures. Results Maternal substance use in pregnancy was common (72% reported any alcohol, 22% any tobacco, and 2% any cannabis) and socially patterned (tobacco associated with deprivation, moderate alcohol and light cannabis with higher maternal education). In adjusted observational analyses, children of mothers who smoked had lower KS4 percentage scores (β −2.7, 95% CI: −3.7 to −1.7) but a similar association was observed for paternal smoking (β −3.0, −3.8 to −2.2). Compared to children of non-drinkers in first trimester, children whose mothers drank ≥7 units per week had lower KS4 scores (β −4.6, −7.9 to −1.4), but children of lighter drinkers did not. The MR analyses were under-powered but provisional results suggest no association between maternal smoking and KS4 score, but that small amounts of alcohol could have a detrimental effect. Neither maternal nor paternal cannabis use was associated with educational attainment in observational analyses, but few mothers in our sample used cannabis regularly in pregnancy. Conclusion The negative association in the observational analysis between maternal smoking in pregnancy and child KS4 attainment is likely due to residual confounding rather than an intrauterine mechanism. Conversely, residual confounding may be masking a negative association between lower levels of alcohol drinking and KS4 attainment in observational analysis.