Genome-wide associations for birth weight and correlations with adult disease

Birth weight (BW) is influenced by both foetal and maternal factors and in observational studies is reproducibly associated with future risk of adult metabolic diseases including type 2 diabetes (T2D) and cardiovascular disease. These lifecourse associations have often been attributed to the impact of an adverse early life environment. We performed a multi-ancestry genome-wide association study (GWAS) meta-analysis of BW in 153,781 individuals, identifying 60 loci where foetal genotype was associated with BW (P<5x10^-8). Overall, ~15% of variance in BW could be captured by assays of foetal genetic variation. Using genetic association alone, we found strong inverse genetic correlations between BW and systolic blood pressure (rg=-0.22, P=5.5x10^-13), T2D (rg=-0.27, P=1.1x10^-6) and coronary artery disease (rg=-0.30, P=6.5x10^-9) and, in large cohort data sets, demonstrated that genetic factors were the major contributor to the negative covariance between BW and future cardiometabolic risk. Pathway analyses indicated that the protein products of genes within BW-associated regions were enriched for diverse processes including insulin signalling, glucose homeostasis, glycogen biosynthesis and chromatin remodelling. There was also enrichment of associations with BW in known imprinted regions (P=1.9x10^-4). We have demonstrated that lifecourse associations between early growth phenotypes and adult cardiometabolic disease are in part the result of shared genetic effects and have highlighted some of the pathways through which these causal genetic effects are mediated.