Birth weight (BW) has been shown to be influenced by both fetal and maternal factors and in observational studies is reproducibly associated with future risk of adult metabolic diseases including type 2 diabetes (T2D) and cardiovascular disease1. These lifecourse associations have often been attributed to the impact of an adverse early life environment. Here, we performed a multi-ancestry genome-wide association study (GWAS) meta-analysis of BW in 153,781 individuals, identifying 60 loci where fetal genotype was associated with BW (P < 5 10-8). Overall, approximately 15% of variance in BW was captured by assays of fetal genetic variation. Using genetic association alone, we found strong inverse genetic correlations between BW and systolic blood pressure (Rg = -0.22, P = 5.5 10-13), T2D (Rg = -0.27, P = 1.1 10-6) and coronary artery disease (Rg = -0.30, P = 6.5 10-9). In addition, using large - cohort datasets, we 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 = 1.9 10-4). We demonstrate that life-course associations between early growth phenotypes and adult cardiometabolic disease are in part the result of shared genetic effects and identify some of the pathways through which these causal genetic effects are mediated.
Mark I McCarthy Rachel M Freathy, et al. Genome-wide associations for birth weight and correlations with adult disease, doi:10.1038/nature19806
Understanding how maternal and fetal genetic and environmental factors influence offspring birth weight
We aim to identify genetic and environmental factors that are causally associated with birth weight. Both lower and higher birth weights in the normal range are observationally associated with a higher risk of type 2 diabetes in later life.
Birth weight is influenced by the maternal intrauterine environment, maternal genetics and fetal genetics. Both high and low birth weights have been associated with higher risk of type 2 diabetes in later life, but the causes of these associations are poorly understood. We aim to identify genetic and environmental factors that are causally associated with birth weight.
Mark I McCarthy, Rachel M Freathy, et al. Genome-wide associations for birth weight and correlations with adult disease, doi:10.1038/nature19806
|Lead investigator:||Rachel Freathy|
|Lead institution:||University of Exeter|