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, but the causes of these associations are poorly understood.
We propose to investigate three related research questions:
(1) Which common fetal genetic variants are robustly associated with offspring birth weight?
(2) Which common maternal genetic variants are robustly associated with offspring birth weight?
(3) Which maternal intra-uterine environmental exposures are causally associated with offspring birth weight? Improving the prevention, diagnosis and treatment of diabetes:
(1) Fetal genetic variants associated with an individual?s own birth weight will highlight biological pathways relevant to fetal growth and may indicate links with pathways relevant to diabetes, enabling a better understanding of what causes the disease.
(2) Maternal genetic variants known to influence diabetes- or obesity-related traits may be used to test the hypothesis that those traits are causally associated with the birth weight of her offspring. This will improve understanding of the factors responsible for increased fetal growth and associated risks in a diabetic or obese pregnancy. We will perform
(a) [hypothesis-free] genome-wide association studies examining
(i) associations between a participant's genotype (fetal) and their own birth weight,
(ii) associations between a female participant's genotype (maternal) and the birth weight of their first child, and
(b) [hypothesis-driven] analyses of associations between maternal genetic variants known to influence traits relevant to the maternal environment (fasting glucose, blood pressure etc) and offspring birth weight. Since genetic variants are unlikely to be confounded, the latter will be a Mendelian randomization analysis to investigate causality in associations between maternal environmental factors and offspring birth weight. We propose to use the full UK Biobank cohort for the fetal genome-wide association study, while for the maternal genome-wide association study and Mendelian randomization analyses, we plan to use the subset of women with data on birth weight of first child (n=221,522).
|Lead investigator:||Dr Rachel Freathy|
|Lead institution:||University of Exeter|
3 related Returns
|Return ID||App ID||Description||Archive Date|
|2881||7036||Association of maternal circulating 25(OH)D and calcium with birth weight: A mendelian randomisation analysis||26 Nov 2020|
|1848||7036||Genome-wide association study of offspring birth weight in 86577 women identifies five novel loci and highlights maternal genetic effects that are independent of fetal genetics||3 Dec 2019|
|2880||7036||Maternal and fetal genetic effects on birth weight and their relevance to cardio-metabolic risk factors||26 Nov 2020|
|753||Genome-wide associations for birth weight and correlations with adult disease||Horikoshi M et al.||2016||Nature|