GWAS: Birth weight (BW) associated with future risk of adult metabolic diseases including type-2 diabetes (T2D) and cardiovascular disease

Here is an intriguing ‘gene-environment interactions’ example in which “genes” are those involved in adult-onset type-2 diabetes (T2D) and cardiovascular disease, and “environment” is the uterus in which the embryo/fetus can be affected by maternal diet and stressors, and the early postpartum care following birth.

Birth weight (BW) is well known to be influenced by both fetal and maternal factors––with growing evidence for its being associated with future risk of adult metabolic diseases including T2D and cardiovascular disease. These life-course associations have often been attributed to the impact of an adverse early life environment (i.e. in utero).

In attached report, authors performed a multi-ancestry genome-wide association study (GWAS) meta-analysis of BW in 153,781 individuals, identifying 60 loci at which fetal genotype was associated with BW (P < 5 × 10–8). Overall, ~15% of variance in BW was captured by assays of fetal genetic variation. Using genetic association alone, authors 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, authors showed that genetic factors were the major contributor to the negative co-variance 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-signaling, glucose homeostasis, glycogen biosynthesis and chromatin remodeling. There was also enrichment of associations with BW in known imprinted regions (P = 1.9 × 10–4). Authors demonstrated that life-course associations between early-growth phenotypes and adult cardiometabolic disease are, in part, the result of shared genetic effects, and they identified some of the pathways through which these causal genetic effects are mediated.

Nature  13 Oct 2o16; 538: 248–252

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