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

Abstract

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 disease1. 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.

10 Years of GWAS Discovery: Biology, Function, and Translation

“…Examples from T2D research highlight the diverse routes by which human genetics can inform translational medicine: (1) the combination of common-variant GWASs and candidate-gene resequencing has demonstrated that loss-of-function mutations in SLC30A8 (MIM: 611145; encoding a zinc transporter expressed in pancreatic islets) are protective for T2D, leading to efforts by several pharma companies to develop ZnT-8 antagonists; 93 (2) the use of genetic variants as instruments that ''simulate'' variation in environmental and biochemical exposures has clarified the extent to which vitamin D intake, early nutrition, circulating lipid levels, and chronic inflammation play causal roles with respect to the development of T2D [94][95][96][97][98] and has defined the relationship between insulin resistance and the distribution of adipose tissue; 99 (3) the identification of genetic variants associated with individual variation in response to commonly used therapeutic agents has refined our understanding of the mechanisms through which those agents operate 100,101 and, in some instances, has led to therapeutic optimization on the basis of genetic and/or clinical phenotype; 102 and (4) the combination of -omic measurements, longitudinal clinical phenotypes, and GWAS data has highlighted sets of molecules (e.g., branched-chain amino acids) that not only are prospectively associated with T2D progression but could also play a causal role in T2D development and thereby provide valuable clinical tools for stratification and prognostication. 103,104 Auto-immune Diseases Variant and Gene Discovery.…”

Obesity Kills: Can Genetics Help in the Targeting of Obesity Prevention?

“…In recent work by Dr. Horikoshi and members of the Early Growth Genetics (EGG) Consortium in Nature [5], the researchers analysed genetic differences throughout the genomes of nearly 154,000 people from across the world. By relating the genetic profiles of these individuals to information on birth weight, the researchers were able to identify 60 regions of the genome that were driving the differences in birth weight.…”

“…Therefore, the obesity prevention should start in childhood and cover the critical growth period from childhood throughout adolescence into adulthood. Most of this overlap involves the baby's genetic profile, but the research team found that the mother's genes also played an important role in influencing her baby's birth weight, most likely through the ways in which they alter the baby's environment during pregnancy [5]. Therefore, it is important to include genetic profiling, i.e.…”

“…Thanks to these new results, we now have a much more detailed view of the ways in which these genetic and environmental elements interact to influence early growth and later disease. Using this new weight-associated genetic loci data [2][3][4][5], we can now form so-called genetic risk scores for polygenic birth weight and adult obesity traits for the identification of babies and children with a genetic risk of obesity in adulthood. This is important, since there is a high degree of continuity when it comes to overweight and obesity throughout the course of an individual's life, indicating that overweight and obesity in childhood tend to persist into adulthood [7].…”

“…• The number of gene loci associated significantly (p<5 × 10 -8 ) in genome-wide analyses (GWA) with adult weigh traits, i.e., body mass index, waist-to-hip ratio and body fat % -is currently over 110 [2][3][4] and 60 loci were recently found to associate with birth weight [5], which is a predictor of adulthood obesity. The identified new loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes.…”