Genome-wide association study for circulating metabolites in 619,372 individuals

Interpreting genetic associations with complex traits can be greatly improved by detailed understanding of the molecular consequences of these variants. However, although genome-wide association studies (GWAS) for common complex diseases routinely profile 1M+ individuals, studies of molecular phenotypes have lagged behind. We performed a GWAS meta-analysis for 249 circulating metabolic traits in the Estonian Biobank and the UK Biobank in up to 619,372 individuals, identifying 88,604 significant locus-metabolite associations and 8,774 independent lead variants, including 987 lead variants with a minor allele frequency less than 1%. We demonstrate how common and low-frequency associations converge on shared genes and pathways, bridging the gap between rare-variant burden testing and common-variant GWAS. We used Mendelian randomisation (MR) to explore putative causal links between metabolic traits, coronary artery disease and type 2 diabetes (T2D). Surprisingly, up to 85% of the tested metabolite-disease pairs had statistically significant genome-wide MR estimates, likely reflecting complex indirect effects driven by horisontal pleiotropy. To avoid these pleiotropic effects, we used cis-MR to test the phenotypic impact of inhibiting specific drug targets. We found that although plasma levels of branched-chain amino acids (BCAAs) have been associated with T2D in both observational and genome-wide MR studies, inhibiting the BCAA catabolism pathway to lower BCAA levels is unlikely to reduce T2D risk. Our publicly available results provide a valuable novel resource for GWAS interpretation and drug target prioritisation.