Abstract
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.