Genetic analysis of circulating metabolic traits in 619,372 individuals

Interpreting the association of genetic variants with complex traits can be improved by gaining a greater understanding of the molecular consequences of these variants. Although genome-wide association studies (GWAS) for complex diseases routinely profile over one million individuals^1-5, studies of molecular traits have lagged behind. Here 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. We identified 88,127 common and low-frequency locus-trait associations from 8,398 loci that converged on shared genes and pathways. Using statistical fine mapping, systematic phenome-wide colocalization and cis-Mendelian randomization, we explored putative causal links between metabolic traits and disease outcomes. We predict that although plasma branched-chain amino acids (BCAAs) have been associated with type 2 diabetes in observational studies^6,7, lowering BCAA levels by targeting the BCAA catabolism pathway is unlikely to reduce type 2 diabetes risk. Leveraging our large sample size and high-quality genotype imputation, we found that 19.4% of the confidently fine-mapped variants had minor allele frequencies between 0.1 and 1%, and these variants were twofold enriched for predicted missense and splice-altering variants. Our results highlight the value of integrating low-frequency variants into genetic association studies.