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

Examining the downstream molecular consequences of genetic variation significantly enhances our understanding of the heritable determinants of complex traits and disease predisposition. Metabolites serve as key indicators of various biological processes and disease states, playing a crucial role in this systematic mapping, also providing opportunities for the discovery of new biomarkers for disease diagnosis and prognosis. Here, we present a genome-wide association study for 249 circulating metabolite traits quantified by nuclear magnetic resonance spectroscopy across various genetic ancestry groups from the Estonian Biobank and the UK Biobank. We generated mixed model associations in the Estonian Biobank and six major genetic ancestry groups of the UK Biobank and performed two separate meta-analyses across the predominantly European genetic ancestry samples (n = 599,249) and across all samples (n = 619,372). In total, we identified 89,489 locus-metabolite pairs and 8,917 independent lead variants, out of which 4,184 appear to be novel associated loci. Moreover, 12.4% of the independent lead variants had a minor allele frequency of less than 1%, highlighting the importance of including low-frequency and rare variants in metabolic biomarker studies. Our publicly available results provide a valuable resource for future GWAS interpretation and drug target prioritisation studies.