Cross-ancestry analyses of Chinese and European populations reveal insights into the genetic architecture and disease implication of metabolites

Differential susceptibilities to various diseases and corresponding metabolite variations have been documented across diverse ethnic populations, but the genetic determinants of these disparities remain unclear. Here, we performed large-scale genome-wide association studies of 171 directly quantifiable metabolites from a nuclear magnetic resonance-based metabolomics platform in 10,792 Han Chinese individuals. We identified 15 variant-metabolite associations, eight of which were successfully replicated in an independent Chinese population (n = 4,480). By cross-ancestry meta-analysis integrating 213,397 European individuals from the UK Biobank, we identified 228 additional variant-metabolite associations and improved fine-mapping precision. Moreover, two-sample Mendelian randomization analyses revealed evidence that genetically predicted levels of triglycerides in high-density lipoprotein were associated with a higher risk of coronary artery disease and that of glycine with a lower risk of heart failure in both ancestries. These findings enhance our understanding of the shared and specific genetic architecture of metabolites as well as their roles in complex diseases across populations.