Ancestry-specific genetics of amino acids and microbiota-related metabolites reveal causal effects on cardiometabolic disease in Chinese populations

Abstract Background The genetic architecture of circulating amino acids (AAs) and microbiota-related metabolites (MRMs) in relation to cardiometabolic disease remains poorly characterized in East Asian populations, limiting ancestry-specific insights. Methods In a prospective cohort of 2953 Chinese individuals, we performed a large-scale genome-wide association study (GWAS) of 28 serum AAs and 22 MRMs. We conducted a cross-ancestry comparison of variant-metabolite associations. Using colocalization and Mendelian randomization (MR), we further investigated causal roles of 50 AAs and MRMs in 25 cardiometabolic diseases from the BioBank Japan. Furthermore, we explored differences in the genetic regulation of these metabolites between incident T2DM cases and healthy controls. Results We identified 33 metabolite-variant associations, 22 of which were previously unreported, and revealed several loci specific to East Asian ancestry. Integrative colocalization and MR analyses established 49 causal relationships between metabolite levels and cardiometabolic diseases, most notably implicating genetically predicted N-acetyltryptophan to increased risk of type 2 diabetes. Moreover, we observed distinct patterns of genetic regulation between T2DM cases and controls, highlighting substantial heterogeneity of effects and dynamic gene-disease interplay. Conclusions These findings offer crucial insights into the ancestry-specific genetic determinants of metabolic traits, and shed new light on their causal roles in the etiology of cardiometabolic diseases in East Asian populations.