Integrative genomic and metabolomic analyses identify novel associations between mQTLs and common diseases in Han Chinese

While prior metabolomic genome-wide association studies (mGWASs) have identified numerous metabolite quantitative trait loci (mQTLs) in European populations, their characterization in East Asians—particularly Han Chinese—remains limited. Here, we integrated genomic and metabolomic data to systematically map plasma mQTLs in Han Chinese individuals and investigated their associations with common traits and diseases. Genome-wide association study (GWAS) analyses of 846 plasma metabolites were performed in 495 Han Chinese individuals to identify mQTLs. Causal genes with robust evidence were prioritized via colocalization analysis and fine-mapping. Subsequently, a phenome-wide association study (PheWAS) was performed to explore links between mQTLs and common chronic diseases. Mendelian randomization (MR) analyses were further applied to infer causal relationships between metabolites and common diseases. We identified 232 genome-wide significant mQTLs (P < 5 × 10⁻⁸), of which 52.6% (122) were novel. Cross-ancestry comparisons revealed 72 novel cohort-specific mQTLs associated with 16 metabolites. Colocalization analysis confirmed 175 high-confidence gene-metabolite pairs with shared genetic drivers. PheWAS linked 118 mQTLs to 39 diseases across 11 clinical categories. MR analyses revealed seven putatively causal metabolite-disease relationships, including one for asthma, two for type 2 diabetes, and four for inflammatory bowel disease. Our study delineates the genetic architecture of the plasma metabolome in the Han Chinese population, uncovering novel causal associations between metabolite levels and diseases such as asthma, type 2 diabetes, and inflammatory bowel disease.