Genetic Mapping of Serum Metabolome to Chronic Diseases Among Han Chinese

Serum metabolites are not just biomarkers but potential regulators for chronic diseases. To gain a better understanding of the genetic regulation of metabolites and their roles in chronic diseases, we quantified 2,759 serum metabolites and performed genome-wide association studies (GWAS) among 3,795 Han Chinese individuals. We identified 245 study-wide significant (P < 1.81×10-11) metabolite quantitative trait loci (metaboQTLs), 55.5% (136) of which were novel. Leveraging the GWAS for 37 clinical traits from East Asians, our Mendelian randomization analyses identified 906 potential causal relationships between metabolites and clinical traits, including 27 for type 2 diabetes and 38 for coronary artery disease. In addition, the putative regulators of several metabolites were revealed by incorporating genetic regulation across the transcriptome and proteome. Particularly, our analyses highlighted the role of lysophosphatidylethanolamine (LPE) in type 2 diabetes and uncovered the putative upstream regulators of LPE, including LIPC and multiple HDL particle-related proteins. In summary, we depict a landscape of the genetic architecture of serum metabolome among Han Chinese and provide insights into the role of serum metabolites in chronic diseases.