作者
Mark D. Benson,Aaron S. Eisman,Usman A. Tahir,Daniel H. Katz,Shuliang Deng,Debby Ngo,Jeremy Robbins,Alissa Hofmann,Xu Shi,Shuning Zheng,Michelle J. Keyes,Zhi Yu,Yan Gao,Laurie Farrell,Dongxiao Shen,Zsu‐Zsu Chen,Daniel E. Cruz,Mario Sims,Adolfo Correa,Russell P. Tracy,Peter Durda,Kent D. Taylor,Yongmei Liu,W. Craig Johnson,Xiuqing Guo,Jie Yao,Yii‐Der Ida Chen,Ani Manichaikul,Deepti Jain,Qiong Yang,Claude Bouchard,Mark A. Sarzynski,Stephen S. Rich,Jerome I. Rotter,Thomas J. Wang,James S. Pankow,Clary B. Clish,Indra Neil Sarkar,Pradeep Natarajan,Robert E. Gerszten
摘要
Although many novel gene-metabolite and gene-protein associations have been identified using high-throughput biochemical profiling, systematic studies that leverage human genetics to illuminate causal relationships between circulating proteins and metabolites are lacking. Here, we performed protein-metabolite association studies in 3,626 plasma samples from three human cohorts. We detected 171,800 significant protein-metabolite pairwise correlations between 1,265 proteins and 365 metabolites, including established relationships in metabolic and signaling pathways such as the protein thyroxine-binding globulin and the metabolite thyroxine, as well as thousands of new findings. In Mendelian randomization (MR) analyses, we identified putative causal protein-to-metabolite associations. We experimentally validated top MR associations in proof-of-concept plasma metabolomics studies in three murine knockout strains of key protein regulators. These analyses identified previously unrecognized associations between bioactive proteins and metabolites in human plasma. We provide publicly available data to be leveraged for studies in human metabolism and disease.