Assessing the potential causal effects of 1099 plasma metabolites on 2099 binary disease endpoints

Xianyong Yin (), Jack Li, Debraj Bose, Jeffrey Okamoto, Annie Kwon, Anne U. Jackson, Lilian Fernandes Silva, Anniina Oravilahti, Xiaomeng Chu, Heather M. Stringham, Lei Liu, Ruyi Peng, Zhijie Xia, Samuli Ripatti, Mark Daly, Aarno Palotie, Laura J. Scott, Charles F. Burant, Eric B. Fauman, Xiaoquan Wen, Michael Boehnke (), Markku Laakso () and Jean Morrison ()
Additional contact information
Xianyong Yin: Nanjing Medical University
Jack Li: University of Michigan School of Public Health
Debraj Bose: University of Michigan School of Public Health
Jeffrey Okamoto: University of Michigan School of Public Health
Annie Kwon: University of Michigan School of Public Health
Anne U. Jackson: University of Michigan School of Public Health
Lilian Fernandes Silva: University of Eastern Finland and Kuopio University Hospital
Anniina Oravilahti: University of Eastern Finland and Kuopio University Hospital
Xiaomeng Chu: Nanjing Medical University
Heather M. Stringham: University of Michigan School of Public Health
Lei Liu: Nanjing Medical University
Ruyi Peng: Nanjing Medical University
Zhijie Xia: Nanjing Medical University
Samuli Ripatti: University of Helsinki
Mark Daly: University of Helsinki
Aarno Palotie: University of Helsinki
Laura J. Scott: University of Michigan School of Public Health
Charles F. Burant: University of Michigan
Eric B. Fauman: Development and Medical
Xiaoquan Wen: University of Michigan School of Public Health
Michael Boehnke: University of Michigan School of Public Health
Markku Laakso: University of Eastern Finland and Kuopio University Hospital
Jean Morrison: University of Michigan School of Public Health

Nature Communications, 2025, vol. 16, issue 1, 1-10

Abstract: Abstract Metabolites are small molecules that are useful for estimating disease risk and elucidating disease biology. Here, we perform two-sample Mendelian randomization to systematically infer the potential causal effects of 1099 plasma metabolites measured in 6136 Finnish men from the METSIM study on risk of 2099 binary disease endpoints measured in 309,154 Finnish individuals from FinnGen. We find evidence for 282 putative causal effects of 70 metabolites on 183 disease endpoints. We also identify 25 metabolites with potential causal effects across multiple disease domains, including ascorbic acid 2-sulfate affecting 26 disease endpoints in 12 disease domains. Our study suggests that N-acetyl-2-aminooctanoate and glycocholenate sulfate affect risk of atrial fibrillation through two distinct metabolic pathways and that N-methylpipecolate may mediate the putative causal effect of N6,N6-dimethyllysine on anxious personality disorder.

Date: 2025
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DOI: 10.1038/s41467-025-58129-2

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