Assessing the potential causal effects of 1099 plasma metabolites on 2099 binary disease endpoints
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.
Authors
- Michael Boehnke (ORCID: https://orcid.org/0000-0002-6442-7754)
- Debraj Bose (ORCID: https://orcid.org/0000-0002-3177-6608)
- Laura J. Scott (ORCID: https://orcid.org/0000-0002-4886-5084)
- Lilian Fernandes Silva (ORCID: https://orcid.org/0000-0003-0225-842X)
- Anne Jackson (ORCID: https://orcid.org/0000-0002-9672-2547)
- Anniina Oravilahti (ORCID: https://orcid.org/0000-0001-8866-4482)
- Heather M. Stringham (ORCID: https://orcid.org/0000-0002-2991-6392)
- Xianyong Yin (ORCID: https://orcid.org/0000-0001-6454-2384)
- Charles Burant (ORCID: https://orcid.org/0000-0001-9189-5003)
- Jean Morrison (ORCID: https://orcid.org/0000-0003-4829-8283)
- Jeffrey Okamoto (ORCID: https://orcid.org/0000-0001-9988-1618)
- Zhi‐Jie Xia (ORCID: https://orcid.org/0000-0003-3018-1925)
- Samuli Ripatti (ORCID: https://orcid.org/0000-0002-0504-1202)
- Annie Kwon (ORCID: https://orcid.org/0000-0002-2331-7575)
- Ru‐Wen Peng (ORCID: https://orcid.org/0000-0003-0424-2771)
- Aarno V. Palotie (ORCID: https://orcid.org/0000-0002-2527-5874)
- Xiaoquan Wen (ORCID: https://orcid.org/0000-0001-8990-2737)
- Lei Liu (ORCID: https://orcid.org/0000-0002-0807-2135)
- Eric B. Fauman (ORCID: https://orcid.org/0000-0002-9739-0249)
- Markku Laakso (ORCID: https://orcid.org/0000-0002-3394-7749)
- Mark J. Daly (ORCID: https://orcid.org/0000-0002-0949-8752)
- Xiaomeng Chu
- Jack Li (ORCID: https://orcid.org/0000-0001-6126-0701)
Institutions
- Broad Institute (US)
- University of Helsinki (FI)
- University of Eastern Finland (FI)
- Pfizer (United States) (US)
- University of Michigan (US)
- Massachusetts General Hospital (US)
- Kuopio University Hospital (FI)
- Institute for Molecular Medicine Finland (FI)
- Statistical Service (CY)
- Nanjing Medical University (CN)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-03-28
- DOI
- https://doi.org/10.1038/s41467-025-58129-2
- Citations
- 2
- Primary Topic
- Genetic Associations and Epidemiology
- Type
- article
- Field-Weighted Citation Impact
- 3.63
Funders
- American Diabetes Association