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

by Peng, Ruyi , Yin, Xianyong , Boehnke, Michael , Jackson, Anne U. , Morrison, Jean , Chu, Xiaomeng , Fauman, Eric B. , Xia, Zhijie , Ripatti, Samuli , Fernandes Silva, Lilian , Palotie, Aarno , Liu, Lei , Burant, Charles F. , Li, Jack , Daly, Mark , Bose, Debraj , Kwon, Annie , Wen, Xiaoquan , Laakso, Markku , Okamoto, Jeffrey , Scott, Laura J. , Oravilahti, Anniina , Stringham, Heather M.

in 631/114/2401 / 631/208/205 / 631/45/320 / Ascorbic acid / Atrial Fibrillation - blood / Atrial Fibrillation - genetics / Atrial Fibrillation - metabolism / Biomarkers - blood / Caprylates - blood / Finland / Health risks / Humanities and Social Sciences / Humans / Lysine - analogs & derivatives / Lysine - blood / Lysine - metabolism / Male / Mendelian Randomization Analysis / Mental disorders / Metabolic pathways / Metabolites / Metabolome / Middle Aged / multidisciplinary / Randomization / Risk / Science / Science (multidisciplinary) / Sulfates

2025

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2025

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2025

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Journal Article

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

Peng, Ruyi,

Yin, Xianyong,

Boehnke, Michael,

Jackson, Anne U.,

Morrison, Jean,

Chu, Xiaomeng,

Fauman, Eric B.,

Xia, Zhijie,

Ripatti, Samuli,

Fernandes Silva, Lilian,

Palotie, Aarno,

Liu, Lei,

Burant, Charles F.,

Li, Jack,

Daly, Mark,

Bose, Debraj,

Kwon, Annie,

Wen, Xiaoquan,

Laakso, Markku,

Okamoto, Jeffrey,

Scott, Laura J.,

Oravilahti, Anniina,

Stringham, Heather M.

2025

Overview

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. Metabolites can be used to estimate disease risk. Here, the authors use Mendelian randomization to infer the potential causal effects of 1099 plasma metabolites on the risk of 2099 binary disease endpoints.

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Publisher

Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio

Subject

/ Atrial Fibrillation - blood

/ Atrial Fibrillation - genetics

/ Atrial Fibrillation - metabolism