The effect of type 2 diabetes genetic predisposition on non-cardiovascular comorbidities

Ana Luiza Arruda (), Ozvan Bocher, Henry J. Taylor, Davis Cammann, Satoshi Yoshiji, Xianyong Yin, Chi Zhao, Jingchun Chen, Alexis C. Wood, Ken Suzuki, Josep M. Mercader, Cassandra N. Spracklen, James B. Meigs, Marijana Vujkovic, George Davey Smith, Jerome I. Rotter, Benjamin F. Voight, Andrew P. Morris and Eleftheria Zeggini ()
Additional contact information
Ana Luiza Arruda: Helmholtz Zentrum München – German Research Center for Environmental Health
Ozvan Bocher: Helmholtz Zentrum München – German Research Center for Environmental Health
Henry J. Taylor: National Institutes of Health
Davis Cammann: Las Vegas
Satoshi Yoshiji: Broad Institute of MIT and Harvard
Xianyong Yin: Nanjing Medical University
Chi Zhao: University of Massachusetts Amherst
Jingchun Chen: Las Vegas
Alexis C. Wood: Baylor College of Medicine
Ken Suzuki: University of Tokyo
Josep M. Mercader: Broad Institute of MIT and Harvard
Cassandra N. Spracklen: University of Massachusetts Amherst
James B. Meigs: Broad Institute of MIT and Harvard
Marijana Vujkovic: Corporal Michael J. Crescenz VA Medical Center
George Davey Smith: University of Bristol
Jerome I. Rotter: Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center
Benjamin F. Voight: Corporal Michael J. Crescenz VA Medical Center
Andrew P. Morris: The University of Manchester
Eleftheria Zeggini: Helmholtz Zentrum München – German Research Center for Environmental Health

Nature Communications, 2025, vol. 16, issue 1, 1-14

Abstract: Abstract Type 2 diabetes is associated with a range of non-cardiovascular non-oncologic comorbidities. To move beyond associations and evaluate causal effects between type 2 diabetes genetic predisposition and 21 comorbidities, we apply Mendelian randomization analysis using genome-wide association studies across multiple genetic ancestries. Additionally, leveraging eight mechanistic clusters of type 2 diabetes genetic profiles, each representing distinct biological pathways, we investigate causal links between cluster-stratified type 2 diabetes genetic predisposition and comorbidity risk. We identify causal effects of type 2 diabetes genetic predisposition driven by distinct genetic clusters. For example, the risk-increasing effects of type 2 diabetes genetic predisposition on cataracts and erectile dysfunction are primarily attributed to adiposity and glucose regulation mechanisms, respectively. We observe opposing effect directions across different genetic ancestries for depression, asthma and chronic obstructive pulmonary disease. Our findings leverage the heterogeneity underpinning type 2 diabetes genetic predisposition to prioritize biological mechanisms underlying causal relationships with comorbidities.

Date: 2025
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DOI: 10.1038/s41467-025-64927-5

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