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

Author

Listed:
  • Ana Luiza Arruda

    (Helmholtz Zentrum München – German Research Center for Environmental Health
    University of Cambridge)

  • Ozvan Bocher

    (Helmholtz Zentrum München – German Research Center for Environmental Health
    UMR 1078)

  • Henry J. Taylor

    (National Institutes of Health
    University of Cambridge
    University of Cambridge)

  • Davis Cammann

    (Las Vegas)

  • Satoshi Yoshiji

    (Broad Institute of MIT and Harvard
    Kyoto University Graduate School of Medicine
    McGill University)

  • Xianyong Yin

    (Nanjing Medical University
    University of Michigan)

  • 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
    Massachusetts General Hospital
    Harvard Medical School)

  • Cassandra N. Spracklen

    (University of Massachusetts Amherst)

  • James B. Meigs

    (Broad Institute of MIT and Harvard
    Harvard Medical School
    Massachusetts General Hospital)

  • Marijana Vujkovic

    (Corporal Michael J. Crescenz VA Medical Center
    University of Pennsylvania Perelman School of Medicine
    University of Pennsylvania Perelman School of Medicine)

  • 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
    University of Pennsylvania Perelman School of Medicine
    University of Pennsylvania Perelman School of Medicine
    University of Pennsylvania Perelman School of Medicine)

  • Andrew P. Morris

    (The University of Manchester
    Manchester Academic Health Science Centre)

  • Eleftheria Zeggini

    (Helmholtz Zentrum München – German Research Center for Environmental Health
    Technical University of Munich University Hospital)

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.

Suggested Citation

  • 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, 2025. "The effect of type 2 diabetes genetic predisposition on non-cardiovascular comorbidities," Nature Communications, Nature, vol. 16(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-64927-5
    DOI: 10.1038/s41467-025-64927-5
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