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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年10月10日

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  • 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,
  • Eleftheria Zeggini

摘要

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.