The effect of type 2 diabetes genetic predisposition on non-cardiovascular comorbidities
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.
Authors
- Marijana Vujković (ORCID: https://orcid.org/0000-0003-4924-5714)
- Davis Cammann (ORCID: https://orcid.org/0009-0008-2202-5790)
- Alexis C. Wood (ORCID: https://orcid.org/0000-0001-7616-2119)
- George Davey Smith (ORCID: https://orcid.org/0000-0002-1407-8314)
- Satoshi Yoshiji (ORCID: https://orcid.org/0000-0001-8863-2413)
- Xianyong Yin (ORCID: https://orcid.org/0000-0001-6454-2384)
- Eleftheria Zeggini (ORCID: https://orcid.org/0000-0003-4238-659X)
- Jingchun Chen (ORCID: https://orcid.org/0000-0001-9408-0117)
- Ozvan Bocher (ORCID: https://orcid.org/0000-0002-2467-9236)
- Benjamin Franklin Voight (ORCID: https://orcid.org/0000-0002-6205-9994)
- James B. Meigs (ORCID: https://orcid.org/0000-0002-2439-2657)
- Jerome I. Rotter (ORCID: https://orcid.org/0000-0001-7191-1723)
- Chi Zhao (ORCID: https://orcid.org/0000-0002-1051-8386)
- Cassandra Nichole Spracklen (ORCID: https://orcid.org/0000-0003-3590-7182)
- Henry J. Taylor (ORCID: https://orcid.org/0000-0003-2088-5240)
- Ken Suzuki (ORCID: https://orcid.org/0000-0003-1065-3593)
- Ana Luiza Arruda (ORCID: https://orcid.org/0000-0002-6550-9794)
- Andrew P. Morris (ORCID: https://orcid.org/0000-0002-6805-6014)
- Josep M. Mercader (ORCID: https://orcid.org/0000-0001-8494-3660)
Institutions
- Broad Institute (US)
- National Institutes of Health (US)
- University of Nevada, Las Vegas (US)
- Harvard University (US)
- Inserm (FR)
- Université de Bretagne Occidentale (FR)
- École nationale d'ingénieurs de Brest (FR)
- Kyoto University (JP)
- University of Cambridge (GB)
- University of Massachusetts Amherst (US)
- University of Michigan (US)
- Manchester Academic Health Science Centre (GB)
- UCLA Medical Center (US)
- University of Manchester (GB)
- Helmholtz Zentrum München (DE)
- British Heart Foundation (GB)
- University of Bristol (GB)
- Massachusetts General Hospital (US)
- National Human Genome Research Institute (US)
- Manchester University NHS Foundation Trust (GB)
- Arthritis UK (GB)
- McGill Genome Centre (CA)
- Laboratoire des Sciences et Techniques de l’Information de la Communication et de la Connaissance (FR)
- Translational Therapeutics (United States) (US)
- Philadelphia VA Medical Center (US)
- Children's Nutrition Research Center at Baylor College of Medicine (US)
- Statistical Research (United States) (US)
- MRC Epidemiology Unit (GB)
- NIHR Manchester Biomedical Research Centre (GB)
- Harbor–UCLA Medical Center (US)
- McGill University (CA)
- Technical University of Munich (DE)
- The University of Tokyo (JP)
- University of Pennsylvania (US)
- Nanjing Medical University (CN)
- Medical Research Council (GB)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-10-10
- DOI
- https://doi.org/10.1038/s41467-025-64927-5
- Citations
- 2
- Primary Topic
- Genetic Associations and Epidemiology
- Type
- article
- Field-Weighted Citation Impact
- 3.63
Funders
- American Diabetes Association
- National Institute for Health and Care Research
- European Commission
- National Institutes of Health
- Manchester Biomedical Research Centre
- National Heart, Lung, and Blood Institute
- National Human Genome Research Institute
- National Institute of Diabetes and Digestive and Kidney Diseases
- National Center for Advancing Translational Sciences