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

Authors: ARRUDA, ANA - German Research Center For Environmental Health; BOCHER, OZVAN - German Research Center For Environmental Health; TAYLOR, HENRY - National Human Genome Research Institute; CAMMANN, DAVIS - University Of Nevada Las Vegas, Las Vegas, Nv; YOSHJI, SATOSHI - Broad Institute Of Mit/harvard; YIN, XIANYONG - University Of Michigan; ZHAO, CHI - University Of Massachusetts, Amherst; CHEN, JINGCHUN - University Of Nevada Las Vegas, Las Vegas, Nv; WOOD, ALEXIS - Children'S Nutrition Research Center (CNRC); SUZUKI, KEN - University Of Tokyo; MERCADER, JOSEP - Broad Institute Of Mit/harvard; SPRACKLEN, CASSANDRA - University Of Massachusetts, Amherst; MEIGS, JAMES - Broad Institute Of Mit/harvard; VUJKOVIC, MARIJANA - University Of Pennsylvania; DAVEY SMITH, GEORGE - University Of Bristol; ROTTER, JEROME - Harbor-Ucla Medical Center; VOIGHT, BENJAMIN - University Of Pennsylvania; MORRIS, ANDREW - University Of Manchester; ZEGGINI, ELEFTHERIA - German Research Center For Environmental Health

Submitted to: Nature Communications
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/2/2025
Publication Date: 10/10/2025
Citation: Arruda, A.L., Bocher, O., Taylor, H.J., Cammann, D., Yoshji, S., Yin, X., Zhao, C., Chen, J., Wood, A.C., Suzuki, K., Mercader, J.M., Spracklen, C.N., Meigs, J.B., Vujkovic, M., Davey Smith, G., Rotter, J.I., Voight, B.F., Morris, A.P., Zeggini, E. 2025. The effect of type 2 diabetes genetic predisposition on non-cardiovascular comorbidities. Nature Communications. 16(1):Article 9042. https://doi.org/10.1038/s41467-025-64927-5.
DOI: https://doi.org/10.1038/s41467-025-64927-5

Interpretive Summary: This study explored how different biological mechanisms underlying type 2 diabetes (T2D) contribute to its many non-cardiometabolic complications. Researchers grouped T2D genetic variants into eight mechanistic clusters and examined their links with conditions such as cataracts, erectile dysfunction, depression, and osteoarthritis. They found that distinct T2D pathways — such as those related to obesity or beta-cell dysfunction — explained different disease connections. The analysis also revealed population-specific patterns, including opposite genetic effects for depression and respiratory diseases across ancestries. By identifying overlap between T2D-related genes and osteoarthritis drug targets, the study highlighted metformin as a potential treatment for both conditions. These findings clarify the shared biological roots of T2D and its diverse comorbidities, informing future precision prevention and therapy efforts for scientists, clinicians, and public-health stakeholders.

Technical 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.