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Arruda, A.L. ; Bocher, O. ; Taylor, H.J.* ; Cammann, D.* ; Yoshiji, S.* ; Yin, X.* ; Zhao, C.* ; Chen, J.* ; Wood, A.C.* ; Suzuki, K.* ; Mercader, J.M.* ; Spracklen, C.N.* ; Meigs, J.B.* ; Vujkovic, M.R.* ; Smith, G.D.* ; Rotter, J.I.* ; Voight, B.F.* ; Morris, A.P.* ; Zeggini, E.

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

Nat. Commun. 16:9042 (2025)
Publ. Version/Full Text Research data DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
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.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Association Analyses Identify; Mendelian Randomization; Risk; Metaanalysis; Prevalence; Ancestry; Mellitus; Glaucoma; Disease
ISSN (print) / ISBN 2041-1723
e-ISSN 2041-1723
Journal Nature Communications
Quellenangaben Volume: 16, Issue: 1, Pages: , Article Number: 9042 Supplement: ,
Publisher Nature Publishing Group
Publishing Place London
Reviewing status Peer reviewed
Institute(s) Institute of Translational Genomics (ITG)
Grants NIHR Manchester Biomedical Research Centre
National Center for Advancing Translational Sciences, CTSI
National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC)
Southern California Diabetes Endocrinology Research Center
National Heart, Lung and Blood Institute (NHLBI)
American Diabetes Association
NHGRI
National Institute Of Diabetes And Digestive And Kidney Diseases of the National Institutes of Health
Foundation for the National Institutes of Health
Medical University of Bialystok (MUB) grant from the Ministry of Science and Higher Education (Poland)
National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutues of Health
European Union's Horizon 2020 research and innovation program