Partitioned polygenic scores show mechanistic heterogeneity in type 2 diabetes and hypertension comorbidity
Type 2 diabetes and hypertension are common health conditions that often occur together, suggesting shared biological mechanisms. To explore this relationship, we analyse large-scale multiomic data to uncover genetic factors underlying type 2 diabetes and blood pressure comorbidity. We curate 1304 independent single-nucleotide variants associated with type 2 diabetes and blood pressure, grouping them into five clusters related to metabolic syndrome, inverse type 2 diabetes/blood pressure risk, impaired pancreatic beta-cell function, higher adiposity, and vascular dysfunction. Colocalization with tissue-specific gene expression highlights significant enrichment in pathways related to thyroid function and fetal development. Partitioned polygenic scores derived from these clusters improve risk prediction for type 2 diabetes/hypertension comorbidity, identifying individuals with more than twice the usual susceptibility. These results reveal a mechanistically heterogeneous genetic architecture shared between type 2 diabetes and blood pressure, enhancing comorbidity risk prediction. Partitioned polygenic risk scores offer a promising approach for early risk stratification, personalised prevention, and improved management of these interconnected conditions.
Authors
- Bart Staels (ORCID: https://orcid.org/0000-0002-3784-1503)
- Liudmila Zudina (ORCID: https://orcid.org/0000-0001-8248-9601)
- Amna Khamis (ORCID: https://orcid.org/0000-0003-1709-304X)
- Amélie Bonnefond (ORCID: https://orcid.org/0000-0001-9976-3005)
- Vincent Pascat (ORCID: https://orcid.org/0000-0002-6227-8812)
- Lucas Maurin (ORCID: https://orcid.org/0009-0004-8607-4146)
- P Froguel
- Igor Pupko (ORCID: https://orcid.org/0000-0003-4093-1742)
- Ayşe Demirkan
- Marika A. Kaakinen
- Jared G. Maina
- P B Munroe
- Anna Ulrich
- François Pattou
- Inga Prokopenko
- Yevheniya Sharhorodska
Institutions
- Centre National de la Recherche Scientifique (FR)
- University of Helsinki (FI)
- Inserm (FR)
- Queen Mary University of London (GB)
- University of Ferrara (IT)
- Université de Lille (FR)
- Institut Pasteur de Lille (FR)
- University of Surrey (GB)
- Centre Hospitalier Universitaire de Lille (FR)
- Finland University (FI)
- Institute for Molecular Medicine Finland (FI)
- William Harvey Research Institute (GB)
- European Genomic Institute for Diabetes (FR)
- Imperial College London (GB)
Publication Details
- Journal
- Nature Communications
- Published
- 2026-02-09
- DOI
- https://doi.org/10.1038/s41467-025-67449-2
- Primary Topic
- Genetic Associations and Epidemiology
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- UK Research and Innovation
- British Academy
- Diabetes UK
- European Commission
- European Foundation for the Study of Diabetes
- Agence Nationale de la Recherche
- Novo Nordisk
- Conseil Régional Hauts-de-France