Genetics in Context: Social Factors Modify Polygenic Risk Across Multiple Cardiometabolic Diseases
Polygenic risk scores (PRS) are increasingly used for disease prediction, but whether their associations vary across social contexts remains poorly understood. Here, we leveraged the large and diverse All of Us cohort to examine interactions between PRS and social determinants of health (SDoH) across eight prevalent chronic diseases and developed disease-specific polysocial risk scores (PsRS). We found consistent evidence of SDoH modification of PRS-disease associations for cardiometabolic diseases, including type 2 diabetes, coronary heart disease and chronic kidney disease, with PRS associations attenuated among more socially vulnerable populations. Joint modeling of PsRS and PRS significantly improved case status prediction across all eight diseases and PsRS were predictive for most diseases in external cohorts. These findings demonstrate that social context modifies associations between genetic risk and disease and suggest that integrating genetic and social information can refine disease prediction across diverse populations.
Authors
- Genevieve L. Wojcik (ORCID: https://orcid.org/0000-0001-7206-8088)
- Alisa Knodle Manning (ORCID: https://orcid.org/0000-0003-0247-902X)
- LáShauntá M. Glover (ORCID: https://orcid.org/0000-0002-7721-8169)
- Laura M. Raffield (ORCID: https://orcid.org/0000-0002-7892-193X)
- Sarah C Hsu (ORCID: https://orcid.org/0000-0001-9823-9711)
- Luciana B. Vargas (ORCID: https://orcid.org/0000-0002-9074-2010)
- Farida S. Akhtari (ORCID: https://orcid.org/0000-0002-1089-4488)
- Megan M. Shuey (ORCID: https://orcid.org/0000-0003-2866-3562)
- Miriam S. Udler (ORCID: https://orcid.org/0000-0003-3824-9162)
- Iain R. Konigsberg (ORCID: https://orcid.org/0000-0001-7356-100X)
- SARA JANE CROMER (ORCID: https://orcid.org/0000-0002-4924-2049)
- Leslie A. Lange (ORCID: https://orcid.org/0000-0002-4220-6766)
- Josep Maria Mercader (ORCID: https://orcid.org/0000-0001-8494-3660)
- Michael D. Green (ORCID: https://orcid.org/0000-0002-4982-8154)
- Micah R. Hysong (ORCID: https://orcid.org/0000-0003-2460-4012)
- Michael I Love
- Alison Motsinger-Reif
Institutions
- Broad Institute (US)
- University of North Carolina at Chapel Hill (US)
- Johns Hopkins University (US)
- Duke University (US)
- University of Colorado System (US)
- Massachusetts General Hospital (US)
- National Institute of Environmental Health Sciences (US)
- Duke Medical Center (US)
- University of Colorado Anschutz Medical Campus (US)
- Vanderbilt University Medical Center (US)
Publication Details
- Journal
- medRxiv
- Published
- 2026-10-29
- DOI
- https://doi.org/10.64898/2026.10.27.26366625
- Primary Topic
- Genetic Associations and Epidemiology
- Type
- preprint
Funders
- National Science Foundation
- American Diabetes Association
- National Institutes of Health
- National Institute on Aging
- National Human Genome Research Institute