Combining polygenic risk scores to understand genetic liability to physical-mental health multimorbidity in UK Biobank

Stow, Daniel, Tsang, Ruby S. M., Katzourou, Ioanna K., Underwood, Jack F. G. ORCID: https://orcid.org/0000-0003-1731-6039, Holmans, Peter ORCID: https://orcid.org/0000-0003-0870-9412 and van den Bree, Marianne B. M. ORCID: https://orcid.org/0000-0002-4426-3254 2026. Combining polygenic risk scores to understand genetic liability to physical-mental health multimorbidity in UK Biobank. Human Molecular Genetics 35 (7) , ddag012. 10.1093/hmg/ddag012

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Abstract

Background: Multimorbidity, also known as multiple long-term conditions, is a major public health concern. Internalising and CardioMetabolic MultiMorbidity (ICM-MM) is a common form of mental-physical health multimorbidity, yet its genetic predisposition is largely unknown. We examined the polygenic nature of ICM-MM by assessing single trait-specific polygenic risk scores (PRSTRAIT) and whether combining them could increase the proportion of variance in liability to ICM-MM explained by genetic variation. Methods: We developed PRSTRAIT using PRS-CS and summary statistics from the largest trait-specific GWAS excluding UK Biobank (UKB). We evaluated PRSTRAIT on ICM-MM risk in 206 452 UKB participants (n = 39 311 (19.0%) with ICM-MM) using logistic regression adjusted for gender and 10 genetic principal components, defining ICM-MM as lifetime occurrence of: ≥1 internalising (depression, anxiety, somatoform disorder) traits AND ≥ 1 cardiometabolic traits (type 2 diabetes, obesity, hypertension, dyslipidemia, chronic kidney disease). We used elastic net regression in a 50% training sample to generate ICM-MM-PRSTRAIT: a weighted combination of PRSTRAIT targeting ICM-MM. Results: The strongest associations were between ICM-MM and PRSTRAIT for depression and type 2 diabetes—both odds ratios (OR) 1.18, [95% confidence interval (CI) 1.17–1.20] per standard deviation increase in PRSTRAIT. ICM-MM-PRSTRAIT retained five PRSTRAIT, with stronger associations (OR = 1.31, [95%CI 1.29–1.34]) than any PRSTRAIT in the testing sample. Discussion: Combining several PRS explains more variance in ICM-MM liability than single-trait PRSs alone. ICM-MM-PRSTRAIT is a measure of genetic risk that could be used to examine premorbid stages of ICM-MM in external and youth cohorts, supporting awareness of earlier presentation and potentially avoidance or intervention.

Item Type:	Article
Date Type:	Published Online
Status:	Published
Schools:	Schools > Medicine
Additional Information:	Full author list available at DOI
Publisher:	Oxford University Press
ISSN:	0964-6906
Date of First Compliant Deposit:	6 May 2026
Date of Acceptance:	10 February 2026
Last Modified:	06 May 2026 11:17
URI:	https://orca.cardiff.ac.uk/id/eprint/186820

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