| Title: | Combining polygenic risk scores to understand genetic liability to physical-mental health multimorbidity in UK Biobank |
| Journal: | Human Molecular Genetics |
| Published: | 15 Apr 2026 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/42044059/ |
| DOI: | https://doi.org/10.1093/hmg/ddag012 |
Publication 17990
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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.</p>
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.</p>
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.</p>
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.</p>
17 Keywords
- Aged
- Biological Specimen Banks
- Diabetes Mellitus, Type 2
- Female
- Genetic Predisposition to Disease
- Genetic Risk Score
- Genome-Wide Association Study
- Humans
- Male
- Mental Health
- Middle Aged
- Multifactorial Inheritance
- Multimorbidity
- Obesity
- Risk Factors
- UK Biobank
- United Kingdom
37 Authors
- Daniel Stow
- Ruby S M Tsang
- Ioanna K Katzourou
- Jack F G Underwood
- M B M Marianne van den Bree
- G George Kirov
- M J Michael Owen
- J T R James Walters
- P A Peter Holmans
- J Jane Lynch
- I K Ioanna Katzourou
- D A David van Heel
- S Sarah Finer
- D Daniel Stow
- G M Golam Khandakar
- N J Nicholas Timpson
- J A A John MacLeod
- J P Julie Clayton
- R S M Ruby Tsang
- J Jane Sprackman
- S Shahid Khan
- I A Inês Barroso
- R A Rupert Payne
- M Mark Mon-Williams
- M L Megan Wood
- Nabila Ali
- H C Hilary Martin
- T Thomas Werge
- A Andrés Ingason
- Lam Opal Huang
- Morteza Vaez
- Peter Holmans
- Inês Barroso
- Hilary Martin
- Marianne B M van den Bree
- Sarah Finer
- Nicholas J Timpson
1 Application
| Application ID | Title |
|---|---|
| 79704 | Physical and mental health multimorbidity across the lifespan (LIfespaN multimorbidity research Collaborative: LINC). |
Enabling scientific discoveries that improve human health