Combining polygenic risk scores to understand genetic liability to physical-mental health multimorbidity in UK BioBank
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Background
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 (PRS TRAIT ) and whether combining them could increase the proportion of variance in liability to ICM-MM explained by genetic variation.
Methods
We developed PRS TRAIT using PRS-CS and summary statistics from the largest trait-specific GWAS excluding UK Biobank (UKB). We evaluated PRS TRAIT 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 trained an elastic net in a 50% subsample to generate ICM-MM-PRS TRAIT : a weighted combination of PRS TRAIT targeting ICM-MM.
Results
The strongest associations were between ICM-MM and PRS TRAIT 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 PRS TRAIT . ICM-MM-PRS TRAIT retained five PRS TRAIT with stronger associations (OR=1.31, [95%CI 1.29–1.34]) than any PRS TRAIT in the validation sample.
Discussion
Combining several PRS explains more variance in ICM-MM liability than single-trait PRSs alone. ICM-MM-PRS TRAIT 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.
