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

BackgroundInternalising 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. MethodsWe 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 trained an elastic net in a 50% subsample to generate ICM-MM-PRSTRAIT: a weighted combination of PRSTRAIT targeting ICM-MM. ResultsThe 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 validation sample. DiscussionCombining 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.