Background Individuals with severe mental illness (SMI), including schizophrenia and bipolar disorder, have elevated rates of physical health conditions, leading to increased morbidity and mortality. While environmental factors such as adverse effects of medication and lifestyle changes contribute to this burden, the role of genetic liability to physical health conditions remains underexplored. We assessed whether genetic risk for physical health conditions influences comorbidities in individuals with SMI and compared these effects to those observed in the general population. Methods We utilized data from two SMI cohorts from the UK: CardiffCOGS (n=721) and the National Centre for Mental Health (NCMH; n=1011). We tested whether polygenic risk scores (PRS) for six physical health conditions (high cholesterol, type 2 diabetes, hypertension, asthma, heart disease, and rheumatoid arthritis) were associated with having the corresponding condition in those with SMI. Models were adjusted for demographic and clinical covariates. Associations between psychiatric PRSs (schizophrenia, bipolar disorder, major depressive disorder, and ADHD) and presence of physical comorbidities were also evaluated. Results PRS for physical health conditions were associated with the presence of the corresponding conditions in SMI cohorts, with effect sizes comparable to those reported in the general population. Adjustments for environmental factors had minimal impact on these associations. Psychiatric PRS showed weaker and less consistent associations with physical comorbidities. Discussion This study provides robust evidence supporting the role of genetic risk in the development of common physical health conditions in individuals with SMI. Our findings indicate that the occurrence of physical health comorbidities was much more strongly associated with genetic liability to physical health conditions, than with psychiatric genetic liability. The genetic risk for physical health conditions contributes additively to environmental and clinical factors in driving comorbidities among individuals with SMI. These findings indicate there would be value in incorporating genetic risk information into predictive algorithms for physical health comorbidities in those with SMI, and that PRS should be included in research studies developing and validating such algorithms.

MJO, MCOD, and JTRW are supported by a collaborative research grant from Takeda Pharmaceuticals Ltd. for a project unrelated to work presented here. AFP, MJO, MCOD, and JTRW also reported receiving grants from Akrivia Health for a project unrelated to this submission. Takeda and Akrivia Health played no part in the conception, design, implementation, or interpretation of this study.

The National Centre for Mental Health (NCMH) is a collaboration between Cardiff, Swansea and Bangor Universities and is funded by Welsh Government through Health and Care Research Wales. This study was supported by the European Union Horizon 2020 program (REALMENT; Grant No. 964874). The overall research was also supported by grants from the Medical Research Council to Cardiff University: Program (MR/P005748/1, MR/Y004094/1), Project (MR/L011794/1, MC_PC_17212) and the Brain and Genomics Hub of the Mental Health Platform (MR/Z503745/1). We acknowledge the support of the Supercomputing Wales project, partly funded by the European Regional Development Fund (ERDF) via the Welsh Government. The funders had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

NCMH was approved by the Health Research Authority and Wales Research Ethics Committee (REC) (REC reference: 16/WA/0323), and CardiffCOGS by the NHS REC (REC reference: 07/WSE03/110). All participants provided written informed consent.

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All data produced in the present study are available upon reasonable request to the authors