Associations between lifestyle, genetic liability for severe mental illness and risk of incident somatic illnesses

People with severe mental illness (SMI), including schizophrenia (SCZ) and bipolar disorder (BD), show elevated risk for somatic conditions and premature mortality. Both genetic liability and modifiable lifestyle factors have been implicated in this comorbidity, yet large-scale studies examining their independent and combined effects across multiple somatic conditions are lacking. We therefore examined whether modifiable lifestyle factors (i.e. smoking, alcohol intake, diet, and exercise) and polygenic risk scores (PRS) for SCZ and BD are associated with the risk of developing somatic illnesses. Data were drawn from 315,313 unrelated individuals in the UK Biobank cohort, with a median follow up of 14 years. Cox proportional hazards models were used to estimate the independent, joint, and interaction effects of PRS-SCZ and PRS-BD and lifestyle factors on the incidence of nine chronic somatic illnesses. Healthy lifestyle was associated with lower risks of type 2 diabetes (T2D), cardiovascular disease (CVD), dementia, rheumatoid arthritis, asthma, chronic liver disease (CLD), and cancer (HRs ranging from 0.43 to 0.80). In addition, higher PRS for SCZ was associated with increased risks of asthma and dementia and lower risk of T2D, while higher PRS for BD was associated with increased risk of T2D. Moreover, likelihood ratio tests confirmed that PRS-SCZ and PRS-BD each contribute independent information to the joint Cox model for T2D, indicating that the opposing directions of their associations with T2D risk are not driven by shared genetic variance between the two scores. Finally, individuals with a healthy lifestyle consistently showed lower risks of CLD, T2D, CVD, and dementia across genetic risk strata; however, no significant additive interaction was observed between genetic risk and lifestyle factors. In conclusion, these findings indicate that genetic liabilities for SCZ and BD show outcome-specific associations with somatic illnesses, while a healthy lifestyle is associated with lower somatic illness risk regardless of genetic risk level.