Modifiable risk factors and risk of schizophrenia and bipolar disorder across severities of genetic risk

Schizophrenia (SCZ) and bipolar disorder (BD) are severe, globally prevalent mental illnesses, influenced by genetic and modifiable risk factors. The brain care score (BCS) is a validated tool comprising 12 modifiable factors across physical, lifestyle, and social-emotional domains, each linked to brain health. This study examines how BCS relates to SCZ or BD risk across different genetic risk levels, quantified by polygenic risk scores (PRS).

Using UK Biobank data, we calculated BCS and PRS scores, and identified incident SCZ and BD cases. Cox proportional hazards models evaluated associations between BCS and SCZ or BD risk. Interaction and stratified analyses assessed how this association varies across genetic risk levels. Contributions of BCS domains were also evaluated.

Among 299,665 participants, 331 SCZ and 787 BD cases were identified over a median 13.7-year follow-up. In low-PRS individuals, higher BCS significantly reduced SCZ risk, particularly in lifestyle (HR = 0.87, P = 0.027) and social-emotional domains (HR = 0.47, P < 0.001). In high-PRS individuals, no overall BCS-SCZ association was observed, though the social-emotional domain remained protective (HR = 0.56, P < 0.001). For BD, low-PRS groups showed stronger BCS protection, especially in lifestyle (HR = 0.91, P = 0.017) and social-emotional domains (HR = 0.44, P < 0.001). In high-PRS groups, BCS protection was attenuated, but remained significant in the social-emotional domain (HR = 0.50, P < 0.001). Sensitivity analysis supported these findings.

Improving lifestyle and social-emotional health can significantly reduce SCZ and BD risk, with effects influenced by genetic risk. Enhancing social emotional health provides protective effects across all genetic risk levels, highlighting it as a key preventive measure.