Exposure-wide association study-assisted identification of modifiable factors for depression prevention

Depression is a leading cause of disability worldwide, yet evidence on modifiable factors remains limited and fragmented. Using UK Biobank data, we comprehensively evaluated 218 modifiable factors across eight predefined domains and integrated polygenic risk scores to inform prevention. Among 290,278 participants (mean age 56.9 years; 47.4% male) followed for 14 years, 11,131 developed depression. We identified 154 significant modifiable factors across all eight domains, with the largest numbers observed in the health and medical history, blood assays, and lifestyles domains. Neuroticism, early depressive symptoms, poor health, and low income ranked highest. Mendelian randomization supported potential causal effects for 18 modifiable factors. Population attributable fractions suggested that up to 78.1% of cases could potentially be prevented through improvements across the eight modifiable domains, with the largest contributions from the psychosocial domain (19.3%), the health and medical history domain (16.2%), and the lifestyles domain (13.4%). Domain-level estimates were broadly consistent across genetic risk strata. Our findings highlight psychosocial support, healthy lifestyles, and chronic disease management as key strategies for depression prevention.