Polygenic depression risk, childhood parental substance abuse, and G×E interaction in divergent depression trajectories from middle to late adulthood.

OBJECTIVE: National life course studies examining the interplay between genetic risk, parental substance abuse, and lifelong depression are lacking, despite the need for individualized interventions. This study investigates how the interaction between polygenic risk for depression and childhood exposure to parental substance abuse is associated with depression trajectories from mid-to late adulthood.

METHOD: Data from 14 waves (1994-2020) of the Health and Retirement Study included 7512 participants of European ancestry aged 51-90 years. Primary predictors were childhood parental substance abuse, polygenic depression-risk scores, and their interaction. Growth-curve linear mixed models estimated depressive symptoms (Center for Epidemiologic Studies-Depression [CES-D] scale, standardized) trajectories, and logistic mixed-effects models applied to binary probable clinical depression.

RESULTS: Higher polygenic risk scores were associated with elevated depressive symptoms (β = 0.074; 95% CI = 0.058-0.090) and greater odds of probable clinical depression (OR = 1.38; 95% CI = 1.28-1.49). Childhood parental substance abuse was also associated with higher depression risk (OR = 1.61; 95% CI = 1.32-1.96). A significant gene × environment interaction revealed that the adverse effect of parental substance abuse on depressive trajectories was amplified among individuals with high genetic risk (P < 0.05), particularly in the mid-fifties and mid-sixties.

CONCLUSIONS: Findings underscore the importance of considering both genetic susceptibility and early-life adversity in understanding lifelong depression. Individualized prevention and intervention strategies may be critical for those with elevated genetic risk who experienced parental substance abuse, with potential to mitigate the progression of depression into later life. Since our analyses were restricted to participants of European genetic ancestry to minimize population stratification in polygenic score estimation, this may limit the generalizability of findings to other ancestral groups.