Polygenic Predisposition, Multifaceted Family Protection, and Mental Health Development from Middle to Late Adulthood: A National Life Course Gene–Environment Study

Depression is one of the most prevalent mental health conditions in middle and late adulthood, contributing substantially to morbidity, mortality, and reduced quality of life. However, limited research has examined the mechanisms linking genetic predisposition and early protective environments to long-term mental health trajectories. Guided by a life course health development perspective, this study investigated how depression polygenic scores (G) and protective childhood family environments (E) interplay to shape depressive symptom trajectories from mid- to late adulthood. We analyzed longitudinal data of 14 waves from the Health and Retirement Study (1994–2020; N = 4817), estimating linear mixed-effects models of depressive symptoms using the validated CES-D scale. Early protective environments were measured by indicators of family structure stability, non-abusive and substance-free parenting, positive parent–child relationships, and parental support. Results showed that genetic predisposition and protective family environments jointly influence depression trajectories across the life course. Specifically, individuals with both low genetic risk and high environmental protection had the lowest depressive symptoms over time. Importantly, when only one favorable factor was present, protective family environments offered a stronger lifelong benefit than low genetic risk. These findings extend prior research by demonstrating that supportive childhood environments can mitigate genetic vulnerability, shaping healthier long-term mental health trajectories. This work underscores the need for early family-based interventions to reduce depression risk, enhance resilience, and promote longevity.