Polygenic scores in the study of gene–environment interplay and stress-related psychopathology

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Abstract
Polygenic scores (PGS) have become valuable tools for quantifying genetic liability to complex mental disorders. This review discusses the application of PGS in gene–environment interaction (GxE) research, focusing on depression and stress-related phenotypes. We synthesize evidence from studies testing whether genetic risk, as indexed by PGS, moderates the impact of environmental exposures, particularly stressful life events (SLEs), on psychological outcomes. Findings from large-scale population studies lend partial support to the diathesis–stress framework, with significant GxE effects observed between polygenic risk for depression and various stressors. Individuals with higher genetic liability tend to be more vulnerable to the adverse effects of stress, though effect sizes are typically modest. Some studies report robust interactions, whereas others find independent main effects of genes and environment without meaningful moderation. We further review genome-wide interaction studies (GWIS) aiming to identify variants underlying stress sensitivity and emerging research employing PGS to predict psychotherapy response. Despite methodological advances, the limited variance explained by current PGS constrains their immediate translational value. Overall, we outline both the promise and current limitations of PGS-based GxE approaches and highlight opportunities for improving their utility in elucidating how genetic predisposition and environmental adversity jointly shape risk for mental disorders.

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