REVIEW article
Front. Psychiatry
Sec. Behavioral and Psychiatric Genetics
Polygenic Scores in the Study of Gene–Environment Interplay and Stress-Related Psychopathology
University of Luxembourg, Luxembourg, Luxembourg
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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.
Summary
Keywords
Depression, gene–environment interaction, Genome-wide interaction studies, GWIS, GxE, PGs, polygenic scores, SLES
Received
31 October 2025
Accepted
09 February 2026
Copyright
© 2026 Kouris and Kumsta. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Robert Kumsta
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