The predictive value of polygenic risk scores for depression in gene-environment interaction studies: a systematic review

Abstract Background According to the diathesis-stress model, genetic liability and environmental exposures interact in the pathogenesis of depression. Polygenic risk scores for depression (PRS D ) based on large-scale genome-wide association studies have opened new avenues for investigating gene-environment interaction (GxE) beyond candidate gene studies. To the best of our knowledge, this is the first systematic review of studies that have taken a polygenic score approach to study GxE interaction effects on depression phenotypes. Methods Based on a preregistered, systematic literature search according to PRISMA guidelines, 56 studies were considered for qualitative analysis. Respective studies investigated a broad range of adverse and protective environmental exposures across the lifespan, e.g., trauma, stressful life events, social environments and (un)healthy lifestyle factors, using cross-sectional and longitudinal designs. Results While most studies reported significant main effects of an individual’s PRS D and different environmental exposures on depression phenotypes, the overall evidence for GxE interactions was considerably heterogeneous. Findings of significant PRS D xE interactions mostly stem from large cohort studies comprising > 40000 participants, in particular, when recent environmental exposures were considered. Conclusion Two general conclusions can be drawn from this review. First, PRS D xE interactions, if at all, add a small amount of explained variance in depression phenotypes to the corresponding additive model and may thus require large samples to be reliably detected. Second, in a considerable number of studies, different environmental exposures were found to depend on an individual’s PRS D , indicating significant gene-environment correlation. We further discuss limitations, future directions and potential clinical relevance of PRSxE research in depression.