Gene?environment interplay in anhedonia and reward-related brain morphology and function

Psychiatric disorders are the consequence of complex interplay between genetic and environmental factors. Anhedonia, as a transdiagnostic symptom in multiple psychiatric disorders, has been linked to both genetic and environmental risk factors. However, the gene?environment interplay that contributes to anhedonia is poorly understood. The goal of this study was to investigate the associations between PRS-anhedonia and environmental risk exposures, and their interactions on phenotypic anhedonia and reward-related brain structure and function in two large population-based samples, UK Biobank and the ABCD study. We investigated gene?environment correlations and interactions in 19667 White European participants (55.30 � 7.49 years, 51.58% females) from UK Biobank and 9213 adolescents of diverse ancestries (9.90 � 0.62 years, 46.5% females) from the ABCD study separately. PRS-anhedonia was derived from an earlier genome-wide association study of state anhedonia. Many environmental risk factors such as parent depression and childhood trauma were included. Phenotypic anhedonia was assessed based on the subscale for depression in DSM-5. Brain characteristics included cortical thickness, surface area, cortical volume, sulcal depth, as well as brain activation during the Monetary Incentive Delay task and analyses were limited to priori regions of interest (seventeen reward-related brain structures). Spearman's rank correlation, logistic regression, linear regression and mixed linear regression were performed, with relevant covariates controlled for and supplementary analyses conducted for clarity. We found PRS-anhedonia was associated with multiple environmental exposures in the expected direction in both cohorts. Family conflict and school disengagement in the ABCD study significantly moderated the effect of PRS-anhedonia on the probability of parent-reported lifetime anhedonia. In addition, analyses on brain morphology and function found significant interactions of PRS-anhedonia with parent depression, adverse life events, family conflict, parent acceptance, and aggregate environmental risk scores. Interactive effects were found on surface area/ cortical volume/ functional activation in middle frontal cortex, cingulate cortex, caudate and pallium, among other reward- and non-reward-related brain structures, with detailed interaction patterns differing for environmental measures. These findings support the gene?environment interplay in psychiatry, especially effects of gene?environment interaction at the neurobiological level. Future efforts are needed to replicate these findings and to further understand the influence of environmental risk on genetic predispositions associated neurobiological vulnerability to mental disorders.