Polygenic Scores and Environmental Factors in Psychiatric Disorders: Gene-Environment Interaction Analyses Using the iPSYCH Study.

Background: Psychiatric disorders represent a significant global health burden with complex etiologies involving both genetic and environmental factors. However, while the main effects of genetic and environmental factors are frequently studied, their interplay in shaping psychiatric disorder risk remains poorly understood. This study investigates the interaction between polygenic scores (PGS) as proxies for genetic risk and environmental factors in the risk of psychiatric disorders. Method: This study utilized the iPSYCH case-cohort sample (n = 141,265). Environmental factors, including region, urbanicity, parental socioeconomic status, parental age, parental psychiatric history and early-life exposures: autoimmune disease, brain injury, and central nervous system (CNS) infections, were obtained from Danish nationwide registers. Logistic regression was used to examine the effects of targeted disorder-specific PGSs, environmental factors and their interactions on psychiatric disorders. Analyses were adjusted for age, sex and ancestral principal components to account for population stratification. Results: Both PGS and environmental factors were associated with psychiatric disorders. We found limited evidence of gene-environment interactions across the investigated psychiatric disorders. Most interaction terms were small and not statistically significant, but a few remained significant. These included a smaller PGS association with attention deficit hyperactivity disorder in Southern Denmark compared with the Capital Region, a reduced PGS association with bipolar disorder in the medium and lowest parental income groups compared with the highest income group, and a weaker PGS association with major depressive disorder in individuals with parental psychiatric history compared with those without such history. In contrast, a larger PGS association with schizophrenia was observed in the paternal age group 31-35 years compared with the 26-30 years reference group, and a stronger PGS association with anorexia nervosa in North Denmark compared with the Capital Region. Conclusion: Genetic liability for psychiatric disorders, captured through PGS, was associated with mental disorder risk across environmental contexts. Only a few gene-environment interactions were significant, and these were modest and mental disorder-specific. Overall, the findings highlight the difficulty of detecting robust gene-environment interactions and the need for studies of sufficient scale and statistical power to identify subtle gene-environment effects and improve understanding of psychiatric disorder etiology.