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Examining the independent and joint effects of molecular genetic liability and environmental exposures in schizophrenia: results from the EUGEI study
Schizophrenia is a heritable complex phenotype associated with a background risk involving multiple common genetic variants of small effect and a multitude of environmental exposures. Early twin and family studies using proxyâgenetic liability measures suggest geneâenvironment interaction in the etiology of schizophrenia spectrum disorders, but the molecular evidence is scarce. Here, by analyzing the main and joint associations of polygenic risk score for schizophrenia (PRSâSCZ) and environmental exposures in 1,699 patients with a diagnosis of schizophrenia spectrum disorders and 1,542 unrelated controls with no lifetime history of a diagnosis of those disorders, we provide further evidence for geneâenvironment interaction in schizophrenia. Evidence was found for additive interaction of molecular genetic risk state for schizophrenia (binary mode of PRSâSCZ above 75% of the control distribution) with the presence of lifetime regular cannabis use and exposure to earlyâlife adversities (sexual abuse, emotional abuse, emotional neglect, and bullying), but not with the presence of hearing impairment, season of birth (winter birth), and exposure to physical abuse or physical neglect in childhood. The sensitivity analyses replacing the a priori PRSâSCZ at 75% with alternative cutâpoints (50% and 25%) confirmed the additive interaction. Our results suggest that the etiopathogenesis of schizophrenia involves genetic underpinnings that act by making individuals more sensitive to the effects of some environmental exposures