The effect of childhood maltreatment and cannabis use on adult psychotic symptoms is modified by the COMT Val¹⁵⁸Met polymorphism

Background: Cannabis use and childhood maltreatment are independent risk factors for the development of psychotic symptoms. These factors have been found to interact in some but not all studies. One of the reasons may be that childhood maltreatment and cannabis primarily induce psychotic symptoms in genetically susceptible individuals. In this context, an extensively studied psychosis vulnerability gene is catechol-methyl-transferase (COMT). Therefore, we aimed to examine whether the COMT Val¹⁵⁸Met polymorphism (rs4680) moderates the interaction between childhood maltreatment and cannabis use on psychotic symptoms in the general population. Method: The discovery sample consisted of 918 individuals from a cross-sectional study. For replication we used an independent sample of 339 individuals from the general population. Results: A significant three-way interaction was found between childhood maltreatment, cannabis use, and the COMT genotype (rs4680) in the discovery sample (P = 0.006). Val-homozygous individuals displayed increased psychotic experiences after exposure to both cannabis use and childhood maltreatment compared to Met-heterozygous and Met-homozygous individuals. Supportive evidence was found in the replication sample with similar effect and direction even though the results did not reach statistical significance (P = 0.25). Conclusions: These findings suggest that a functional polymorphism in the COMT gene may moderate the interaction between childhood maltreatment and cannabis use on psychotic experiences in the general population. In conclusion, the COMT Val¹⁵⁸Met polymorphism may constitute a genetic risk factor for psychotic symptoms in the context of combined exposure to childhood maltreatment and cannabis use.