BackgroundNeither environmental nor genetic factors are sufficient to predict the transdiagnostic expression of psychosis. Therefore, analysis of gene-environment interactions may be productive.ObjectiveA meta-analysis was performed using papers investigating the interaction between cannabis use and catechol-O-methyl transferase (COMT) polymorphism Val158Met (COMTVal158Met).Data sourcesPubMed, Embase, PsychInfo.Study eligibility criteriaAll observational studies assessing the interaction between COMTVal158Met and cannabis with any psychosis or psychotic symptoms measure as an outcome.Study appraisal and synthesis methodsA meta-analysis was performed using the Meta-analysis of Observational Studies in Epidemiology guidelines and forest plots were generated. Thirteen articles met the selection criteria: 7 clinical studies using a case-only design, 3 clinical studies with a dichotomous outcome, and 3 studies analysing a continuous outcome of psychotic symptoms below the threshold of psychotic disorder. The three study types were analysed separately. Validity of the included studies was assessed using "A Cochrane Risk of Bias Assessment Tool: for Non-Randomized Studies of Interventions".ResultsFor case-only studies, a significant interaction was found between cannabis use and COMTVal158Met, with an OR of 1.45 (95% Confidence Interval = 1.05–2.00; Met/Met as the risk genotype). However, there was no evidence for interaction in either the studies including dichotomous outcomes (B = -0.51, 95% Confidence Interval -1.72, 0.70) or the studies including continuous outcomes (B = -0.04 95% Confidence Interval -0.16–0.08).LimitationA substantial part of the included studies used the case-only design, which has lower validity and tends to overestimate true effects.ConclusionThe interaction term between cannabis use and COMTVal158Met was only statistically significant in the case-only studies, but not in studies using other clinical or non-clinical psychosis outcomes. Future additional high quality studies might change current perspectives, yet currently evidence for the interaction remains unconvincing.

Purpose Whilst childhood trauma (CT) is a known risk factor across the spectrum of psychosis expression, little is known about possible interplay with genetic liability. Methods The TwinssCan Study collected data in general population twins, focussing on expression of psychosis at the level of subthreshold psychotic experiences. A multilevel mixed-effects linear regression analysis was performed including 745 subjects to assess the interaction between genetic liability and CT. The Symptom Checklist-90 (SCL-90-R) score of the cotwin was used as an indirect measure of genetic liability to psychopathology, while the Childhood Trauma Questionnaire Short-Form (CTQ-SF) was used to assess CT in the domains of physical, emotional and sexual abuse, as well as physical and emotional neglect. The Community Assessment of Psychic Experience (CAPE) questionnaire was used to phenotypically characterize psychosis expression. Results In the model using the CAPE total score, the interaction between CT and genetic liability was close to statistical significance (χ 2 = 5.6, df = 2, p = 0.06). Analyses of CAPE subscales revealed a significant interaction between CT and genetic liability (χ 2 = 8.8, df = 2, p = 0.012) for the CAPE-negative symptoms subscale, but not for the other two subscales (i.e. positive and depressive). Conclusion The results suggest that the impact of CT on subthreshold expression of psychosis, particularly in the negative subdomain, may be larger in the co-presence of significant genetic liability for psychopathology.