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Gene-environment interplay between cannabis and psychosis.

ABSTRACT: Cannabis use is considered a contributory cause of schizophrenia and psychotic illness. However, only a small proportion of cannabis users develop psychosis. This can partly be explained by the amount and duration of the consumption of cannabis and by its strength but also by the age at which individuals are first exposed to cannabis. Genetic factors, in particular, are likely to play a role in the short- and the long-term effects cannabis may have on psychosis outcome. This review will therefore consider the interplay between genes and exposure to cannabis in the development of psychotic symptoms and schizophrenia. Studies using genetic, epidemiological, experimental, and observational techniques will be discussed to investigate gene-environment correlation gene-environment interaction, and higher order interactions within the cannabis-psychosis association. Evidence suggests that mechanisms of gene-environment interaction are likely to underlie the association between cannabis and psychosis. In this respect, multiple variations within multiple genes--rather than single genetic polymorphisms--together with other environmental factors (eg, stress) may interact with cannabis to increase the risk of psychosis. Further research on these higher order interactions is needed to better understand the biological pathway by which cannabis use, in some individuals, may cause psychosis in the short- and long term.

SUBMITTER: Henquet C

PROVIDER: S-EPMC2632498 | biostudies-literature | 2008 Nov

REPOSITORIES: biostudies-literature

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Gene-environment interplay between cannabis and psychosis.

Henquet Cécile C Di Forti Marta M Morrison Paul P Kuepper Rebecca R Murray Robin M RM

Schizophrenia bulletin 20080822 6

Cannabis use is considered a contributory cause of schizophrenia and psychotic illness. However, only a small proportion of cannabis users develop psychosis. This can partly be explained by the amount and duration of the consumption of cannabis and by its strength but also by the age at which individuals are first exposed to cannabis. Genetic factors, in particular, are likely to play a role in the short- and the long-term effects cannabis may have on psychosis outcome. This review will therefor ...[more]

PMID: 18723841

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Project description:IntroductionResearch data show the impact of the endocannabinoid system on psychosis through its neurotransmission homeostatic functions. However, the effect of the endocannabinoid system genetic variability on the relationship between cannabis use and psychosis has been unexplored, even less in first-episode patients. Here, through a case-only design, we investigated the effect of cannabis use and the genetic variability of endocannabinoid receptors on clinical and cognitive outcomes in first-episode psychosis (FEP) patients.MethodsThe sample comprised 50 FEP patients of European ancestry (mean age (sd) = 26.14 (6.55) years, 76% males), classified as cannabis users (58%) or cannabis non-users. Two Single Nucleotide Polymorphisms (SNP) were genotyped at the cannabinoid receptor type 1 gene (CNR1 rs1049353) and cannabinoid receptor type 2 gene (CNR2 rs2501431). Clinical (PANSS, GAF) and neuropsychological (WAIS, WMS, BADS) assessments were conducted. By means of linear regression models, we tested the main effect of cannabis use and its interaction with the polymorphic variants on the clinical and cognitive outcomes.ResultsFirst, as regards cannabis effects, our data showed a trend towards more severe positive symptoms (PANSS, p = 0.05) and better performance in manipulative abilities (matrix test-WAIS, p = 0.041) among cannabis users compared to non-users. Second, concerning the genotypic effects, the T allele carriers of the CNR1 rs1049353 presented higher PANSS disorganization scores than CC homozygotes (p = 0.014). Third, we detected that the observed association between cannabis and manipulative abilities is modified by the CNR2 polymorphism (p = 0.022): cannabis users carrying the G allele displayed better manipulative abilities than AA genotype carriers, while the cannabis non-users presented the opposite genotype-performance pattern. Such gene-environment interaction significantly improved the overall fit of the cannabis-only model (Δ-R2 = 8.4%, p = 0.019).DiscussionDespite the preliminary nature of the sample, our findings point towards the role of genetic variants at CNR1 and CNR2 genes in the severity of the disorganized symptoms of first-episode psychosis and modulating cognitive performance conditional to cannabis use. This highlights the need for further characterization of the combined role of endocannabinoid system genetic variability and cannabis use in the understanding of the pathophysiology of psychosis.

Project description:Abstract Background Cannabis use, particularly regular use in adolescence, is associated with an increased risk of developing psychosis earlier. An earlier age of onset negates the protective effects of more mature psychosocial and individual variables, thus the potential for worse outcomes. Genetic variations in this relationship are important to understand as this will allow not only a better understanding of the biological interaction of cannabis and psychosis, but would inform future genetic approaches to risk identification as well. We uniquely examined the mediation of this association (gene x cannabis associations in age of onset of psychosis (AoP)) in 3 genetic variants which, while each have been examined separately, not in combination in the same population. We examined: 1) COMT Val158Met (rs4680) 2) BDNF Val66Met (rs6265) and 3) the AKT1 variant rs2494732. Methods 168 subjects with a diagnosis of psychosis were recruited from 2 sites in Canada, Edmonton Alberta and Halifax Nova Scotia. Cannabis use data (age at first and regular use) were collected using an electronic self-report survey (to address potential minimization of use to a researcher) and saliva samples were used for genotyping. Kaplan-Meier and Cox regression analyses were used to study the gene – cannabis effects. Results In those who had used cannabis, first use of cannabis prior to 20 years of age was associated with earlier AoP (p = .005). In those who used cannabis before age 20, rs4680 had a trend level association with AoP (log rank test: p=0.0617). A trend effect for an rs6265 x gender interaction (HR = 2.08, p = 0.067) on AoP, controlling for regular cannabis use was also observed. No association was observed between rs2494732 and rs6265 - rs2494732 interaction, and AoP. Discussion The trends in our associations are in keeping with previous literature, however our gender analyses underscores the importance of examining sex and gender as we further move towards risk identification for the cannabis and psychosis interaction. Our results also suggest that not all genetic variants associated with psychosis are involved with the association between cannabis and AoP. While our results offer support for future research in this area, larger sample sizes are required to test the gene-cannabis-AoP relationship.

Project description:Neither environmental nor genetic factors are sufficient to predict the transdiagnostic expression of psychosis. Therefore, analysis of gene-environment interactions may be productive.A meta-analysis was performed using papers investigating the interaction between cannabis use and catechol-O-methyl transferase (COMT) polymorphism Val158Met (COMTVal158Met).PubMed, Embase, PsychInfo.All observational studies assessing the interaction between COMTVal158Met and cannabis with any psychosis or psychotic symptoms measure as an outcome.A 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".For 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).A substantial part of the included studies used the case-only design, which has lower validity and tends to overestimate true effects.The 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.

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Gene-environment interplay between cannabis and psychosis.

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Gene-environment interplay between cannabis and psychosis.

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