Moderation of the Effect of Adolescent-Onset Cannabis Use on Adult Psychosis by a Functional Polymorphism in the Catechol-O-Methyltransferase Gene: Longitudinal Evidence of a Gene X Environment Interaction

The moderation by the serotonin transporter gene of environmental adversity in the aetiology of mental illness: review and methodological analysis

“…[4][5][6][7] In the last five years, G Â E involving specific gene polymorphisms has been identified in animals 8,9 and humans. [10][11][12][13] Encouragingly, replications 14,15 and a positive metaanalysis 16 indicate that measuring environment improves the reliability of genetic research.…”

An Experimental Study of Catechol-O-Methyltransferase Val158Met Moderation of Δ-9-Tetrahydrocannabinol-Induced Effects on Psychosis and Cognition

“…This finding is relevant, as schizophrenia is associated with severe cognitive deficits that are also present, to a lesser degree, in the healthy first-degree relatives of patients (Krabbendam et al, 2001) who, compared to the general population, have a 10 times higher risk to develop schizophrenia (Kendler and Diehl, 1993). A first clue to the genes controlling abnormal sensitivity to the psychosis-inducing effects of cannabis was provided in a recent study by Caspi and colleagues, who showed that a functional polymorphism in the catechol-O-methyltransferase (COMT) gene moderated the risk to develop adult psychotic disorder following cannabis use in adolescence (exposure rate of 26% in the sample examined; Caspi et al, 2005). For individuals homozygous for the COMT Valine (Val) allele, the relative risk to develop psychotic illness after cannabis exposure was 10.9, whereas in individuals homozygous for the COMT Methionine (Met) allele, this risk was only 1.1.…”

“…Increased COMT activity may result in a combination of (i) reduced dopamine neurotransmission in the prefrontal cortex, hypothesized to result in poorer performance of frontally mediated cognitive tasks, in particular working memory and attention (Egan et al, 2001;Meyer-Lindenberg et al, 2005;Rosa et al, 2004) and (ii) increased levels of meso-limbic dopamine signaling hypothesized to result in increased risk for delusions and hallucinations, the core symptoms of psychosis (Akil et al, 2003;Bilder et al, 2004). The work to date therefore suggests that COMT genotype, psychometric psychosis liability, and being a patient with a psychotic disorder moderate the effect of cannabis on psychosis outcomes in the community (Caspi et al, 2005;Henquet et al, 2005a) and that differential sensitivity to cannabis not only involves the positive symptoms of psychosis, but also cognition, in particular memory (D'Souza et al, 2005). It is unlikely that the moderating effects of psychometric psychosis liability and COMT on the association between cannabis and expression of psychosis represent one and the same underlying mechanism, because psychometric psychosis liability is strongly associated with psychotic disorder whereas recent systematic reviews show only weak evidence of an association between COMT genotype and psychotic disorders (Fan et al, 2005;Munafo et al, 2005).…”

Investigation of the COMT Val158Met variant association with age of onset of psychosis, adjusting for cannabis use

“…These results echo the investigation of rs4680 in the Dunedin birth cohort study, with the Val/Val genotype being the at risk genotype for a psychotic disorder in Caucasians (Caspi et al., 2005). Our study had similarities to the Dunedin study, for example, the majority of our patients had a schizophrenia spectrum disorder, and the association described in the former was with schizophreniform disorder.…”

“…(2005) reported that a functional variant (rs4680, a G>A substitution that results in a valine to methionine substitution at amino acid codon 158) in the COMT gene encoding the enzyme catechol‐ O ‐methyltransferase (COMT) was associated with increased risk of schizophreniform disorder at age 26 years for those with a history of adolescent cannabis use (Caspi et al., 2005). The risk genotype was Val/Val (OR 10.9, CI 2.2–54.1), with the Val/Met being associated with a lesser degree of risk (OR 2.5, CI 0.78–8.2).…”