Vulnerability to cannabis-related psychosis: association with frequency and potency of cannabis use, and interaction with genes regulating dopamine signalling

Abstract

BackgroundEpidemiological studies implicate cannabis use as a risk factor for psychosis. Daily users of high potency types of cannabis have the highest risk of developing psychotic disorders. Nevertheless, only a small proportion of users develop the illness, suggesting an underlying genetic susceptibility to the psychogenic effect. This study set out to assess whether three candidate genes that affect dopamine signalling contribute to this vulnerability. MethodsDNA and data on history of cannabis use were obtained from 333 patients with their first episode of psychosis and 317 healthy population controls. We built a measure of pattern of use from frequency of use and type of cannabis used (low potency, hash; high potency, skunk). We selected for genotyping three genetic variants that regulate dopamine signalling: the 3′-untranslated region (3′-UTR) 9/10 repeat for SLC6A3, COMT Val156Met single nucleotide polymorphism (SNP), which affects breakdown of dopamine, and the AKT1 rs2494732 (C/T) SNP, which affects post-D2-receptor-dependent signalling. The average allele count scores for the postulated minor/risk alleles (AKT1*C, COMT *Val, DAT1*9) were collapsed into three groups (scores 0, 1, and 2) termed the oligogenic score. Adjusted multivariate logistic regression tested for the interaction between oligogenic score and pattern of cannabis use. FindingsThe overall interaction between the oligogenic score and the measure of frequency and type of cannabis use in modifying the risk of psychosis was not significant (likelihood ratio test 13·44, p=0·062). Among never users and those who used low-potency cannabis, there was no significant change in risk of psychosis according to oligogenic score. However, among users of high-potency cannabis less than daily, those with an oligogenic score of 2 had a three-fold higher risk of psychosis than did those with a score of 0 (odds ratio [OR] 3·33, 95% CI 1·7–6·2). Furthermore, daily users of high-potency cannabis with scores of 1 and 2 had, respectively, a six-fold (OR 6·1, 95% CI 1·2–36·2) and eight-fold (OR 7·9, 95% CI 1·8–22·1) increased risk of psychosis compared with those with a score of 0. InterpretationThese findings suggest that individual susceptibility to the psychosis-inducing effect of cannabis use could be conditional on the pattern of use and interaction with genetic variants that regulate dopamine signalling. FundingNational Institute of Health Research, South London and Maudsley NHS Foundation Trust, The Psychiatry Research Trust, Maudsley Charity research fund, European Community's Seventh Framework Program.