Genetic Variation Underlying Psychosis-inducing Effects of Cannabis: Critical Review and Future Directions
Jeroen Decoster, Jim van Os, Inez Myin-Germeys, Marc De Hert and Ruud van Winkel
Affiliation: Dept. of Psychiatry and Psychology. Maastricht University Medical Centre, PO BOX 616 (location VIJV SN2), 6200 MD Maastricht. The Netherlands.
Cannabis use is associated with an increased risk for psychotic disorder, yet most cannabis users do not develop psychosis,
suggesting that other factors are also involved. This paper reviews the available evidence suggesting that differential sensitivity to the
psychosis-inducing effects of cannabis may be related to underlying genetic liability. There is robust evidence that persons at psychometric
risk for psychosis are most vulnerable to display psychotic symptoms subsequent to the use of cannabis. Multiple studies have also
found that persons at familial risk for psychosis have an increased sensitivity to the effects of cannabis. Together, these findings support
the concept of a biological interaction between cannabis use and one’s underlying genetic vulnerability. At the molecular-genetic level,
however, few (if any) interactions have been consistently replicated, although a reported interaction with variation in AKT1 is promising
and deserves further follow-up. The apparent lack of consistent replication can be ascribed to problems of initial gene selection, statistical
power, a bias towards positive results and insufficient attempts at true replication, leading to the conclusion that increased sample sizes,
greater density of genetic markers and a stronger focus on true replication are necessary. The major challenge for molecular-genetic geneenvironment
interaction research will be to combine the agnostic detection of disorder-associated genetic variants from genome-wide
studies with the hypothesis-based approach from epidemiological and neurobiological studies. Possible strategies for future cannabis interaction
studies are discussed.
Keywords: Gene-environment interaction (GxE), psychotic disorder, cannabis, differential sensitivity, molecular genetics, Gene-Environment Wide Interaction Study (GEWIS), symptoms, replication, genetic markers, hypothesis-based approach.
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