Summary

This sibling analysis found that genetic variation in AKT1 affects risk of psychosis associated with cannabis use. The authors hypothesize that signaling downstream from dopamine D2 receptor may be affected, potentially explaining why antipsychotics are less effective in this population.

Design

• N=801 patients with psychosis and their unaffected siblings (n=740) participated.
• 152 SNPs in 42 candidate genes were examined for moderation of association between psychosis symptoms and recent cannabis use.
• Psychosis measured by Structured Interview for Schizotypy–Revised (SIS-R), assessing signs and symptoms such as flatness of affect, magical ideation, illusions, referential thinking.
• Cannabis use assessed by urine testing.
• Setting: The Netherlands and Flanders, Belgium.
• Main outcome measure: significant interaction between any SNP and cannabis use, and selective case-only, case-sibling, and case-control analysis.

Results

• 7.6% of unaffected sibling group screened positive for recent cannabis use.
• Recent cannabis use was significantly associated with psychosis symptoms based on SIS-R (P<0.0001).
• Three genes (in AKT1 and LRRTM1) had significant interaction in the unaffected siblings (P<0.0003) after correction for multiple comparisons. AKT1 is a serine/threonine kinase involved in cellular processes such as apoptosis, endoplasmic reticulum stress response, cell proliferation, and cell survival. Postmortem examination of the prefrontal cortex in patients with schizophrenia have shown decreased levels of AKT1.
• For patients with daily cannabis use, one of the SNPs in the AKT1 gene showed significantly higher relative risk with the C/C genotype (relative risk = 1.90, P<0.01) compared with the T/T genotype.
• The authors cite evidence of the involvement of AKT1 in dopamine D2 receptor signaling, and hypothesize that this may explain the poor response of cannabis-using patients with schizophrenia to antipsychotic medications.

Reference

van Winkel R, Genetic Risk and Outcome of Psychosis (GROUP) Investigators. Family-based analysis of genetic variation underlying psychosis-inducing effects of cannabis: sibling analysis and proband follow-up. Arch Gen Psychiatry. 2011;68(2):148-157. doi:10.1001/archgenpsychiatry.2010.152.