rs2023239

A longitudinal prospective study of 338 young adult offspring from families at high and low risk for alcohol dependence examined predictors of cannabis use patterns and cannabis abuse/dependence from ages 8-30. A low P300 amplitude trajectory in childhood predicted cannabis abuse/dependence in males (P=0.01). A four-SNP ANKK1-DRD2 haplotype (rs4938012-rs4938015-rs1800497-rs6277, G-G-G-C) was significantly associated with cannabis use frequency patterns (P=0.0008). Among individuals with cannabis abuse/dependence, the CNR1 rs806368 A>G minor allele conferred a 5.4-fold increase in likelihood of frequent persistent use versus declining use (P=0.003, OR=5.4).

This association study examined polymorphisms in the cannabinoid receptor 1 (CNR1) gene and cannabis dependence in 1,923 individuals from the COGA family study. Two SNPs showed significant association with DSM-III-R cannabis dependence: rs806380 (p=0.009) and rs806368 (p=0.05), with rs806380 driving the haplotype association. Results support a role for CNR1 variation in cannabis dependence risk.

This candidate gene association study tested the hypothesis that the cannabinoid receptor 1 (CNR1) gene is associated with nicotine dependence across two independent samples from the Mid-Atlantic Twin Registry. In the VAND sample (n=688), haplotype 1-1-2 of markers rs2023239-rs12720071-rs806368 showed female-specific association with nicotine dependence and smoking initiation (P<.001 for SI, P=.02 for ND). Replication in the VAANX sample (n=961) confirmed female-specific haplotype associations with FTND score (P=.009 for haplotype 1-1-2 of combination 7-9-10). The findings suggest sex-specific genetic effects of CNR1 variants on nicotine dependence risk.

This translational study examined the cannabinoid receptor 1 gene (CNR1) variant rs2023239 and its association with alcohol dependence across multiple levels of analysis. The C allele of rs2023239 was associated with greater CB1 receptor binding in the prefrontal cortex (F=9.62, P<0.01), greater alcohol cue-elicited brain activation in the midbrain and prefrontal cortex (P<0.05), increased subjective reward from alcohol consumption (F=6.27, P<0.05), and more positive treatment outcomes with olanzapine (a medication targeting mesocorticolimbic neurocircuitry). Strong correlations were found between cue-elicited brain activation and alcohol consumption measures in individuals carrying the C allele.

This association study examined 4 SNPs (rs6928499, rs806379, rs1535255, rs2023239) in the CNR1 gene exon 3 alternative promoter region in 895 substance-dependent and 472 control subjects, attempting to replicate Zhang et al.'s earlier report of association with polysubstance abuse. A modest association was found for rs1535255 with alcohol dependence in European Americans (P=0.04), but this did not survive multiple testing correction. The study failed to replicate the original findings of association between these CNR1 markers and polysubstance dependence.