CNR1 Variation Modulates Risk for Drug and Alcohol Dependence

BackgroundHuman cannabinoid receptor 1 (CB1), which is encoded by the CNR1 gene, may play a role in the development of substance dependence (SD). Following initial reports of association of CNR1 with SD, we studied multiple markers at this locus in a large case–control sample.MethodsTen CNR1 markers and 38 ancestry-informative markers were genotyped in 451 healthy control subjects and 550 SD (AD and/or DD) patients (including European Americans [EAs] and African Americans [AAs]). Common confounding effects on association analysis of population stratification and admixture, age, and sex were controlled for using regression analysis. Disease risk and protective alleles were fine-mapped using a linkage disequilibrium measure (δ).ResultsIn EAs, risk for each SD subtype significantly increased with the number of “G” alleles at rs6454674 (single nucleotide polymorphisms [SNP]3). SNP3^G+ (the genotypes containing a G allele) and SNP8^T/T genotypes had significant interaction effects (p = .0003 for comorbid DD and AD, .0002 for DD, and .007 for AD). SNP3 and SNP8 together exerted stronger genetic effects on SD than either did individually. The peak δ values among all the markers were seen for SNP3 and SNP8 (rs806368).ConclusionsWe demonstrate that CNR1 variation and interactive effects play important roles in risk for both DD and AD.