Cannabinoid receptor 1 gene association with nicotine dependence

Abstract

Context: The endogenous cannabinoid system has been implicated in drug addiction in animal models. The cannabinoid receptor 1 (CNR1) gene is 1 of the 2 receptors expressed in the brain. It has been reported to be associated with alcoholism and multiple drug abuse and dependence.

Objective: To test the hypothesis that the CNR1 gene is associated with nicotine dependence.

Design: Genotype-phenotype association study. Ten single-nucleotide polymorphisms were genotyped in the CNR1 gene in 2 independent samples. For the first sample (n = 688), a 3-group case-control design was used to test allele association with smoking initiation and nicotine dependence. For the second sample (n = 961), association was assessed with scores from the Fagerström Test for Nicotine Dependence (FTND). Settings Population samples selected from the Mid-Atlantic Twin Registry.

Participants: White patients aged 18 to 65 years who met the criteria of inclusion.

Main outcome measures: Fagerström Tolerance Questionnaire and FTND scores.

Results: Significant single-marker and haplotype associations were found in both samples, and the associations were female specific. Haplotype 1-1-2 of markers rs2023239-rs12720071-rs806368 was associated with nicotine dependence and FTND score in the 2 samples (P < .001 and P = .009, respectively).

Conclusion: Variants and haplotypes in the CNR1 gene may alter the risk for nicotine dependence, and the associations are likely sex specific.

Figure 1

Distribution of the Fagerström Test for Nicotine Dependence (FTND) scores in the Virginia Study of Anxiety and Neuroticism sample.

Figure 2

The cannabinoid receptor 1 (CNR1) gene and linkage disequilibrium (LD) structure in the Virginia Study of Nicotine Dependence (VAND) and the Virginia Study of Anxiety and Neuroticism (VAANX) samples. A, Gene structure and genotyped single-nucleotide polymorphisms. An estrogen response element (ERE) in the promoter region is also shown. B, The LD structure of the VAND sample. C, The LD structure of the VAANX sample. kb indicates kilobase.