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Xiangning Chen, PhD; Vernell S. Williamson, MSc; Seon-Sook An, PhD; John M. Hettema, MD, PhD; Steven H. Aggen, PhD; Michael C. Neale, PhD; Kenneth S. Kendler, MD

Arch Gen Psychiatry. 2008;65(7):816-823.

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.

Author Affiliations: Virginia Institute of Psychiatric and Behavioral Genetics and Department of Psychiatry, Virginia Commonwealth University, Richmond.

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