Abstract
We recently reported that, in a European-American (EA) sample, the interaction between two cannabinoid receptor 1 gene (CNR1) variants significantly increased risk for drug dependence (DD), including cocaine dependence (CD). This study aimed to investigate directly the association between CNR1 and CD in four independent samples. Eight markers across the 45 kb CNR1 region and four large samples, ie, family-based European-American (EA) sample (n=734), case–control EA sample (n=862), family-based African-American (AA) sample (n=834) and case–control AA sample (n=619) were examined in the present study. We investigated the association of these markers with CD and cocaine-induced paranoia (CIP) in the EA family sample first, and then replicated positive results in the other three samples. The interaction between two independent CNR1 variants, ie, the G allele-containing genotypes of rs6454674 (SNP3∧G+), and the T/T genotype of rs806368 (SNP8∧T/T), significantly increased risk for CD in the EA family (PGEE=0.015) and EA case–control (Pregression=0.003) samples. EA subjects with SNP3∧G+ and SNP8∧T/T had higher risk to develop CD than those EA subjects with the other genotypes for these two SNPs (LR+=1.4). The SNP3∧G-SNP8∧T haplotype also showed significant association (P=0.018) with CD in the EA case–control sample. SNP8-containing haplotypes showed significant association with both CD (Pglobal=0.007) and CIP (Pglobal=0.003) in the EA family sample. In the AA family sample, SNP8∧T/T significantly conferred higher risk for CD (P=0.019). We conclude that two independent CNR1 variants have significant interaction effects on risk for CD in EAs; they may also have effects on risk for CD in AAs.
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Acknowledgements
Ann Marie Lacobelle and Greg Kay provided excellent technical assistance. This work was supported in part by National Institute on Drug Abuse (NIDA) grants R01-DA12849, R01-DA12690, K24-DA15105, NIAAAR01- AA11330 (J. Gelernter), and K24-DA022288 (R, Weiss); National Institute on Alcohol Abuse and Alcoholism (NIAAA) grants R01-AA016015, P50-AA12870, P50-AA03510, and K24-AA13736 (H. Kranzler); National Center for Research Resources (NCRR) grant M01-RR06192; and by Alcoholic Beverage Medical Research Foundation (ABMRF) grant award R06932 (X. Luo); U.S. Department of Veterans Affairs (the VA Medical Research Program, VA Alcohol Research Center, and the VA Connecticut–Massachusetts Mental Illness Research, Education and Clinical Center (MIRECC); and the VA Research Enhancement Award Program (REAP) research center).
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Dr Kranzler has received financial support or compensation for the following: related to consultation on grant reviews for the National Institutes of Health and related to academic lectures and editorial functions in various scientific venues; and has been a paid consultant to Alkermes Inc., Ortho-McNeil Pharmaceuticals, Thomson Healthcare, Sanofi-Aventis, Lundbeck, Forest Pharmaceuticals, Elbion NV, Bristol-Myers Squibb Co., and Solvay Pharmaceuticals. He has received research support from Ortho-McNeil Pharmaceuticals and Bristol-Myers Squibb Co. Dr Weiss has received financial support or compensation for the following: related to consultation on grant reviews for the National Institutes of Health and related to academic lectures and editorial functions in various scientific venues; and has been a paid consultant to Eli Lilly Co., Novartis Pharmaceuticals, Titan Pharmaceuticals and AstraZeneca Pharmaceuticals. Dr Gelernter has received financial support or compensation for the following: related to consultation for Columbia University, the Thailand Center for Excellence for Life Sciences (TCELS), the University of CT Health Center, NIH, related to grant reviews for the National Institutes of Health; and related to academic lectures and editorial functions in various scientific venues (including from ACNP). The other authors declare that they have not received any compensation for research or professional service that could be perceived as constituting a potential conflict of interest.
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Zuo, L., Kranzler, H., Luo, X. et al. Interaction between Two Independent CNR1 Variants Increases Risk for Cocaine Dependence in European Americans: A Replication Study in Family-Based Sample and Population-Based Sample. Neuropsychopharmacol 34, 1504–1513 (2009). https://doi.org/10.1038/npp.2008.206
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