title: Further evidence for association of polymorphisms in the CNR1 gene with cocaine addiction: confirmation in an independent sample and meta-analysis.
abstract: Genetic research on cocaine dependence (CD) may help clarify our understanding of the disorder as well as provide insights for effective treatment. As endocannabinoid signaling and dopamine neurotransmission have been shown to be involved in drug reward, genes related to these systems are plausible candidates for susceptibility to CD. The cannabinoid receptor 1 protein regulates both the endocannabinoid and dopaminergic neurobiological systems, and polymorphisms in the cannabinoid receptor gene, CNR1, have been associated previously with substance dependence. In this study, we attempt to replicate findings associating CNR1 with CD in African Americans. Cocaine-addicted individuals (n=860) and unaffected controls (n=334) of African descent were genotyped for two single nucleotide polymorphisms (SNPs) in CNR1 (rs6454674, rs806368). We observed a significant difference in genotype frequencies between cases and controls for both SNPs (P≤0.042). A meta-analysis was also performed combining our data with that of Zuo et al. who also studied these polymorphisms in African American cocaine addicts (total n=1253 cases versus 543 controls). When our data were combined, rs6454674 increased in significance to P=0.027; however, rs806368 was no longer significant. This study confirms the association between rs6454674 and CD. However, because there is considerable co-morbidity of CD with other drugs of abuse, additional studies are necessary to determine whether polymorphisms in CNR1 induce a general susceptibility to substance dependence or are specific to cocaine addiction. Furthermore, as this population consists of American individuals of African descent, the possibility of population stratification should not be excluded.
authors.affiliation: Psychiatric Pharmacogenetics Laboratory Center for Neurobiology and Behavior Treatment Research Center Department of Psychiatry, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
authors.forename: Toni-Kim
authors.initials: TK
authors.lastname: Clarke
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Bloch
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Ambrose-Lanci
authors.forename: Thomas N
authors.initials: TN
authors.lastname: Ferraro
authors.forename: Wade H
authors.initials: WH
authors.lastname: Berrettini
authors.forename: Kyle M
authors.initials: KM
authors.lastname: Kampman
authors.forename: Charles A
authors.initials: CA
authors.lastname: Dackis
authors.forename: Helen M
authors.initials: HM
authors.lastname: Pettinati
authors.forename: Charles P
authors.initials: CP
authors.lastname: O'Brien
authors.forename: David W
authors.initials: DW
authors.lastname: Oslin
authors.forename: Falk W
authors.initials: FW
authors.lastname: Lohoff
mesh_terms: D000293:Adolescent; D001741:Black or African American / Q000235:genetics*; D016022:Case-Control Studies; D016009:Chi-Square Distribution; D003042:Cocaine / Q000009:adverse effects / Q000494:pharmacology; D019970:Cocaine-Related Disorders / Q000235:genetics*; D039721:Diagnostic and Statistical Manual of Mental Disorders; D004298:Dopamine / Q000378:metabolism / Q000502:physiology; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D043884:Receptor, Cannabinoid, CB1 / Q000235:genetics*; D012201:Reward; D014481:United States / Q000453:epidemiology
chemical_list: C571130:CNR1 protein, human; D043884:Receptor, Cannabinoid, CB1; D003042:Cocaine; D004298:Dopamine