Dataset Information

Variants near CHRNB3-CHRNA6 are associated with DSM-5 cocaine use disorder: evidence for pleiotropy.

ABSTRACT: In the U.S.A., cocaine is the second most abused illicit drug. Variants within the CHRNB3-A6 gene cluster have been associated with cigarette consumption in several GWAS. These receptors represent intriguing candidates for the study of cocaine dependence because nicotinic receptors are thought to be involved in generalized addiction pathways. Using genotypic data from a GWAS of the Study of Addiction: Genetics and Environment (SAGE) dataset, we tested for association of CHRNB3-A6 SNPs with DSM-5 cocaine use disorder. Multiple SNPs in the region were significantly associated with increased risk of cocaine use disorder. Inclusion of the most significant SNP as a covariate in a linear regression model provided evidence for an additional independent signal within this locus for cocaine use disorder. These results suggest that the CHRNB3-A6 locus contains multiple variants affecting risk for vulnerability to cocaine and nicotine dependence as well as bipolar disorder, suggesting that they have pleiotropic effects.

SUBMITTER: Sadler B

PROVIDER: S-EPMC4894386 | biostudies-literature | 2014 Mar

REPOSITORIES: biostudies-literature

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Variants near CHRNB3-CHRNA6 are associated with DSM-5 cocaine use disorder: evidence for pleiotropy.

Sadler Brooke B Haller Gabe G Agrawal Arpana A Culverhouse Rob R Bucholz Kathleen K Brooks Andy A Tischfield Jay J Johnson Eric O EO Edenberg Howard H Schuckit Marc M Saccone Nancy N Bierut Laura L Goate Alison A

Scientific reports 20140328

In the U.S.A., cocaine is the second most abused illicit drug. Variants within the CHRNB3-A6 gene cluster have been associated with cigarette consumption in several GWAS. These receptors represent intriguing candidates for the study of cocaine dependence because nicotinic receptors are thought to be involved in generalized addiction pathways. Using genotypic data from a GWAS of the Study of Addiction: Genetics and Environment (SAGE) dataset, we tested for association of CHRNB3-A6 SNPs with DSM-5 ...[more]

PMID: 24675634

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Project description:Cigarette smoking is a leading cause of preventable death throughout the world. Nicotine, the primary addictive compound in tobacco, plays a vital role in the initiation and maintenance of its use. Nicotine exerts its pharmacological roles through nicotinic acetylcholine receptors (nAChRs), which are ligand-gated ion channels consisting of five membrane-spanning subunits. Besides the CHRNA4, CHRNB2 and CHRNA5/A3/B4 cluster on chromosome 15, which has been investigated intensively, recent evidence from both genome-wide association studies and candidate gene-based association studies has revealed the crucial roles of the CHRNB3-CHRNA6 gene cluster on chromosome 8 in nicotine dependence (ND). These studies demonstrate two distinct loci within this region. The first one is tagged by rs13277254, upstream of the CHRNB3 gene, and the other is tagged by rs4952, a coding single nucleotide polymorphism in exon 5 of that gene. Functional studies by genetic manipulation in mice have shown that ?6*-nAChRs, located in the ventral tegmental area (VTA), are of great importance in controlling nicotine self-administration. However, when the ?6 subunit is selectively re-expressed in the VTA of the ?6(-/-) mouse by a lentiviral vector, the reinforcing property of nicotine is restored. To further determine the role of ?6*-nAChRs in the process of nicotine-induced reward and withdrawal, genetic knock-in strains have been examined, which showed that replacement of Leu with Ser in the 9' residue in the M2 domain of ?6 produces nicotine-hypersensitive mice (?6 L9'S) with enhanced dopamine release. Moreover, nicotine-induced upregulation may be another ingredient in the pathology of nicotine addiction although the effect of chronic nicotine exposure on the expression of ?6-containing receptors is controversial. To gain a better understanding of the pathological processes underlying ND and ND-related behaviors and to promote the development of effective smoking cessation therapies, we here present the most recent studies concerning the genetic effects of the CHRNB3-CHRNA6 gene cluster in ND.

Dataset Information

Variants near CHRNB3-CHRNA6 are associated with DSM-5 cocaine use disorder: evidence for pleiotropy.

Publications

Variants near CHRNB3-CHRNA6 are associated with DSM-5 cocaine use disorder: evidence for pleiotropy.

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