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CHRNA5/A3/B4 Variant rs3743078 and Nicotine-Related Phenotypes: Indirect Effects Through Nicotine Craving.

ABSTRACT: OBJECTIVE:Nicotine craving is considered an important element in the persistence of cigarette smoking, but little is known about the role of craving in the widely recognized association between variants mapped to the neuronal nicotinic acetylcholine receptor (CHRN) genes on chromosome 15 and nicotine phenotypes. METHOD:The associations between CHRNA5-CHRNA3-CHRNB4 variants and cigarettes per day (CPD), the Fagerström Test for Nicotine Dependence (FTND), and craving were analyzed in data from 662 lifetime smokers from an Israeli adult Jewish household sample. Indirect effects of genotype on nicotine phenotypes through craving were formally tested using regression and bootstrapping procedures. RESULTS:At CHRNA3, allele G of rs3743078 was associated with increased craving, CPD, and FTND scores: Participants with one or two copies of the G allele had, on average, higher scores on the craving scale (p = .0025), more cigarettes smoked (p = .0057), and higher scores on the FTND (p =.0024). With craving in the model, variant rs3743078 showed a significant indirect effect through craving on CPD (p = .0026) and on FTND score (p = .0024). A sizeable proportion of the total rs3743078 effect on CPD (56.4%) and FTND (65.2%) was indirect through craving. CONCLUSIONS:These results suggest that nicotine craving may play a central role in nicotine use disorders and may have utility as a therapeutic target.

SUBMITTER: Shmulewitz D

PROVIDER: S-EPMC4803655 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

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CHRNA5/A3/B4 Variant rs3743078 and Nicotine-Related Phenotypes: Indirect Effects Through Nicotine Craving.

Shmulewitz Dvora D Meyers Jacquelyn L JL Wall Melanie M MM Aharonovich Efrat E Frisch Amos A Spivak Baruch B Weizman Abraham A Edenberg Howard J HJ Gelernter Joel J Hasin Deborah S DS

Journal of studies on alcohol and drugs 20160301 2

<h4>Objective</h4>Nicotine craving is considered an important element in the persistence of cigarette smoking, but little is known about the role of craving in the widely recognized association between variants mapped to the neuronal nicotinic acetylcholine receptor (CHRN) genes on chromosome 15 and nicotine phenotypes.<h4>Method</h4>The associations between CHRNA5-CHRNA3-CHRNB4 variants and cigarettes per day (CPD), the Fagerström Test for Nicotine Dependence (FTND), and craving were analyzed i ...[more]

PMID: 26997181

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Project description:BackgroundThe CHRNA5/A3/B4 gene locus is associated with nicotine dependence and other smoking related disorders. While the non-synonymous CHRNA5 variant rs16969968 appears to be the main risk factor, linkage disequilibrium (LD) bins in the gene cluster carry frequent variants that regulate expression. Pairwise LD and haplotype analyses had identified at least three haplotype tagging SNPs including rs16969968 as main genetic risk factors. Searching for variants with evidence of regulatory functions, we have reported interactions between CHRNA5 and CHRNA3 enhancer variants (tagged by rs880395 and rs1948, respectively) and rs16969968, forming 3-SNP haplotypes and diplotypes that may more accurately reflect the cluster's combined effects on nicotine dependence (Barrie et al., Hum Mutat 38:112-9, 2017). Here we address further contributions by variants affecting CHRNB4, a possibly limiting component of nicotinic receptors.ResultsWe identify an LD bin (tagged by rs4887074) associated with expression of CHRNB4. Additive logistic regression models indicate that rs4887074 is associated with nicotine dependence and modulates the effect of rs16969968 in GWAS datasets (COGEND, UW-TTURC, SAGE). 4-SNP haplotype and diplotype analyses (rs880395-rs16969968-rs1948 -rs4887074) yield nicotine dependence risk values that further differentiate those obtained with the 3-SNP model. Moreover, both the main G allele of rs16969968 and the minor G allele of rs4887074 (associated with reduced expression of CHRNB4), residing predominantly on common haplotypes that are protective, represent significant allele-specific variance QTLs, indicating that they interact with each other.ConclusionsThese results indicate rs4887074 is associated with CHRNB4 expression, and along with two regulatory variants of CHRNA3 and CHRNA5, modulates the effect of rs16969968 on nicotine dependence risk. Assignable to individuals because of strong LD structures, 4-SNP haplotypes and diplotypes serve to assess the combined genetic influence of this multi-gene cluster on complex traits, accounting for complex LD relationships and tissue-specific genetic effects (CHRNA5/3) relevant to the traits analyzed. The 4-SNP haplotypes account at least in part for previous tagging SNPs, including the highly GWAS-significant rs6495308, located in a distinct pair-wise LD bin but included in protective 4-SNP haplotypes. Our approach refines and integrates the cluster's overall genetic influence, an important variable when integrating the genetics of multiple genomic loci.

Dataset Information

CHRNA5/A3/B4 Variant rs3743078 and Nicotine-Related Phenotypes: Indirect Effects Through Nicotine Craving.

Publications

CHRNA5/A3/B4 Variant rs3743078 and Nicotine-Related Phenotypes: Indirect Effects Through Nicotine Craving.

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