Dataset Information

Combined genetic influence of the nicotinic receptor gene cluster CHRNA5/A3/B4 on nicotine dependence.

ABSTRACT: BACKGROUND:The 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. RESULTS:We 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. CONCLUSIONS:These 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.

SUBMITTER: Lee SH

PROVIDER: S-EPMC6245894 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Combined genetic influence of the nicotinic receptor gene cluster CHRNA5/A3/B4 on nicotine dependence.

Lee Sung-Ha SH Ahn Woo-Young WY Seweryn Michał M Sadee Wolfgang W

BMC genomics 20181120 1

<h4>Background</h4>The 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 regulato ...[more]

PMID: 30453884

Similar Datasets

Project description:Multiple genome-wide and targeted association studies reveal a significant association of variants in the CHRNA5-CHRNA3-CHRNB4 (CHRNA5/A3/B4) gene cluster on chromosome 15 with nicotine dependence. The subjects examined in most of these studies had a European origin. However, considering the distinct linkage disequilibrium patterns in European and other ethnic populations, it would be of tremendous interest to determine whether such associations could be replicated in populations of other ethnicities, such as Asians. In this study, we performed comprehensive association and interaction analyses for 32 single-nucleotide polymorphisms (SNPs) in CHRNA5/A3/B4 with smoking initiation (SI), smoking quantity (SQ), and smoking cessation (SC) in a Korean sample (N = 8,842). We found nominally significant associations of 7 SNPs with at least one smoking-related phenotype in the total sample (SI: P = 0.015 approximately 0.023; SQ: P = 0.008 approximately 0.028; SC: P = 0.018 approximately 0.047) and the male sample (SI: P = 0.001 approximately 0.023; SQ: P = 0.001 approximately 0.046; SC: P = 0.01). A spectrum of haplotypes formed by three consecutive SNPs located between rs16969948 in CHRNA5 and rs6495316 in the intergenic region downstream from the 5' end of CHRNB4 was associated with these three smoking-related phenotypes in both the total and the male sample. Notably, associations of these variants and haplotypes with SC appear to be much weaker than those with SI and SQ. In addition, we performed an interaction analysis of SNPs within the cluster using the generalized multifactor dimensionality reduction method and found a significant interaction of SNPs rs7163730 in LOC123688, rs6495308 in CHRNA3, and rs7166158, rs8043123, and rs11072793 in the intergenic region downstream from the 5' end of CHRNB4 to be influencing SI in the male sample. Considering that fewer than 5% of the female participants were smokers, we did not perform any analysis on female subjects specifically. Together, our detected associations of variants in the CHRNA5/A3/B4 cluster with SI, SQ, and SC in the Korean smoker samples provide strong evidence for the contribution of this cluster to the etiology of SI, ND, and SC in this Asian population.

Dataset Information

Combined genetic influence of the nicotinic receptor gene cluster CHRNA5/A3/B4 on nicotine dependence.

Publications

Combined genetic influence of the nicotinic receptor gene cluster CHRNA5/A3/B4 on nicotine dependence.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets