ArticleBMC genomics2018
Combined genetic influence of the nicotinic receptor gene cluster CHRNA5/A3/B4 on nicotine dependence.
Article in BMC genomics, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers, 1 of them a synthesis that pooled it.
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Who cites it
13 citing papers in PubMed, 1 synthesis or guideline pooled it, 28 citations in OpenAlex.
- Pooled it
- Genetic Basis of Tobacco Use Disorder.Genes · 2026Review
- Disruption ofiScience · 2026Article
- CHRNA5-A3-B4, CYP2A6, and DBH Genetic Associations With Smoking Cessation Throughout Adulthood Within Two Longitudinal Studies of Women.Nicotine & tobacco research : official journal of the Society for Research on Nicotine and Tobacco · 2025Article
- Unveiling the heritability of selected unexplored pharmacogenetic markers in the Saudi population.Frontiers in pharmacology · 2025Article
- Enhanced Novel Object Recognition and Spatial Memory in Rats Selectively Bred for High Nicotine Preference.Brain sciences · 2024Article
- Deep sequencing of candidate genes identified 14 variants associated with smoking abstinence in an ethnically diverse sample.Scientific reports · 2024Article
- Pharmacogenomics: Driving Personalized Medicine.Pharmacological reviews · 2023Review
- Smoking-mediated nicotinic acetylcholine receptors (nAChRs) for predicting outcomes for head and neck squamous cell carcinomas.BMC cancer · 2022Article
- Association of PolymorphismInternational journal of environmental research and public health · 2022Article
- Association Study of Polymorphisms in Neuronal Nicotinic Acetylcholine Receptor Subunit Genes With Schizophrenia in the Han Chinese Population.Psychiatry investigation · 2021Article
- Challenges of Immune Response Diversity in the Human Population Concerning New Tuberculosis Diagnostics, Therapies, and Vaccines.Frontiers in cellular and infection microbiology · 2020Article
- TheArab journal of basic and applied sciences · 2020Article
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Authors and funding
4 authors at 2 institutions in 3 countries.
Funding
Abstract
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.
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