Distinct loci in the CHRNA5/CHRNA3/CHRNB4 gene cluster are associated with onset of regular smoking

source extracted confidence: high 2026-04-09
#adolescent #age-of-onset #cotinine #female #genetic-loci

Distinct loci in the CHRNA5/CHRNA3/CHRNB4 gene cluster are associated with onset of regular smoking

Stephens et al., 2013 | Genet Epidemiol | Meta Analysis

Citation

Stephens Sarah H, Hartz Sarah M, ... Ehringer Marissa A. Distinct loci in the CHRNA5/CHRNA3/CHRNB4 gene cluster are associated with onset of regular smoking. Genet Epidemiol. 2013-Dec;37(8):846-59. doi:10.1002/gepi.21760

Abstract

Neuronal nicotinic acetylcholine receptor (nAChR) genes (CHRNA5/CHRNA3/CHRNB4) have been reproducibly associated with nicotine dependence, smoking behaviors, and lung cancer risk. Of the few reports that have focused on early smoking behaviors, association results have been mixed. This meta-analysis examines early smoking phenotypes and SNPs in the gene cluster to determine: (1) whether the most robust association signal in this region (rs16969968) for other smoking behaviors is also associated with early behaviors, and/or (2) if additional statistically independent signals are important in early smoking. We focused on two phenotypes: age of tobacco initiation (AOI) and age of first regular tobacco use (AOS). This study included 56,034 subjects (41 groups) spanning nine countries and evaluated five SNPs including rs1948, rs16969968, rs578776, rs588765, and rs684513. Each dataset was analyzed using a centrally generated script. Meta-analyses were conducted from summary statistics. AOS yielded significant associations with SNPs rs578776 (beta = 0.02, P = 0.004), rs1948 (beta = 0.023, P = 0.018), and rs684513 (beta = 0.032, P = 0.017), indicating protective effects. There were no significant associations for the AOI phenotype. Importantly, rs16969968, the most replicated signal in this region for nicotine dependence, cigarettes per day, and cotinine levels, was not associated with AOI (P = 0.59) or AOS (P = 0.92). These results provide important insight into the complexity of smoking behavior phenotypes, and suggest that association signals in the CHRNA5/A3/B4 gene cluster affecting early smoking behaviors may be different from those affecting the mature nicotine dependence phenotype.

Key Findings

These results provide important insight into the complexity of smoking behavior phenotypes, and suggest that association signals in the CHRNA5/A3/B4 gene cluster affecting early smoking behaviors may be different from those affecting the mature nicotine dependence phenotype.

Outcomes Measured

  • Requires manual extraction

Population

Field Value
Population See abstract
Sample Size 56034
Age Range See abstract
Condition See abstract

MeSH Terms

  • Adolescent
  • Age of Onset
  • Cotinine
  • Female
  • Genetic Loci
  • Genetic Predisposition to Disease
  • Humans
  • Internationality
  • Linkage Disequilibrium
  • Male
  • Multigene Family
  • Nerve Tissue Proteins
  • Phenotype
  • Polymorphism, Single Nucleotide
  • Receptors, Nicotinic
  • Smoking
  • Tobacco Use Disorder

Evidence Classification

  • Level: Meta Analysis
  • Publication Types: Journal Article, Meta-Analysis, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't
  • Vertical: niacin

Provenance

Source extracted via PubMed E-utilities API on 2026-04-09