title: Association of the CHRNA5-A3-B4 gene cluster with heaviness of smoking: a meta-analysis.
abstract: BACKGROUND
  Variation in the CHRNA5-A3-B4 gene cluster is a promising candidate region for smoking behavior and has been linked to multiple smoking-related phenotypes (e.g., nicotine dependence) and diseases (e.g., lung cancer). Two single nucleotide polymorphisms (SNPs), rs16969968 in CHRNA5 and rs1051730 in CHRNA3, have generated particular interest.
  
  
  METHODS
  We evaluated the published evidence for association between rs16969968 (k = 27 samples) and rs1051730 (k = 44 samples) SNPs with heaviness of smoking using meta-analytic techniques. We explored which SNP provided a stronger genetic signal and investigated study-level characteristics (i.e., ancestry, disease state) to establish whether the strength of association differed across populations. We additionally tested for small study bias and explored the impact of year of publication.
  
  
  CONCLUSIONS
  Meta-analysis indicated compelling evidence of an association between the rs1051730/rs16966968 variants and daily cigarette consumption (fixed effects: B = 0.91, 95% CI = 0.77, 1.06, p < .001; random effects: B = 1.01, 95% CI = 0.81, 1.22, p < .001), equivalent to a per-allele effect of approximately 1 cigarette/day. SNP rs1051730 was found to provide a stronger signal than rs16966968 in stratified analyses (p(diff) = .028), although this difference was only qualitatively observed in the subset of samples that provided data on both SNPs. While the functional relevance of rs1051730 is unknown, it may be a strong tagging SNP for functional haplotypes in this region.
authors.affiliation: Department of Psychological Medicine, Cardiff University, 1 Floor Neuadd Merionydd, Heath Park Campus, Cardiff CF14 4YS, UK.  warejj@cardiff.ac.uk.
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Ware
authors.forename: Marianne B M
authors.initials: MB
authors.lastname: van den Bree
authors.forename: Marcus R
authors.initials: MR
authors.lastname: Munafò
mesh_terms: D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D015810:Linkage Disequilibrium; D008175:Lung Neoplasms / Q000235:genetics; D008297:Male; D005810:Multigene Family / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011978:Receptors, Nicotinic / Q000235:genetics*; D012907:Smoking / Q000235:genetics*; D014029:Tobacco Use Disorder / Q000235:genetics
chemical_list: D009419:Nerve Tissue Proteins; D011978:Receptors, Nicotinic; C447158:CHRNA5 protein, human; C447159:CHRNB4 protein, human
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