Genome-wide meta-analysis reveals common splice site acceptor variant in CHRNA4 associated with nicotine dependence

Transl Psychiatry. 2015 Oct 6;5(10):e651. doi: 10.1038/tp.2015.149.

Abstract

We conducted a 1000 Genomes-imputed genome-wide association study (GWAS) meta-analysis for nicotine dependence, defined by the Fagerström Test for Nicotine Dependence in 17 074 ever smokers from five European-ancestry samples. We followed up novel variants in 7469 ever smokers from five independent European-ancestry samples. We identified genome-wide significant association in the alpha-4 nicotinic receptor subunit (CHRNA4) gene on chromosome 20q13: lowest P=8.0 × 10(-9) across all the samples for rs2273500-C (frequency=0.15; odds ratio=1.12 and 95% confidence interval=1.08-1.17 for severe vs mild dependence). rs2273500-C, a splice site acceptor variant resulting in an alternate CHRNA4 transcript predicted to be targeted for nonsense-mediated decay, was associated with decreased CHRNA4 expression in physiologically normal human brains (lowest P=7.3 × 10(-4)). Importantly, rs2273500-C was associated with increased lung cancer risk (N=28 998, odds ratio=1.06 and 95% confidence interval=1.00-1.12), likely through its effect on smoking, as rs2273500-C was no longer associated with lung cancer after adjustment for smoking. Using criteria for smoking behavior that encompass more than the single 'cigarettes per day' item, we identified a common CHRNA4 variant with important regulatory properties that contributes to nicotine dependence and smoking-related consequences.

Publication types

  • Meta-Analysis
  • Research Support, N.I.H., Extramural

MeSH terms

  • European Continental Ancestry Group / genetics
  • Female
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study
  • Humans
  • Male
  • Polymorphism, Single Nucleotide
  • RNA Splice Sites
  • Receptors, Nicotinic / genetics*
  • Tobacco Use Disorder / genetics*

Substances

  • RNA Splice Sites
  • Receptors, Nicotinic
  • nicotinic acetylcholine receptor alpha4 subunit