CHRNA4 and tobacco dependence: from gene regulation to treatment outcome

Arch Gen Psychiatry. 2007 Sep;64(9):1078-86. doi: 10.1001/archpsyc.64.9.1078.


Context: Given the probable importance of the alpha4 subunit of the neuronal nicotinic acetylcholine receptor, the gene that codes for this subunit (CHRNA4) represents an excellent starting point for a genetic investigation of smoking behavior.

Objective: To achieve a better understanding of the role of this gene in the cause and treatment of tobacco dependence, we adopted a transdisciplinary pharmacogenetic approach.

Design: Study at the behavioral and clinical levels of analysis.

Setting: Academic research.

Participants: Smokers (n = 316) between the ages of 18 and 50 years were recruited from the Denver, Colorado, metropolitan area.

Main outcome measures: Bioinformatics analyses, cell culture experiments, and analyses of CHRNA4 expression and nicotine binding in postmortem human brain tissue advanced 2 single-nucleotide polymorphisms (rs6122429 and rs2236196).

Results: Both single-nucleotide polymorphisms were associated with subjective responses to smoking in the laboratory among 316 smokers. Likewise, among 353 participants in a clinical trial, rs2236196 was associated with smoking cessation outcomes.

Conclusions: Results of analyses ranging from basic biological approaches to clinical outcome data provide consistent evidence that 2 single-nucleotide polymorphisms in CHRNA4 are functional at a biological level and are associated with nicotine dependence phenotypes. This interdisciplinary approach to the genetics of nicotine dependence provides a model for testing how functional genetic variation is translated from changes in messenger RNA and protein to individual differences in behavior and treatment outcome.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Cutaneous
  • Adolescent
  • Adult
  • Binding Sites / genetics
  • Brain / metabolism
  • Female
  • Gene Expression Regulation
  • Genetic Variation / genetics
  • Genotype
  • Humans
  • Male
  • Middle Aged
  • Nicotine / administration & dosage
  • Nicotine / metabolism
  • Nucleus Accumbens / metabolism
  • Phenotype
  • Polymorphism, Single Nucleotide
  • Receptors, Nicotinic / genetics*
  • Smoking / genetics
  • Smoking / psychology
  • Smoking Cessation / methods
  • Smoking Prevention
  • Tobacco Use Disorder / genetics*
  • Tobacco Use Disorder / prevention & control
  • Tobacco Use Disorder / psychology
  • Treatment Outcome


  • Receptors, Nicotinic
  • nicotinic acetylcholine receptor alpha4 subunit
  • Nicotine