A rare missense mutation in CHRNA4 associates with smoking behavior and its consequences

Mol Psychiatry. 2016 May;21(5):594-600. doi: 10.1038/mp.2016.13. Epub 2016 Mar 8.

Abstract

Using Icelandic whole-genome sequence data and an imputation approach we searched for rare sequence variants in CHRNA4 and tested them for association with nicotine dependence. We show that carriers of a rare missense variant (allele frequency=0.24%) within CHRNA4, encoding an R336C substitution, have greater risk of nicotine addiction than non-carriers as assessed by the Fagerstrom Test for Nicotine Dependence (P=1.2 × 10(-4)). The variant also confers risk of several serious smoking-related diseases previously shown to be associated with the D398N substitution in CHRNA5. We observed odds ratios (ORs) of 1.7-2.3 for lung cancer (LC; P=4.0 × 10(-4)), chronic obstructive pulmonary disease (COPD; P=9.3 × 10(-4)), peripheral artery disease (PAD; P=0.090) and abdominal aortic aneurysms (AAAs; P=0.12), and the variant associates strongly with the early-onset forms of LC (OR=4.49, P=2.2 × 10(-4)), COPD (OR=3.22, P=2.9 × 10(-4)), PAD (OR=3.47, P=9.2 × 10(-3)) and AAA (OR=6.44, P=6.3 × 10(-3)). Joint analysis of the four smoking-related diseases reveals significant association (P=6.8 × 10(-5)), particularly for early-onset cases (P=2.1 × 10(-7)). Our results are in agreement with functional studies showing that the human α4β2 isoform of the channel containing R336C has less sensitivity for its agonists than the wild-type form following nicotine incubation.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Aortic Aneurysm, Abdominal / etiology
  • Aortic Aneurysm, Abdominal / genetics
  • European Continental Ancestry Group / genetics
  • Female
  • Genetic Association Studies
  • Genetic Predisposition to Disease*
  • Humans
  • Iceland
  • Lung Neoplasms / etiology
  • Lung Neoplasms / genetics
  • Male
  • Middle Aged
  • Mutation, Missense*
  • Peripheral Arterial Disease / etiology
  • Peripheral Arterial Disease / genetics
  • Pulmonary Disease, Chronic Obstructive / etiology
  • Pulmonary Disease, Chronic Obstructive / genetics
  • Receptors, Nicotinic / genetics*
  • Smoking / genetics*
  • Tobacco Use Disorder / complications*
  • Tobacco Use Disorder / genetics*
  • Young Adult

Substances

  • Receptors, Nicotinic
  • nicotinic acetylcholine receptor alpha4 subunit