Massive withdrawal symptoms and affective vulnerability are associated with variants of the CHRNA4 gene in a subgroup of smokers

PLoS One. 2014 Jan 30;9(1):e87141. doi: 10.1371/journal.pone.0087141. eCollection 2014.

Abstract

Heterogeneous phenotypes of complex disorders pose a great challenge for genetic association studies and for the development of personalized treatment strategies. Cluster analysis of phenotypic data has been recently proposed as a reliable auxiliary method for such studies. A cohort of 236 treatment-seeking smokers was investigated after overnight nicotine abstinence. Alpha4 nicotinic acetylcholine receptor (nAChR) subunit-related phenotypes were assessed by the Fagerström Test for Nicotine Dependence (FTND), exhaled carbon monoxide (CO) measurements, the Minnesota Nicotine Withdrawal Scale (MNWS) and the Zung Self-Rating Depression Scale (ZSDS). Seven tag SNPs (single-nucleotide polymorphisms) across CHRNA4 (the gene encoding alpha4 subunit of the nicotinic acetylcholine receptor) were genotyped and two-step cluster analysis was used for phenotypic cluster characterization. Haplotype estimation was determined by HapStat module of R 2.0 software. Three different phenotypic clusters were identified and the C3 cluster was characterized by the highest ZSDS and MNWS scores compared to others. Furthermore, lifetime prevalence of major depression was significantly higher in the C3 cluster (p = 0.019). In genetic association tests, this cluster was also significantly associated with rs3787138 genotypes (p = 0.004) while haplotype analyses of three SNPs (rs3787138, rs1044396, rs3787140) revealed that the risk for C3 phenotype was almost three times higher in GCC haplotype carriers compared to others (pperm = 0.013). This is the first report on a significant association between CHRNA4 variants and a subgroup of smokers characterized by massive withdrawal symptoms and affective vulnerability. Identification of such a phenotypic cluster can be a pivotal step for further pharmacogenetic studies on ligands of the alpha4 nAChR subunit. Our results suggest that performing cluster analysis in genetic association studies can be proposed for complex disorders.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Female
  • Genetic Predisposition to Disease / genetics*
  • Genotype
  • Humans
  • Male
  • Middle Aged
  • Nicotine / adverse effects
  • Phenotype
  • Polymorphism, Single Nucleotide / genetics*
  • Receptors, Nicotinic / genetics*
  • Self Report
  • Smoking / genetics*
  • Substance Withdrawal Syndrome / genetics*

Substances

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

Grants and funding

This study was supported by the Norwegian Financial Mechanism (HU0125) (J Lazary, P Dome, G Kovacs, G Faludi, B Dome); OTKA K108465 (B Dome); TÁMOP 424A/1-11-1-2012-0001 (B Dome); KTIA AIK 12-1-2013-0041 (B Dome); OTKA K109626 (B Dome). P Dome is a recipient of the János Bolyai Research Scholarship of the Hungarian Academy of Sciences. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.