Massive withdrawal symptoms and affective vulnerability are associated with variants of the CHRNA4 gene in a subgroup of smokers.
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.
Department of Clinical and Theoretical Mental Health, Semmelweis University, Budapest, Hungary.
Judit
J
Lazary
Department of Clinical and Theoretical Mental Health, Semmelweis University, Budapest, Hungary ; National Institute of Psychiatry and Addictions, Budapest, Hungary.
Peter
P
Dome
Department of Clinical and Theoretical Mental Health, Semmelweis University, Budapest, Hungary ; Institute of Behavioral Sciences, Semmelweis University, Budapest, Hungary.
Iren
I
Csala
Department of Tumor Biology, National Koranyi Institute of Pulmonology, Budapest, Hungary.
Gabor
G
Kovacs
Department of Clinical and Theoretical Mental Health, Semmelweis University, Budapest, Hungary.
Gabor
G
Faludi
Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland ; Folkhälsan Institute of Genetics, Helsinki, Finland.
Mari
M
Kaunisto
Department of Tumor Biology, National Koranyi Institute of Pulmonology, Budapest, Hungary ; Department of Thoracic Surgery, National Institute of Oncology, Budapest, Hungary ; Translational Thoracic Oncology Lab, Department of Thoracic Surgery, Medical University of Vienna, Vienna, Austria.
Balazs
B
Dome
D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009538:Nicotine / Q000009:adverse effects; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011978:Receptors, Nicotinic / Q000235:genetics*; D057566:Self Report; D012907:Smoking / Q000235:genetics*; D013375:Substance Withdrawal Syndrome / Q000235:genetics*
D009538:Nicotine; D011978:Receptors, Nicotinic