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.
Highlights
Nicotine dependence is the most prevalent psychiatric disorder in the world and it is responsible for the highest preventable mortality in developed countries [1,2]
Comparing different variables between the two genders we found that women scored significantly higher on Zung Self-Rating Depression Scale (ZSDS) (35.866.5 vs. 39.468.4, p = 0.006) but other factors did not differ from men
Despite of the crucial role of alpha4 subunit in the development of nicotine withdrawal symptoms, this is the first study assessing the association between CHRNA4 variants and acute nicotine withdrawal symptoms
Summary
Nicotine dependence is the most prevalent psychiatric disorder in the world and it is responsible for the highest preventable mortality in developed countries [1,2]. One of the most important candidate genes of smoking behavior is the gene encoding alpha subunit of the nicotinic acetylcholine receptor (CHRNA4) because among nicotinic acetylcholine receptors (nAChRs) those containing alpha subunit have the highest affinity for nicotine, the primary psychoactive component of tobacco [3]. The most effective pharmacological agent for smoking cessation, varenicline is a partial agonist on alpha4beta nAChRs. Despite of the evident role of CHRNA4 in multiple smoking-related phenotypes including nicotine dependence, withdrawal and affective symptoms, association studies have provided partly inconsistent results. Positive associations between nicotine dependence and CHRNA4 were reported in casecontrol and family studies [4,5]. Spruell et al (2012) reported that effect of CHRNA4 was not significant on smoking cessation outcome in a nicotine replacement therapy (NRT) treatment study [7]
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