Csala, Iren

Dome, Balazs

Dome, Peter

Faludi, Gabor

Kaunisto, Mari

Kovacs, Gabor

Lazary, Judit

PLoS ONE

PubMed

Judit Lazary

Peter Dome

Iren Csala

Gabor Kovacs

Gabor Faludi

Mari Kaunisto

Balazs Dome

Crossref

Massive Withdrawal Symptoms and Affective Vulnerability Are Associated with Variants of the CHRNA4 Gene in a Subgroup of Smokers

Helsingin yliopiston digitaalinen arkisto

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

Fagerstro¨m 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

Lazáry, J.

Döme, P.

Csala, I.

Kovács, G.

Faludi, G.

Kaunisto, M.

Döme, B.

Repository of the Academy's Library

Massive

withdrawal symptoms and affective vulnerability are associated with variants of

the CHRNA4 gene in a subgroup of smokers

Lazáry Judit

Döme Péter

Csala Irén

Kovacs G

Faludi Gábor

Kaunisto M

Döme Balázs

Semmelweis Repository

<div>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.</div

Judit Lazary (517038)

Peter Dome (517039)

Iren Csala (517040)

Gabor Kovacs (3523568)

Gabor Faludi (126748)

Mari Kaunisto (443248)

Balazs Dome (4246111)

FigShare

Massive Withdrawal Symptoms and Affective Vulnerability Are Associated with Variants of the CHRNA4 Gene in a Subgroup of Smokers

Lazary Judit

Dome Peter

Csala Iren

Kovacs Gabor

Faludi Gabor

Kaunisto Mari

Dome Balazs

Public Library of Science (PLOS)

 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

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Massive Withdrawal Symptoms and Affective Vulnerability Are Associated with Variants of the CHRNA4 Gene in a Subgroup of Smokers

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Helsingin yliopiston digitaalinen arkisto

Repository of the Academy's Library

Semmelweis Repository

FigShare

Public Library of Science (PLOS)

Public Library of Science (PLOS)

Directory of Open Access Journals