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Genomewide linkage survey of nicotine dependence phenotypes.

ABSTRACT: A comprehensive understanding of the etiology and neurobiology of nicotine dependence is not available. We sought to identify genomic regions that might contain etiologically-relevant loci using genomewide univariate and bivariate linkage analyses.We conducted secondary data analyses of 626 all possible sibling pairs ascertained in Ireland and Northern Ireland on the basis of alcohol dependence. A set of 1020 short tandem repeat genetic markers were genotyped in all subjects. The phenotypes analyzed were the Fagerström Test for Nicotine Dependence (FTND), a history of nicotine dependence, the number of symptoms of alcohol dependence (AlcSx), and a history of alcohol dependence. Genomewide linkage analyses were conducted with non-parametric and variance components methods.For the bivariate variance component analysis of the continuous FTND and AlcSx scores, multipoint LOD scores were >4 in two genomic regions--an 11cM region on chr7 (D7S2252-D7S691, empirical p=0.0006) and an 8cM region on chr18 flanking D18S63 (empirical p=0.0007). These findings did not exceed a conservative estimate of study-wide significance. The remaining sets of findings had considerably smaller or less consistent peak signals. Notably, strong linkage signal at D4S1611 for AlcSx from a prior report (PMID 16534506) was not found when jointly analyzed with FTND.Replication is required. However, chromosomes 7 and 18 may contain genetic loci relevant to the etiology of nicotine-related phenotypes.

SUBMITTER: Sullivan PF

PROVIDER: S-EPMC2258277 | biostudies-literature | 2008 Mar

REPOSITORIES: biostudies-literature

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Genomewide linkage survey of nicotine dependence phenotypes.

Sullivan Patrick F PF Kuo Po-Hsiu PH Webb B Todd BT Neale Michael C MC Vittum Jen J Furberg Helena H Walsh Dermot D Patterson Diana G DG Riley Brien B Prescott Carol A CA Kendler Kenneth S KS

Drug and alcohol dependence 20071119 3

<h4>Background</h4>A comprehensive understanding of the etiology and neurobiology of nicotine dependence is not available. We sought to identify genomic regions that might contain etiologically-relevant loci using genomewide univariate and bivariate linkage analyses.<h4>Methods</h4>We conducted secondary data analyses of 626 all possible sibling pairs ascertained in Ireland and Northern Ireland on the basis of alcohol dependence. A set of 1020 short tandem repeat genetic markers were genotyped i ...[more]

PMID: 18023296

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Project description:BackgroundWhile the heritability of cigarette smoking and nicotine dependence (ND) is well-documented, the contribution of specific genetic variants to specific phenotypes has not been closely examined. The objectives of this study were to test the associations between 321 tagging single-nucleotide polymorphisms (SNPs) that capture common genetic variation in 24 genes, and early smoking and ND phenotypes in novice adolescent smokers, and to assess if genetic predictors differ across these phenotypes.MethodsIn a prospective study of 1294 adolescents aged 12-13 years recruited from ten Montreal-area secondary schools, 544 participants who had smoked at least once during the 7-8 year follow-up provided DNA. 321 single-nucleotide polymorphisms (SNPs) in 24 candidate genes were tested for an association with number of cigarettes smoked in the past 3 months, and with five ND phenotypes (a modified version of the Fagerstrom Tolerance Questionnaire, the ICD-10 and three clusters of ND symptoms representing withdrawal symptoms, use of nicotine for self-medication, and a general ND/craving symptom indicator).ResultsThe pattern of SNP-gene associations differed across phenotypes. Sixteen SNPs in seven genes (ANKK1, CHRNA7, DDC, DRD2, COMT, OPRM1, SLC6A3 (also known as DAT1)) were associated with at least one phenotype with a p-value <0.01 using linear mixed models. After permutation and FDR adjustment, none of the associations remained statistically significant, although the p-values for the association between rs557748 in OPRM1 and the ND/craving and self-medication phenotypes were both 0.076.ConclusionsBecause the genetic predictors differ, specific cigarette smoking and ND phenotypes should be distinguished in genetic studies in adolescents. Fifteen of the 16 top-ranked SNPs identified in this study were from loci involved in dopaminergic pathways (ANKK1/DRD2, DDC, COMT, OPRM1, and SLC6A3).ImpactDopaminergic pathways may be salient during early smoking and the development of ND.

Project description:Tobacco use is a complex, multistage behaviour. The particular stages of this behaviour, including nicotine dependence (ND), are influenced by both genetics and the environment. Surveys on factors influencing tobacco use and ND, conducted in ethnically homogenous populations, can provide results less influenced by genetic and cultural heterogeneity. We aimed to assess ND in a sample of current smokers, derived from the geographically and culturally isolated population of Kashubians from North Poland, and evaluate its potential association with age, sex, and self-reported comorbidities. In addition, we attempted to replicate - for the first time in this population - previous findings on the association between ND and several variants within the CHRNA5A3-A5-B4 nicotine receptor subunit gene cluster.The study sample consisted of 969 unrelated subjects who were all current smokers. ND was evaluated using four measures: the Fagerstrom Test for Nicotine Dependence (FTND), the Heavy Smoking Index (HSI), the number of cigarettes per day (CPD) and the time to first cigarette after waking (TTF). All subjects underwent genotyping for CHRNA5 rs16969968, CHRNA3 rs578776, and CHRNB4 rs12914008 variants. Multivariate regression analysis was used for the assessment of the studied correlations. A significance level of 0.05 with the Bonferroni correction for multiple testing was set for a type 1 error in the analyses.The mean CPD, FTND and HSI scores in the study sample were 17.3 ± 7.7, 3.9 ± 2.3 and 2.6 ± 1.5, respectively. No association between ND defined by FTND, HSI or TTF and age was found. In turn, heavy smoking was significantly associated with older age (odds ratio (OR)?= 1.72, 95% confidence interval (CI): 1.14-2.59, p = 0.009), and men were more likely than women to be heavy smokers (OR = 1.70, 95% CI: 1.09-2.65, p = 0.018). Chronic comorbidity did not significantly influence ND. An analysis of association of studied polymorphisms with ND showed a borderline association of rs16969968 with CPD (OR = 1.63, 95% CI: 1.09-2.45, p = 0.017).Our study showed a low to moderate level of ND in the Kashubians, influenced by age, sex, as well as the CHRNA5 rs16969968 variant.

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Genomewide linkage survey of nicotine dependence phenotypes.

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Genomewide linkage survey of nicotine dependence phenotypes.

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