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A twin association study of nicotine dependence with markers in the CHRNA3 and CHRNA5 genes.

ABSTRACT: Twin and family studies have provided overwhelming evidence for the genetic basis of individual differences in tobacco initiation (TI), regular smoking (RS) and nicotine dependence (ND). However, only a few genes have been reliably associated with ND. We used a finite mixture distribution model to examine the significance and effect size of the association of previously identified and replicated specific variants in the CHRNA5 and CHRNA3 receptor genes with ND, against the background of genetic and environmental risk factors for ND. We hypothesize that additional phenotypic information in relatives who have not been genotyped can be used to increase the power of detecting the genetic variant. The nicotine measures were assessed by personal interview in female, male and opposite sex twin pairs (N = 4,153) from the population-based Virginia Twin Registry. Three SNPs in the CHRNA5 and CHRNA3 receptor genes, previously shown to be significantly associated with ND in this sample, were replicated in the augmented analyses; they accounted for less than one percent of the genetic variance in liability to ND, which is estimated to be over 50% of the phenotypic variance. The significance of these effects was increased by adding twins with phenotype but without genotype data, but gains are limited and variable. The SNPs associated with ND did not show a significant association with either TI or RS and appear to be specific to the addictive stage of ND, characterized by current smoking and smoking a large amount of cigarettes per day. Furthermore, these SNPs did not appear to be associated with the remaining items comprising the FTND scale. This study confirmed a significant contribution of the CHRNA receptor on different forms of tobacco dependence. However, the genetic variant only accounted for little of the total genetic variance for liability to ND. Including phenotypic data on ungenotyped relatives can improve the statistical power to detect the effects of genetic variants when they contribute to individual differences in the phenotype.

SUBMITTER: Maes HH

PROVIDER: S-EPMC3400498 | biostudies-literature | 2011 Sep

REPOSITORIES: biostudies-literature

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A twin association study of nicotine dependence with markers in the CHRNA3 and CHRNA5 genes.

Maes Hermine H HH Neale Michael C MC Chen Xiangning X Chen Jingchun J Prescott Carol A CA Kendler Kenneth S KS

Behavior genetics 20110712 5

Twin and family studies have provided overwhelming evidence for the genetic basis of individual differences in tobacco initiation (TI), regular smoking (RS) and nicotine dependence (ND). However, only a few genes have been reliably associated with ND. We used a finite mixture distribution model to examine the significance and effect size of the association of previously identified and replicated specific variants in the CHRNA5 and CHRNA3 receptor genes with ND, against the background of genetic ...[more]

PMID: 21748402

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Project description:Smoking is a major risk factor for several somatic diseases and is also emerging as a causal factor for neuropsychiatric disorders. Genome-wide association (GWA) and candidate gene studies for smoking behavior and nicotine dependence (ND) have disclosed too few predisposing variants to account for the high estimated heritability. Previous large-scale GWA studies have had very limited phenotypic definitions of relevance to smoking-related behavior, which has likely impeded the discovery of genetic effects. We performed GWA analyses on 1114 adult twins ascertained for ever smoking from the population-based Finnish Twin Cohort study. The availability of 17 smoking-related phenotypes allowed us to comprehensively portray the dimensions of smoking behavior, clustered into the domains of smoking initiation, amount smoked and ND. Our results highlight a locus on 16p12.3, with several single-nucleotide polymorphisms (SNPs) in the vicinity of CLEC19A showing association (P<1 × 10(-6)) with smoking quantity. Interestingly, CLEC19A is located close to a previously reported attention-deficit hyperactivity disorder (ADHD) linkage locus and an evident link between ADHD and smoking has been established. Intriguing preliminary association (P<1 × 10(-5)) was detected between DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, 4th edition) ND diagnosis and several SNPs in ERBB4, coding for a Neuregulin receptor, on 2q33. The association between ERBB4 and DSM-IV ND diagnosis was replicated in an independent Australian sample. Recently, a significant increase in ErbB4 and Neuregulin 3 (Nrg3) expression was revealed following chronic nicotine exposure and withdrawal in mice and an association between NRG3 SNPs and smoking cessation success was detected in a clinical trial. ERBB4 has previously been associated with schizophrenia; further, it is located within an established schizophrenia linkage locus and within a linkage locus for a smoker phenotype identified in this sample. In conclusion, we disclose novel tentative evidence for the involvement of ERBB4 in ND, suggesting the involvement of the Neuregulin/ErbB signalling pathway in addictions and providing a plausible link between the high co-morbidity of schizophrenia and ND.

Dataset Information

A twin association study of nicotine dependence with markers in the CHRNA3 and CHRNA5 genes.

Publications

A twin association study of nicotine dependence with markers in the CHRNA3 and CHRNA5 genes.

Similar Datasets

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