Nicotinic Receptor Gene Variants Influence Susceptibility to Heavy Smoking (original) (raw)
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α-5/α-3 nicotinic receptor subunit alleles increase risk for heavy smoking
Molecular Psychiatry, 2008
Twin studies indicate that additive genetic effects explain most of the variance in nicotine dependence (ND), a construct emphasizing habitual heavy smoking despite adverse consequences, tolerance and withdrawal. To detect ND alleles, we assessed cigarettes per day (CPD) regularly smoked, in two European populations via whole genome association techniques. In these ∼7500 persons, a common haplotype in the CHRNA3-CHRNA5 nicotinic receptor subunit gene cluster was associated with CPD (nominal P = 6.9 × 10 −5 ). In a third set of European populations (n = ∼7500) which had been genotyped for ∼6000 SNPs in ∼2000 genes, an allele in the same haplotype was associated with CPD (nominal P = 2.6 × 10 −6 ). These results (in three independent populations of European origin, totaling ∼15 000 individuals) suggest that a common haplotype in the CHRNA5/CHRNA3 gene cluster on chromosome 15 contains alleles, which predispose to ND.
Variants in the nicotinic receptors alter the risk for nicotine dependence
The American journal …, 2008
ObjectiveA recent study provisionally identified numerous genetic variants as risk factors for the transition from smoking to the development of nicotine dependence, including an amino acid change in the α5 nicotinic cholinergic receptor (CHRNA5). The purpose of this study is to replicate these findings in an independent dataset and more thoroughly investigate the role of genetic variation in the cluster of physically linked nicotinic receptors, CHRNA5-CHRNA3-CHRNB4, and the risk of smoking.MethodsIndividuals from 219 European American families (N=2,284) were genotyped across this gene cluster to test the genetic association with smoking. The frequency of the amino acid variant (rs16969968) was studied in 995 individuals from diverse ethnic populations. In vitro studies were performed to directly test whether the amino acid variant in the CHRNA5 influenced receptor function.ResultsA genetic variant marking an amino acid change showed association with the smoking phenotype (p=0.007)....
The contribution of rare and common variants in 30 genes to risk nicotine dependence
Molecular psychiatry, 2014
Genetic and functional studies have revealed that both common and rare variants of several nicotinic acetylcholine receptor subunits are associated with nicotine dependence (ND). In this study, we identified variants in 30 candidate genes including nicotinic receptors in 200 sib pairs selected from the Mid-South Tobacco Family population with equal numbers of African Americans (AAs) and European Americans (EAs). We selected 135 of the rare and common variants and genotyped them in the Mid-South Tobacco Case-Control (MSTCC) population, which consists of 3088 AAs and 1430 EAs. None of the genotyped common variants showed significant association with smoking status (smokers vs non-smokers), Fagerström Test for ND scores or indexed cigarettes per day after Bonferroni correction. Rare variants in NRXN1, CHRNA9, CHRNA2, NTRK2, GABBR2, GRIN3A, DNM1, NRXN2, NRXN3 and ARRB2 were significantly associated with smoking status in the MSTCC AA sample, with weighted sum statistic (WSS) P-values ra...
American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 2012
Smoking many cigarettes per day (CPD) and short interval to first cigarette (TTF) after waking are two of the most heritable smoking phenotypes and comprise the Heavy Smoking Index (HSI). These phenotypes are often used as proxies for nicotine dependence (ND) and are associated with smoking cessation outcomes. Case-control and genome-wide association studies have reported links between single nucleotide polymorphisms (SNPs) in the alpha-5 and -3 nicotinic receptor subunit (CHRNA5 and CHRNA3) genes and CPD but few have examined TTF or cessation outcomes. In this study we longitudinally assessed 1301 European-American smokers at four time-points from 1988 to 2005. One CHRNA5 (rs16969968) and two CHRNA3 (rs1051703, rs6495308) SNPs were examined for their ability to predict smokers who ''ever'' reported ND based on three phenotypic classifications: (1) 25þ CPD, (2) TTF < 10 min, and (3) HSI ! 4. In a subsample of 1157 quit attempters, we also examined each SNP's ability to predict ''ever'' quitting for a period of >6 months. Demographically adjusted logistic regressions showed significant allelic and genotypic associations between all three SNPs and CPD but not TTF, HSI, or smoking cessation. Carriers of both the rs16969968-AA and rs6495308-TT genotypes had approximately twofold greater odds for ND defined using CPD or TTF. Results suggest nicotinic receptor variants are associated with greater odds of ND according to CPD and to a lesser extent TTF. Research examining the effect of nicotinic receptor genetic variation on ND phenotypes beyond CPD is warranted.
American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 2009
Tobacco smoking continues to be a leading cause of preventable death. Recent research has underscored the important role of specific cholinergic nicotinic receptor subunit (CHRN) genes in risk for nicotine dependence and smoking. To detect and characterize the influence of genetic variation on vulnerability to nicotine dependence, we analyzed 226 SNPs covering the complete family of 16 CHRN genes, which encode the nicotinic acetylcholine receptor (nAChR) subunits, in a sample of 1050 nicotine-dependent cases and 879 non-dependent controls of European descent. This expanded SNP coverage has extended and refined the findings of our previous large scale genome-wide association and candidate gene study. After correcting for the multiple tests across this gene family, we found significant association for two distinct loci in the CHRNA5-CHRNA3-CHRNB4 gene cluster, one locus in the CHRNB3-CHRNA6 gene cluster, and a fourth, novel locus in the CHRND-CHRNG gene cluster. The two distinct loci in CHRNA5-CHRNA3-CHRNB4 are represented by the non-synonymous SNP rs16969968 in CHRNA5 and by rs578776 in CHRNA3, respectively, and joint analyses show that the associations at these two SNPs are statistically independent. Nominally significant single-SNP association was detected in CHRNA4 and CHRNB1. In summary, this is the most comprehensive study of the CHRN genes for involvement with nicotine dependence to date. Our analysis reveals significant evidence for at least four distinct loci in the nicotinic receptor subunit genes that each influence the transition from smoking to nicotine dependence and may inform the development of improved smoking cessation treatments and prevention initiatives.
Regulatory Variants in Nicotine Dependence Risk Genes
Introduction: Genetic variants within nicotinic receptors have been shown to modulate an individual’s risk for nicotine dependence. Among the most reproducible risk factor is a non-synonymous polymorphism (rs16969968) within the alpha5 nicotinic receptor subunit gene, CHRNA5. Genetic factors also contribute to CHRNA5 mRNA expression and risk for substance abuse, but the specific variants responsible for changes in mRNA expression are unclear. Methodology: To determine the presence of cis-acting functional genetic variants contributing to CHRNA5 mRNA expression, we measured allelic expression of CHRNA5 within post-mortem human prefrontal cortex brain tissue. Using allelic expression as a phenotype, we scanned the CHRNA5 gene locus for polymorphisms responsible for imbalanced allelic expression. Polymorphisms determined to be responsible for allelic expression were genotyped in our full brain cohort and total CHRNA5 expression was compared across genotype using quantitative PCR. We then tested these expression-related variants for clinical association with nicotine dependence. Results: We uncovered a functional genetic locus 13.5kb upstream of CHRNA5 acting as an enhancer of CHRNA5 mRNA expression. Minor allele carriers for enhancer variants displayed >2- fold differences in allelic expression, while individuals homozygous for the enhancer minor alleles expressed >4-fold more cortical CHRNA5 mRNA. Haplotype structure analysis predicts that the enhancer SNPs rarely occur on the same allele as the previously implicated non-synonymous variant. Taking into account this relationship, enhancer region SNPs confer significant risk only when you control for the presence of the non-synonymous variant in a joint SNP analysis. Conclusions: Polymorphisms within a transcriptional enhancer located 13.5kb upstream of CHRNA5 modulate CHRNA5 mRNA transcription. These enhancer variants confer risk for nicotine dependence in a context-dependent manner. Understanding the biological functions of these clinically relevant genetic variants revealed a SNP-SNP interaction increasing risk for nicotine dependence that is otherwise obscured by haplotype structure when using traditional clinical association methods. These findings aid in the construction of complex biological or genetic models of nicotine dependence that mimic human factors. The relevance of the enhancer CHRNA5 polymorphism in other brain regions and peripheral tissues (e.g., the lung) needs further study. Moreover, identification of functional CHRNA5 variants facilitates the analysis of gene-gene interactions with respect to nicotine and other drug addictions.
Variants in Nicotinic Receptors and Risk for Nicotine Dependence
American Journal of Psychiatry, 2008
Objective-A recent study provisionally identified numerous genetic variants as risk factors for the transition from smoking to the development of nicotine dependence, including an amino acid change in the α5 nicotinic cholinergic receptor (CHRNA5). The purpose of this study is to replicate these findings in an independent dataset and more thoroughly investigate the role of genetic variation in the cluster of physically linked nicotinic receptors, CHRNA5-CHRNA3-CHRNB4, and the risk of smoking.
Human molecular …, 2007
Nicotine dependence is one of the world's leading causes of preventable death. To discover genetic variants that influence risk for nicotine dependence, we targeted over 300 candidate genes and analyzed 3713 single nucleotide polymorphisms (SNPs) in 1050 cases and 879 controls. The Fagerströ m test for nicotine dependence (FTND) was used to assess dependence, in which cases were required to have an FTND of 4 or more. The control criterion was strict: control subjects must have smoked at least 100 cigarettes in their lifetimes and had an FTND of 0 during the heaviest period of smoking. After correcting for multiple testing by controlling the false discovery rate, several cholinergic nicotinic receptor genes dominated the top signals. The strongest association was from an SNP representing CHRNB3, the b3 nicotinic receptor subunit gene (P 5 9.4 3 10 25 ). Biologically, the most compelling evidence for a risk variant came from a non-synonymous SNP in the a5 nicotinic receptor subunit gene CHRNA5 (P 5 6.4 3 10 24 ). This SNP exhibited evidence of a recessive mode of inheritance, resulting in individuals having a 2-fold increase in risk of developing nicotine dependence once exposed to cigarette smoking. Other genes among the top signals were KCNJ6 and GABRA4. This study represents one of the most powerful and extensive studies of nicotine dependence to date and has found novel risk loci that require confirmation by replication studies.