The Experts below are selected from a list of 4362 Experts worldwide ranked by ideXlab platform
Yan Shen - One of the best experts on this subject based on the ideXlab platform.
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A novel mutation of the nicotinic acetylcholine receptor gene CHRNA4 in sporadic nocturnal frontal lobe epilepsy.
Epilepsy Research, 2009Co-Authors: Yan Chen, Yue Fang, Bingwei Peng, Yan ShenAbstract:Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is known to be partly caused by mutations in the transmembrane domain (TM) 1-3 of the genes of the neuronal nicotinic acetylcholine receptor (nAChR) alpha4-subunit (CHRNA4), beta2-subunit (CHRNB2) and alpha2-subunit (CHRNA2). The more common cases of sporadic nocturnal frontal lobe epilepsy (NFLE) that are not differentiated from ADNFLE by phenotype have been found to be associated with the mutation of CHRNA4 reported in ADNFLE. In order to assess the genetic defects in NFLE, we performed a mutation screening in 33 unrelated patients with sporadic NFLE by amplifying and sequencing bidirectionally TM 1-3 of CHRNA4, CHRNB2 and CHRNA2 which contain the mutations reported in ADNFLE. In screening CHRNA4, we identified a novel mutation in one patient that causes a alpha4-R308H amino acid exchange outside the TM, and in the second intracellular loop between the third and fourth transmembrane domains. The mutation was not observed in 400 control chromosomes. No mutations were present in parts of CHRNB2 and CHRNA2.
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A novel mutation of the nicotinic acetylcholine receptor gene CHRNA4 in sporadic nocturnal frontal lobe epilepsy
Epilepsy Research, 2008Co-Authors: Yan Chen, Yue Fang, Bingwei Peng, Yan ShenAbstract:Summary Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is known to be partly caused by mutations in the transmembrane domain (TM) 1-3 of the genes of the neuronal nicotinic acetylcholine receptor (nAChR) α4-subunit ( CHRNA4 ), β2-subunit ( CHRNB2 ) and α2-subunit ( CHRNA2 ). The more common cases of sporadic nocturnal frontal lobe epilepsy (NFLE) that are not differentiated from ADNFLE by phenotype have been found to be associated with the mutation of CHRNA4 reported in ADNFLE. In order to assess the genetic defects in NFLE, we performed a mutation screening in 33 unrelated patients with sporadic NFLE by amplifying and sequencing bidirectionally TM 1-3 of CHRNA4 , CHRNB2 and CHRNA2 which contain the mutations reported in ADNFLE. In screening CHRNA4 , we identified a novel mutation in one patient that causes a α4-R308H amino acid exchange outside the TM, and in the second intracellular loop between the third and fourth transmembrane domains. The mutation was not observed in 400 control chromosomes. No mutations were present in parts of CHRNB2 and CHRNA2 .
Laura J Bierut - One of the best experts on this subject based on the ideXlab platform.
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variants in the chrna5 chrna3 chrnb4 region of chromosome 15 predict gastrointestinal adverse events in the transdisciplinary tobacco use research center smoking cessation trial
Nicotine & Tobacco Research, 2019Co-Authors: Robert Culverhouse, Lishiun Chen, Nancy L Saccone, Timothy B Baker, Megan E Piper, Laura J BierutAbstract:INTRODUCTION: Reducing adverse events from pharmacologic treatment is an important goal of precision medicine and identifying genetic predictors of adverse events is a step towards this goal. In 2012 King et al. reported associations between genetic variants and adverse events in a placebo-controlled smoking cessation trial of varenicline and bupropion. Strong associations were found between gastrointestinal adverse events and 11 variants in the CHRNA5-CHRNA3-CHRNB4 region of chromosome 15, a region repeatedly associated with smoking-related phenotypes. Our goal was to replicate, in an independent sample, the impact of variants in the CHRNA5-CHRNA3-CHRNB4 region on gastrointestinal adverse events, and to extend the analyses to adherence and smoking cessation. METHODS: The University of Wisconsin Transdisciplinary Tobacco Use Research Center (TTURC) conducted a multi-armed, placebo-controlled smoking cessation trial of bupropion and nicotine replacement therapy (NRT) that included 985 genotyped European-ancestry participants. We evaluated relations between our key variables using logistic regression. RESULTS: Gastrointestinal adverse events were experienced by 31.6% of the TTURC participants. Each of the CHRNA5-CHRNA3-CHRNB4 associations from the King study was found in TTURC, with the same direction of effect. Neither these variants nor the gastrointestinal adverse events themselves were associated with adherence to medication or successful smoking cessation. CONCLUSIONS: Variants in the CHRNA5-CHRNA3-CHRNB4 region of chromosome 15 are associated with gastrointestinal adverse events in smoking cessation. Additional independent variants in this region strengthen the association. The consistency between the results of these two independent studies supports the conclusion that these findings reflect biological response to the use of smoking cessation medication. IMPLICATIONS: The fact that our findings from the TTURC smoking cessation trial, support the independent findings of King et al. suggest that associations of variants in the CHRNA5-CHRNA3-CHRNB4 region of chromosome 15 with gastrointestinal adverse events while taking medications for smoking cessation reflect biology. However, although adherence to medication was a strong predictor of successful smoking cessation in TTURC, neither adverse events nor the genetic variants associated with them predicted either adherence or successful cessation in this study. Thus, although we should strive to minimize adverse events during treatment, we should not expect that to increase successful smoking cessation substantially.
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A multiancestry study identifies novel genetic associations with CHRNA5 methylation in human brain and risk of nicotine dependence
Human Molecular Genetics, 2015Co-Authors: Dana B. Hancock, Jen-chyong Wang, Jerry A Stitzel, Nancy L Saccone, Laura J Bierut, Alison Goate, Nathan C. Gaddis, Joshua L. Levy, Eric O. JohnsonAbstract:Nicotine dependence is influenced by chromosome 15q25.1 single nucleotide polymorphisms (SNPs), including the missense SNP rs16969968 that alters function of the α5 nicotinic acetylcholine receptor (CHRNA5) and noncoding SNPs that regulate CHRNA5 mRNA expression. We tested for cis-methylation quantitative trait loci (cis-meQTLs) using SNP genotypes and DNA methylation levels measured across the IREB2-HYKK-PSMA4-CHRNA5-CHRNA3-CHRNB4 genes on chromosome 15q25.1 in the BrainCloud and Brain QTL cohorts [total N = 175 European-Americans and 65 African-Americans (AAs)]. We identified eight SNPs that were significantly associated with CHRNA5 methylation in prefrontal cortex: P ranging from 6.0 × 10(-10) to 5.6 × 10(-5). These SNP-methylation associations were also significant in frontal cortex, temporal cortex and pons: P ranging from 4.8 × 10(-12) to 3.4 × 10(-3). Of the eight cis-meQTL SNPs, only the intronic CHRNB4 SNP rs11636753 was associated with CHRNA5 methylation independently of the known SNP effects in prefrontal cortex, and it was the most significantly associated SNP with nicotine dependence across five independent cohorts (total N = 7858 European ancestry and 3238 AA participants): P = 6.7 × 10(-4), odds ratio (OR) [95% confidence interval (CI)] = 1.11 (1.05-1.18). The rs11636753 major allele (G) was associated with lower CHRNA5 DNA methylation, lower CHRNA5 mRNA expression and increased nicotine dependence risk. Haplotype analyses showed that rs11636753-G and the functional rs16969968-A alleles together increased risk of nicotine dependence more than each variant alone: P = 3.1 × 10(-12), OR (95% CI) = 1.32 (1.22-1.43). Our findings identify a novel regulatory SNP association with nicotine dependence and connect, for the first time, previously observed differences in CHRNA5 mRNA expression and nicotine dependence risk to underlying DNA methylation differences.
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genomics and personalized medicine chrna5 chrna3 chrnb4 and smoking cessation treatment
Journal of Food and Drug Analysis, 2013Co-Authors: Lishiun Chen, Laura J BierutAbstract:Abstract Cigarette smoking is highly addictive, and modern genetic research has identified robust genetic influences on nicotine dependence. An important step in translating these genetic findings is to identify the genetic factors affecting smoking cessation in order to enhance current smoking cessation treatments. We review the significance of variants in the nicotinic receptor gene cluster ( CHRNA5–CHRNA3–CHRNB4 ) in the prediction of smoking quantity, smoking cessation, and response to cessation medication in multiple studies of smoking cessation. Three common haplotypes (low-risk, intermediate-risk, and high-risk) in the CHRNA5–CHRNA3–CHRNB4 region are defined by rs16969968 and rs680244. The genetic variants in the CHRNA5–CHRNA3–CHRNB4 region that predict nicotine dependence also predicted a later age of smoking cessation in a community-based sample. In a smoking cessation trial, these variants predicted abstinence at the end of treatment in individuals receiving placebo medication, but not among individuals receiving active medication. Pharmacological treatments moderate the genetic risk in affecting cessation success. These pharmacogenetic interactions have been reproduced by a recent meta-analysis of smoking cessation trials. The number needed to treat was four for smokers with the high-risk haplotype, seven for smokers with the intermediate-risk haplotype, and > 1000 for smokers with the low-risk haplotype. The wide variation in number needed to treat between smokers with different haplotypes supports the notion that personalized smoking cessation intervention based upon genotype could meaningfully increase the efficiency of such treatment. In summary, variants in the CHRNA5–CHRNA3–CHRNB4 region identify individuals at increased risk of cessation failure, and this increased risk can be ameliorated by cessation pharmacotherapy.
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Multiple cholinergic nicotinic receptor genes affect nicotine dependence risk in African and European Americans
Genes Brain and Behavior, 2010Co-Authors: Nancy L Saccone, Dorothy Hatsukami, Richard A Grucza, Naomi Breslau, Eric O. Johnson, Tae-hwi Schwantes-an, Jen C. Wang, John P. Rice, Alison Goate, Laura J BierutAbstract:Several independent studies show that the chromosome 15q25.1 region, which contains the CHRNA5–CHRNA3–CHRNB4 gene cluster, harbors variants strongly associated with nicotine dependence, other smoking behaviors, lung cancer and chronic obstructive pulmonary disease. We investigated whether variants in other cholinergic nicotinic receptor subunit (CHRN) genes affect the risk of nicotine dependence in a new sample of African Americans (AAs) (N = 710). We also analyzed this AA sample together with a European American (EA) sample (N = 2062, 1608 of which have been previously studied), allowing for differing effects in the two populations. Cases are current nicotine-dependent smokers and controls are non-dependent smokers. Variants in or near CHRND–CHRNG, CHRNA7 and CHRNA10 show modest association with nicotine dependence risk in the AA sample. In addition, CHRNA4, CHRNB3–CHRNA6 and CHRNB1 show association in at least one population. CHRNG and CHRNA4 harbor single nucleotide polymorphisms (SNPs) that have opposite directions of effect in the two populations. In each of the population samples, these loci substantially increase the trait variation explained, although no loci meet Bonferroni-corrected significance in the AA sample alone. The trait variation explained by three key associated SNPs in CHRNA5–CHRNA3–CHRNB4 is 1.9% in EAs and also 1.9% in AAs; this increases to 4.5% in EAs and 7.3% in AAs when we add six variants representing associations at other CHRN genes. Multiple nicotinic receptor subunit genes outside chromosome 15q25 are likely to be important in the biological processes and development of nicotine dependence, and some of these risks may be shared across diverse populations.
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Nicotinic Receptor Gene Variants Influence Susceptibility to Heavy Smoking
Cancer Epidemiology Biomarkers & Prevention, 2008Co-Authors: Victoria L. Stevens, Anthony L. Hinrichs, Laura J Bierut, Jen C. Wang, Alison Goate, Jeffrey T. Talbot, Juzhong Sun, Michael J. Thun, Eugenia E. CalleAbstract:Heavy smoking is a strong predictor of nicotine dependence, which is a major impediment to smoking cessation. Although both heavy smoking and nicotine dependence are highly heritable, previous attempts to identify genes influencing these phenotypes have been largely unsuccessful until very recently. We studied 1,452 heavy smokers (defined as smoking at least 30 cigarettes per day for at least 5 years) and 1,395 light smokers (defined as smoking 2-fold. Our findings identify two loci in the CHRNA5-CHRNA3-CHRNB4 gene cluster that predict smoking behavior and provide strong evidence for the involvement of the α5 nicotinic receptor in heavy smoking. (Cancer Epidemiol Biomarkers Prev 2008;17(12):3517–25)
Bernard Lerer - One of the best experts on this subject based on the ideXlab platform.
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Association of nicotine dependence susceptibility gene, CHRNA5, with Parkinson's disease age at onset: Gene and smoking status interaction
Parkinsonism & Related Disorders, 2013Co-Authors: Lior Greenbaum, Amihai Rigbi, Rosanna Asselta, Nurit Lipshtat, Roberto Cilia, Silvana Tesei, Ruth Djaldetti, Stefano Goldwurm, Bernard LererAbstract:Abstract Background Smoking is a well documented environmental factor that reduces susceptibility to Parkinson's disease (PD). Several genetic variants within the nicotinic cholinergic receptor gene cluster, CHRNA5 - CHRNA3 - CHRNB4 have been reported to be associated with nicotine dependence (ND), and this association has been validated in multiple studies. Objectives Due to the inverse correlation between smoking and PD susceptibility, we investigated whether ND-related genetic variants are associated with age at onset (AAO) of PD among smokers. Methods We performed a genetic association study in a sample of 677 Italian PD patients, ages 34–76. 438 had never smoked (NS), and 239 were current or past smokers (ever-smokers, ES). Three independent SNPs within the CHRNA5 - CHRNA3 - CHRNB4 gene cluster (rs588765, rs16969968, rs578776) were analyzed for association with AAO. Results We demonstrated an interaction between the rs588765 SNP and smoking status (NS vs. ES) that was nominally significant in its effect on PD AAO ( p = 0.04). The rs588765 ND risk allele ‘C’ was associated with delayed AAO among ES (even when smoking intensity variables are accounted for), but had no significant effect among NS. In the ES group, a dominant model of inheritance was observed: carriers of the ‘CC’ genotype presented delayed AAO compared to carriers of the ‘CT’ or ‘TT’ genotypes. Conclusion Our preliminary results suggest that the ND risk variant, rs588765, has a protective effect in PD, and is associated with later AAO, but only when the individual was previously exposed to nicotine. This may be explained by modulating the neuroprotective effect of chronic nicotine exposure against striatal dopaminergic damage. Further validation studies in additional populations are required.
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role of genetic variants in the chrna5 chrna3 chrnb4 cluster in nicotine dependence risk importance of gene environment interplay
Molecular Psychiatry, 2009Co-Authors: Lior Greenbaum, Amihai Rigbi, Omri Teltsh, Bernard LererAbstract:Role of genetic variants in the CHRNA5–CHRNA3–CHRNB4 cluster in nicotine dependence risk: importance of gene–environment interplay
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Role of genetic variants in the CHRNA5–CHRNA3–CHRNB4 cluster in nicotine dependence risk: importance of gene–environment interplay
Molecular Psychiatry, 2009Co-Authors: Lior Greenbaum, Amihai Rigbi, Omri Teltsh, Bernard LererAbstract:Role of genetic variants in the CHRNA5–CHRNA3–CHRNB4 cluster in nicotine dependence risk: importance of gene–environment interplay
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Why do young women smoke? V. Role of direct and interactive effects of nicotinic cholinergic receptor gene variation on neurocognitive function.
Genes Brain and Behavior, 2008Co-Authors: Amihai Rigbi, Lior Greenbaum, Kyra Kanyas, A Yakir, Yehuda Pollak, Edna Ben-asher, Doron Lancet, S. Kertzman, Bernard LererAbstract:Previous work suggests that young women who smoke cigarettes regularly, or did so in the past, manifest a neurocognitive profile that is characterized by small but significant impairments of response inhibition and attention. The present study sought to determine whether variation in nicotinic cholinergic receptor (nAchR) genes impacts upon cognitive function in these domains by overall or differential effects on the performance of current, former and non-smokers. The study sample consisted of 100 female college students, current or past smokers, and 144 who had never smoked. All performed a computerized neurocognitive test battery and were genotyped for 39 single nucleotide polymorphisms in 11 nAchR genes. The results, derived from linear or logistic regression, show significant direct and interactive relationships between single nucleotide polymorphisms and haplotypes in several nAchR genes and performance on the Matching Familiar Figures Test (MFFT) Stroop test, Continuous Performance Task (CPT) and Tower of London (TOL) test. Response inhibition (MFFT, Stroop, CPT Loading Phase, TOL) was associated with variants in CHRNA2, CHRNA4, CHRNA5, CHRNA7, CHRNA9, CHRNA10, CHRNB2 and CHRNB3. Selective attention (Stroop) was associated with CHRNA4, CHRNA5, CHRNA9 and CHRNB2. Sustained attention (CPT Boring Phase) was associated with CHRNA4, CHRNA5, CHRNA7, CHRNA10 and CHRNB3. Up to 37% of the variance among the smokers and up to 47% of the variance among the non-smokers on the test measures was explained. Differences between smokers and non-smokers in neurocognitive function, putatively implicated in susceptibility to nicotine dependence, may be modulated by variants in nAchR genes, with potential implications for prevention and treatment.
Yan Chen - One of the best experts on this subject based on the ideXlab platform.
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A novel mutation of the nicotinic acetylcholine receptor gene CHRNA4 in sporadic nocturnal frontal lobe epilepsy.
Epilepsy Research, 2009Co-Authors: Yan Chen, Yue Fang, Bingwei Peng, Yan ShenAbstract:Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is known to be partly caused by mutations in the transmembrane domain (TM) 1-3 of the genes of the neuronal nicotinic acetylcholine receptor (nAChR) alpha4-subunit (CHRNA4), beta2-subunit (CHRNB2) and alpha2-subunit (CHRNA2). The more common cases of sporadic nocturnal frontal lobe epilepsy (NFLE) that are not differentiated from ADNFLE by phenotype have been found to be associated with the mutation of CHRNA4 reported in ADNFLE. In order to assess the genetic defects in NFLE, we performed a mutation screening in 33 unrelated patients with sporadic NFLE by amplifying and sequencing bidirectionally TM 1-3 of CHRNA4, CHRNB2 and CHRNA2 which contain the mutations reported in ADNFLE. In screening CHRNA4, we identified a novel mutation in one patient that causes a alpha4-R308H amino acid exchange outside the TM, and in the second intracellular loop between the third and fourth transmembrane domains. The mutation was not observed in 400 control chromosomes. No mutations were present in parts of CHRNB2 and CHRNA2.
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A novel mutation of the nicotinic acetylcholine receptor gene CHRNA4 in sporadic nocturnal frontal lobe epilepsy
Epilepsy Research, 2008Co-Authors: Yan Chen, Yue Fang, Bingwei Peng, Yan ShenAbstract:Summary Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is known to be partly caused by mutations in the transmembrane domain (TM) 1-3 of the genes of the neuronal nicotinic acetylcholine receptor (nAChR) α4-subunit ( CHRNA4 ), β2-subunit ( CHRNB2 ) and α2-subunit ( CHRNA2 ). The more common cases of sporadic nocturnal frontal lobe epilepsy (NFLE) that are not differentiated from ADNFLE by phenotype have been found to be associated with the mutation of CHRNA4 reported in ADNFLE. In order to assess the genetic defects in NFLE, we performed a mutation screening in 33 unrelated patients with sporadic NFLE by amplifying and sequencing bidirectionally TM 1-3 of CHRNA4 , CHRNB2 and CHRNA2 which contain the mutations reported in ADNFLE. In screening CHRNA4 , we identified a novel mutation in one patient that causes a α4-R308H amino acid exchange outside the TM, and in the second intracellular loop between the third and fourth transmembrane domains. The mutation was not observed in 400 control chromosomes. No mutations were present in parts of CHRNB2 and CHRNA2 .
Alison Goate - One of the best experts on this subject based on the ideXlab platform.
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A multiancestry study identifies novel genetic associations with CHRNA5 methylation in human brain and risk of nicotine dependence
Human Molecular Genetics, 2015Co-Authors: Dana B. Hancock, Jen-chyong Wang, Jerry A Stitzel, Nancy L Saccone, Laura J Bierut, Alison Goate, Nathan C. Gaddis, Joshua L. Levy, Eric O. JohnsonAbstract:Nicotine dependence is influenced by chromosome 15q25.1 single nucleotide polymorphisms (SNPs), including the missense SNP rs16969968 that alters function of the α5 nicotinic acetylcholine receptor (CHRNA5) and noncoding SNPs that regulate CHRNA5 mRNA expression. We tested for cis-methylation quantitative trait loci (cis-meQTLs) using SNP genotypes and DNA methylation levels measured across the IREB2-HYKK-PSMA4-CHRNA5-CHRNA3-CHRNB4 genes on chromosome 15q25.1 in the BrainCloud and Brain QTL cohorts [total N = 175 European-Americans and 65 African-Americans (AAs)]. We identified eight SNPs that were significantly associated with CHRNA5 methylation in prefrontal cortex: P ranging from 6.0 × 10(-10) to 5.6 × 10(-5). These SNP-methylation associations were also significant in frontal cortex, temporal cortex and pons: P ranging from 4.8 × 10(-12) to 3.4 × 10(-3). Of the eight cis-meQTL SNPs, only the intronic CHRNB4 SNP rs11636753 was associated with CHRNA5 methylation independently of the known SNP effects in prefrontal cortex, and it was the most significantly associated SNP with nicotine dependence across five independent cohorts (total N = 7858 European ancestry and 3238 AA participants): P = 6.7 × 10(-4), odds ratio (OR) [95% confidence interval (CI)] = 1.11 (1.05-1.18). The rs11636753 major allele (G) was associated with lower CHRNA5 DNA methylation, lower CHRNA5 mRNA expression and increased nicotine dependence risk. Haplotype analyses showed that rs11636753-G and the functional rs16969968-A alleles together increased risk of nicotine dependence more than each variant alone: P = 3.1 × 10(-12), OR (95% CI) = 1.32 (1.22-1.43). Our findings identify a novel regulatory SNP association with nicotine dependence and connect, for the first time, previously observed differences in CHRNA5 mRNA expression and nicotine dependence risk to underlying DNA methylation differences.
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Functional characterization improves associations between rare non-synonymous variants in CHRNB4 and smoking behavior.
PLoS ONE, 2014Co-Authors: Gabe Haller, Alison Goate, Caroline Esch, Simon Hsu, Joe Henry SteinbachAbstract:Smoking is the leading cause of preventable death worldwide. Accordingly, effort has been devoted to determining the genetic variants that contribute to smoking risk. Genome-wide association studies have identified several variants in nicotinic acetylcholine receptor genes that contribute to nicotine dependence risk. We previously undertook pooled sequencing of the coding regions and flanking sequence of the CHRNA5, CHRNA3, CHRNB4, CHRNA6 and CHRNB3 genes and found that rare missense variants at conserved residues in CHRNB4 are associated with reduced risk of nicotine dependence among African Americans. We identified 10 low frequency (
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functional characterization improves associations between rare non synonymous variants in chrnb4 and smoking behavior
PLOS ONE, 2014Co-Authors: Gabe Haller, Alison Goate, Caroline Esch, Simon Hsu, Joe Henry SteinbachAbstract:Smoking is the leading cause of preventable death worldwide. Accordingly, effort has been devoted to determining the genetic variants that contribute to smoking risk. Genome-wide association studies have identified several variants in nicotinic acetylcholine receptor genes that contribute to nicotine dependence risk. We previously undertook pooled sequencing of the coding regions and flanking sequence of the CHRNA5, CHRNA3, CHRNB4, CHRNA6 and CHRNB3 genes and found that rare missense variants at conserved residues in CHRNB4 are associated with reduced risk of nicotine dependence among African Americans. We identified 10 low frequency (<5%) non-synonymous variants in CHRNB4 and investigated functional effects by co-expression with normal α3 or α4 subunits in human embryonic kidney cells. Voltage-clamp was used to obtain acetylcholine and nicotine concentration-response curves and qRT-PCR, western blots and cell-surface ELISAs were performed to assess expression levels. These results were used to functionally weight genetic variants in a gene-based association test. We find that there is a highly significant correlation between carrier status weighted by either acetylcholine EC50 (β = -0.67, r2 = 0.017, P = 2 × 10(-4)) or by response to low nicotine (β = -0.29, r2 = 0.02, P = 6 × 10(-5)) when variants are expressed with the α3 subunit. In contrast, there is no significant association when carrier status is unweighted (β = -0.04, r2 = 0.0009, P = 0.54). These results highlight the value of functional analysis of variants and the advantages to integrating such data into genetic studies. They also suggest that an increased sensitivity to low concentrations of nicotine is protective from the risk of developing nicotine dependence.
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eLS - Genetics of Nicotine Addiction
eLS, 2014Co-Authors: A. Joseph Bloom, Alison GoateAbstract:Diseases associated with addiction to nicotine, the key reinforcing constituent of tobacco, remain the largest cause of preventable death worldwide. Although twin studies indicate a large genetic contribution to the variation in smoking-related behaviours, the polymorphisms underlying this heritability remain largely unidentified. Candidate gene studies have investigated several pathways, but thus far only those few genetic loci identified in unbiased genome-wide association studies have been consistently replicated; these are the direct targets of nicotine in the nervous system, the nicotinic acetylcholine receptor subunit genes CHRNA5–CHRNA3–CHRNB4 and the primary nicotine metabolism gene CYP2A6. These variants may differ in their influences regarding different aspects of smoking behaviour, and their frequencies vary widely among different ethnic populations. Use of more-targeted phenotypes including biomarkers of smoke exposure such as cotinine, nicotine's major metabolite, and exhaled carbon monoxide, may provide the key to detecting further genetic correlates of nicotine dependence and related diseases. Key Concepts: Variation in nicotine addiction-related traits have large genetic components. Genetic studies of nicotine addiction seek to identify drug targets for smoking cessation treatment and to improve treatments using genotype-based personalised medicine. Candidate gene studies have focussed on the nicotinic acetylcholine receptors and genes in the nicotine metabolism, dopaminergic, serotonergic, GABAergic, and opioid pathways, but few associations have been convincingly replicated. Unbiased genome-wide studies have identified very few consistent genetic associations with smoking-related phenotypes. A functional variant in the CHRNA5–CHRNA3–CHRNB4 gene cluster is robustly associated with multiple smoking behaviours and related disease risk. Functional variation in the CYP2A6 nicotine metabolism gene is associated with cigarette consumption and related disease risk. Genetic factors contributing to nicotine addiction vary by ethnic population. Genotype–environment and genotype–treatment interactions are important factors determining smoking initiation, dependence and cessation outcomes. Use of biomarkers and other endophenotypes may provide greater power to identify genetic correlates of nicotine dependence. Keywords: Nicotine; addiction; genetics; polymorphism; smoking; tobacco; CHRNA5; CYP2A6
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Multiple cholinergic nicotinic receptor genes affect nicotine dependence risk in African and European Americans
Genes Brain and Behavior, 2010Co-Authors: Nancy L Saccone, Dorothy Hatsukami, Richard A Grucza, Naomi Breslau, Eric O. Johnson, Tae-hwi Schwantes-an, Jen C. Wang, John P. Rice, Alison Goate, Laura J BierutAbstract:Several independent studies show that the chromosome 15q25.1 region, which contains the CHRNA5–CHRNA3–CHRNB4 gene cluster, harbors variants strongly associated with nicotine dependence, other smoking behaviors, lung cancer and chronic obstructive pulmonary disease. We investigated whether variants in other cholinergic nicotinic receptor subunit (CHRN) genes affect the risk of nicotine dependence in a new sample of African Americans (AAs) (N = 710). We also analyzed this AA sample together with a European American (EA) sample (N = 2062, 1608 of which have been previously studied), allowing for differing effects in the two populations. Cases are current nicotine-dependent smokers and controls are non-dependent smokers. Variants in or near CHRND–CHRNG, CHRNA7 and CHRNA10 show modest association with nicotine dependence risk in the AA sample. In addition, CHRNA4, CHRNB3–CHRNA6 and CHRNB1 show association in at least one population. CHRNG and CHRNA4 harbor single nucleotide polymorphisms (SNPs) that have opposite directions of effect in the two populations. In each of the population samples, these loci substantially increase the trait variation explained, although no loci meet Bonferroni-corrected significance in the AA sample alone. The trait variation explained by three key associated SNPs in CHRNA5–CHRNA3–CHRNB4 is 1.9% in EAs and also 1.9% in AAs; this increases to 4.5% in EAs and 7.3% in AAs when we add six variants representing associations at other CHRN genes. Multiple nicotinic receptor subunit genes outside chromosome 15q25 are likely to be important in the biological processes and development of nicotine dependence, and some of these risks may be shared across diverse populations.