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Ortrud K Steinlein - One of the best experts on this subject based on the ideXlab platform.
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Pleiotropic functional effects of the first epilepsy-associated mutation in the human CHRNA2 gene
FEBS Letters, 2009Co-Authors: Jean-charles Hoda, Mario Wanischeck, Daniel Bertrand, Ortrud K SteinleinAbstract:Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) can be caused by mutations in the neuronal nicotinic acetylcholine receptor (nAChR) subunit genes CHRNA4 and CHRNB2. Recently, a point mutation (alpha2-I279N) associated with sleep-related epilepsy has been described in a third nAChR gene, CHRNA2. We demonstrate here that alpha2-I279N can be co-expressed with the major structural subunit CHRNB2. alpha2-I279N causes a marked gain-of-function effect and displays a distinct biopharmacological profile, including markedly reduced inhibition by carbamazepine and increased nicotine sensitivity.
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A major role of the nicotinic acetylcholine receptor gene CHRNA2 in autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is unlikely
Neuroscience Letters, 2007Co-Authors: Daniel Bertrand, Ortrud K SteinleinAbstract:Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is known to be caused by mutations in the transmembrane regions of the neuronal nicotinic acetylcholine receptor (nAChR) genes CHRNA4 and CHRNB2. A third nAChR gene, CHRNA2, has been recently reported as mutated in an Italian family with nocturnal frontal lobe epilepsy, nocturnal wandering and ictal fear. We have now evaluated the role of CHRNA2 in families with "classical" ADNFLE. Mutation screening was performed in 47 families by amplification and subsequent sequencing of part of CHRNA2 exon 6 containing transmembrane regions 1-3. Detected variants were tested in a case-control association study. No mutations were identified in the parts of CHRNA2 that contribute to the ion pore. Sequencing identified a novel synonymous nucleotide exchange (c.771C/T) that was also present in two of 78 controls and is therefore likely to be non-pathogenic. The absence of mutations in our sample of 47 families renders a major role of CHRNA2 in ADNFLE unlikely.
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Schizophrenia, psychotic illness and other psychiatric symptoms in families with autosomal dominant nocturnal frontal lobe epilepsy caused by different mutations.
Psychiatric Genetics, 2003Co-Authors: Andres Magnusson, Eystein Stordal, Eylert Brodtkorb, Ortrud K SteinleinAbstract:ObjectivesAutosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is characterized by a strong family history of epileptic seizures, which predominantly occur during sleep. ADNFLE has been associated with mutations in two genes coding for the nicotinic acetylcholine receptor (CHRNA4 and CHRNB2).
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Mutation screening of the CHRNA4 and CHRNB2 nicotinic cholinergic receptor genes in Alzheimer's disease.
NeuroReport, 1999Co-Authors: Ortrud K Steinlein, Jens Stoodt, Rob A.i. De Vos, Ernst N.h. Jansen Steur, Andrea Wevers, Ulrich Schütz, Hannsjörg SchröderAbstract:POTENTIAL genomic changes leading to decreased nicotine binding, crucial for cognitive dysfunction in Alzheimer's disease (AD), have not yet been studied. A search for mutations of the genes coding for the most widely distributed nicotinic receptor subtype α4β2 (CHRNA4/CHRNB2) has been performed in AD patients by screening the coding regions of both genes by single strand conformation analysis and heteroduplex analysis of fibroblast-derived genomic DNA. Polymorphisms in CHRNA4, none of which led to amino acid changes in the predicted sequence, were found in three patients. Although the other receptor subunits have yet to be screened, it appears likely that the reduction of nicotine binding sites in AD is not due to genomic changes.
Nancy L Saccone - 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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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, 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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the chrna5 chrna3 chrnb4 nicotinic receptor subunit gene cluster affects risk for nicotine dependence in african americans and in european americans
Cancer Research, 2009Co-Authors: Nancy L Saccone, Weimin Duan, Jen C Wang, Scott F Saccone, John P Budde, Richard A Grucza, Naomi Breslau, Eric O. Johnson, Robert CulverhouseAbstract:Genetic association studies have shown the importance of variants in the CHRNA5-CHRNA3-CHRNB4 cholinergic nicotinic receptor subunit gene cluster on chromosome 15q24-25.1 for the risk of nicotine dependence, smoking, and lung cancer in populations of European descent. We have carried out a detailed study of this region using dense genotyping in both European-Americans and African-Americans. We genotyped 75 known single nucleotide polymorphisms (SNPs) and one sequencing-discovered SNP in an African-American sample ( N = 710) and in a European-American sample ( N = 2,062). Cases were nicotine-dependent and controls were nondependent smokers. The nonsynonymous CHRNA5 SNP rs16969968 is the most significant SNP associated with nicotine dependence in the full sample of 2,772 subjects [ P = 4.49 × 10 −8 ; odds ratio (OR), 1.42; 95% confidence interval (CI), 1.25–1.61] as well as in African-Americans only ( P = 0.015; OR, 2.04; 1.15–3.62) and in European-Americans only ( P = 4.14 × 10 −7 ; OR, 1.40; 1.23–1.59). Other SNPs that have been shown to affect the mRNA levels of CHRNA5 in European-Americans are associated with nicotine dependence in African-Americans but not in European-Americans. The CHRNA3 SNP rs578776, which has a low correlation with rs16969968, is associated with nicotine dependence in European-Americans but not in African-Americans. Less common SNPs (frequency ≤ 5%) are also associated with nicotine dependence. In summary, multiple variants in this gene cluster contribute to nicotine dependence risk, and some are also associated with functional effects on CHRNA5 . The nonsynonymous SNP rs16969968, a known risk variant in populations of European-descent, is also significantly associated with risk in African-Americans. Additional SNPs contribute to risk in distinct ways in these two populations. [Cancer Res 2009;69(17):6848–56]
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Multiple distinct risk loci for nicotine dependence identified by dense coverage of the complete family of nicotinic receptor subunit (CHRN) genes.
American journal of medical genetics. Part B Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics, 2009Co-Authors: Nancy L Saccone, Weimin Duan, Scott F Saccone, Jerry A Stitzel, Anthony L. Hinrichs, Richard A Grucza, Naomi Breslau, Arpana Agrawal, Michele L Pergadia, Dorothy HatsukamiAbstract: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 1,050 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.
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Risk for nicotine dependence and lung cancer is conferred by mRNA expression levels and amino acid change in CHRNA5
Human Molecular Genetics, 2009Co-Authors: Carlos Cruchaga, Weimin Duan, John P Budde, Sarah Bertelsen, Nancy L Saccone, Richard A Grucza, Louis Fox, Pengyuan Liu, Jason KernAbstract:Nicotine dependence risk and lung cancer risk are associated with variants in a region of chromosome 15 encompassing genes encoding the nicotinic receptor subunits CHRNA5, CHRNA3 and CHRNB4. To identify potential biological mechanisms that underlie this risk, we tested for cis-acting eQTLs for CHRNA5, CHRNA3 and CHRNB4 in human brain. Using gene expression and disease association studies, we provide evidence that both nicotine-dependence risk and lung cancer risk are influenced by functional variation in CHRNA5. We demonstrated that the risk allele of rs16969968 primarily occurs on the low mRNA expression allele of CHRNA5. The non-risk allele at rs16969968 occurs on both high and low expression alleles tagged by rs588765 within CHRNA5. When the non-risk allele occurs on the background of low mRNA expression of CHRNA5, the risk for nicotine dependence and lung cancer is significantly lower compared to those with the higher mRNA expression. Together, these variants identify three levels of risk associated with CHRNA5. We conclude that there are at least two distinct mechanisms conferring risk for nicotine dependence and lung cancer: altered receptor function caused by a D398N amino acid variant in CHRNA5 (rs16969968) and variability in CHRNA5 mRNA expression.
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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smoking cessation pharmacogenetics analysis of varenicline and bupropion in placebo controlled clinical trials
Neuropsychopharmacology, 2012Co-Authors: David P King, Laura J Bierut, Jaakko Kaprio, Sara Paciga, Neal L Benowitz, David V Conti, Caryn Lerman, Eve H Pickering, Peter W ParkAbstract:Despite effective therapies for smoking cessation, most smokers find quitting difficult and most successful quitters relapse. Considerable evidence supports a genetic risk for nicotine dependence; however, less is known about the pharmacogenetics of smoking cessation. In the first pharmacogenetic investigation of the efficacy of varenicline and bupropion, we examined whether genes important in the pharmacodynamics and pharmacokinetics of these drugs and nicotine predict medication efficacy and adverse events. Subjects participated in randomized, double-blind, placebo-controlled smoking cessation clinical trials, comparing varenicline, a nicotinic acetylcholine receptor (nAChR) partial agonist, with bupropion, a norepinephrine/dopamine reuptake inhibitor, and placebo. Primary analysis included 1175 smokers of European ancestry, and 785 single nucleotide polymorphisms from 24 genes, representing 254 linkage disequilibrium (LD) bins (genes included nAChR subunits, additional varenicline-specific genes, and genes involved in nicotine or bupropion metabolism). For varenicline, continuous abstinence (weeks 9–12) was associated with multiple nAChR subunit genes (including CHRNB2, CHRNA5, and CHRNA4) (OR=1.76; 95% CI: 1.23–2.52) (p<0.005); for bupropion, abstinence was associated with CYP2B6 (OR=1.78; 95% CI: 1.27–2.50) (p<0.001). Incidence of nausea was associated with several nAChR subunit genes (OR=0.50; 95% CI: 0.36–0.70) (p<0.0001) and time to relapse after quitting was associated with HTR3B (HR=1.97; 95% CI: 1.45–2.68) (p<0.0001). These data provide evidence for multiple genetic loci contributing to smoking cessation and therapeutic response. Different loci are associated with varenicline vs bupropion response, suggesting that additional research may identify clinically useful markers to guide treatment decisions.
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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, 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, Jen C Wang, Anthony L. Hinrichs, Laura J Bierut, 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)
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Variants in nicotinic receptors and risk for nicotine dependence
American Journal of Psychiatry, 2008Co-Authors: Laura J Bierut, Scott F Saccone, Xiaoling Xuei, Jerry A Stitzel, Anthony L. Hinrichs, Sarah Bertelsen, Nancy L Saccone, Richard A Grucza, Louis FoxAbstract: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 was to replicate these findings in an independent data set 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. Method: Individuals 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 influences receptor function. Results: A genetic variant marking an amino acid change showed association with the smoking phenotype (p=0.007). This varia...
Robert C Elston - One of the best experts on this subject based on the ideXlab platform.
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Gene-Gene Interactions Among CHRNA4, CHRNB2, BDNF, and NTRK2 in Nicotine Dependence
Biological Psychiatry, 2008Co-Authors: Xiang-yang Lou, Jennie Z, Guo-bo Chen, Robert C ElstonAbstract:Background Epidemiological data indicate that nicotine dependence (ND) are influenced by genes, environmental factors, and their interactions. Although it has been documented from molecular experiments that brain-derived neurotrophic factor ( BDNF ) exerts its functions via neurotrophic tyrosine kinase receptor 2 ( NTRK2 ) and both alpha 4 ( CHRNA4 ) and beta 2 ( CHRNB2 ) subunits are required to form functional α4β2-containing nicotinic receptors (nAChRs), no study is reported demonstrating that there exist gene-gene interactions among the four genes in affecting ND. Methods To determine if gene-gene interactions exist among the four genes, we genotyped six single nucleotide polymorphisms (SNPs) for CHRNA4 and BDNF , nine SNPs for NTRK2 , and four SNPs for CHRNB2 in a case-control sample containing 275 unrelated smokers with a Fagerstrom Test for Nicotine Dependence score of 4.0 or more and 348 unrelated nonsmokers. Results By using a generalized multifactor dimensionality reduction algorithm recently developed by us, we found highly significant gene-gene interactions for the gene pairs of CHRNA4 and CHRNB2, CHRNA4 and NTRK2, CHRNB2 and NTRK2 , and BDNF and NTRK2 ( p CHRNA4 and BDNF ( p = .031) on ND. No significant interaction was detected for CHRNB2 and BDNF ( p = .068). Conclusions Our study provides first evidence on the presence of gene-gene interaction among the four genes in affecting ND. Although CHRNB2 alone was not significantly associated with ND in several previously reported association studies on ND, we found it affects ND through interactions with CHRNA4 and NTRK2 .
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ethnic and gender specific association of the nicotinic acetylcholine receptor α4 subunit gene chrna4 with nicotine dependence
Human Molecular Genetics, 2005Co-Authors: Ming D Li, Thomas J Payne, Joke Beuten, Veronica Garcia, Aristeo S Duenes, Karen M Crews, Robert C ElstonAbstract:We tested six single nucleotide polymorphisms (SNPs) in the a4 subunit gene (CHRNA4) and four SNPs in the b2 subunit gene (CHRNB2) of nicotinic acetylcholine receptors (nAChRs) for association with nicotine dependence (ND), which was assessed by smoking quantity (SQ), the heaviness of smoking index (HSI) and the Fagerstrom test for ND (FTND) in 2037 subjects from 602 nuclear families of either European- American (EA) or African-American (AA) ancestry. Analysis of the six SNPs within CHRNA4 demonstrated that in the EA sample SNPs rs2273504 and rs1044396 are significantly associated with the adjusted SQ and FTND score, respectively. In the AA samples, SNPs rs3787137 and rs2236196 are each significantly associated with at least two adjusted ND measures. Association of rs2236196 with the adjusted HSI and FTND scores in the AA samples remained significant after correction for multiple testing. Furthermore, analy- sis revealed gender- and ethnic-specific associations for several SNPs with ND measures in both ethnic samples; however, only the association of SNP rs2236196 with the three adjusted ND measures remained sig- nificant after correcting for multiple testing in the AA female samples. Haplotype analysis of rs2273505- rs2273504-rs2236196 showed significant association after Bonferroni correction of a C-G-G haplotype (53.4%) with three adjusted ND measures in samples from the AA females. A similar analysis for the four SNPs within CHRNB2 did not reveal significant association with the three ND measures. In summary, our findings provide convincing evidence for the involvement of the nAChR a4 subunit, but not of the nAChR b2 subunit, in nicotine addiction.
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Ethnic- and gender-specific association of the nicotinic acetylcholine receptor α4 subunit gene (CHRNA4) with nicotine dependence
Human Molecular Genetics, 2005Co-Authors: Joke Beuten, Thomas J Payne, Jennie Z, Veronica Garcia, Aristeo S Duenes, Karen M Crews, Xiang-yang Lou, Robert C ElstonAbstract:We tested six single nucleotide polymorphisms (SNPs) in the alpha4 subunit gene (CHRNA4) and four SNPs in the beta2 subunit gene (CHRNB2) of nicotinic acetylcholine receptors (nAChRs) for association with nicotine dependence (ND), which was assessed by smoking quantity (SQ), the heaviness of smoking index (HSI) and the Fagerstrom test for ND (FTND) in 2037 subjects from 602 nuclear families of either European-American (EA) or African-American (AA) ancestry. Analysis of the six SNPs within CHRNA4 demonstrated that in the EA sample SNPs rs2273504 and rs1044396 are significantly associated with the adjusted SQ and FTND score, respectively. In the AA samples, SNPs rs3787137 and rs2236196 are each significantly associated with at least two adjusted ND measures. Association of rs2236196 with the adjusted HSI and FTND scores in the AA samples remained significant after correction for multiple testing. Furthermore, analysis revealed gender- and ethnic-specific associations for several SNPs with ND measures in both ethnic samples; however, only the association of SNP rs2236196 with the three adjusted ND measures remained significant after correcting for multiple testing in the AA female samples. Haplotype analysis of rs2273505-rs2273504-rs2236196 showed significant association after Bonferroni correction of a C-G-G haplotype (53.4%) with three adjusted ND measures in samples from the AA females. A similar analysis for the four SNPs within CHRNB2 did not reveal significant association with the three ND measures. In summary, our findings provide convincing evidence for the involvement of the nAChR alpha4 subunit, but not of the nAChR beta2 subunit, in nicotine addiction.
Jennie Z - One of the best experts on this subject based on the ideXlab platform.
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significant associations of CHRNA2 and chrna6 with nicotine dependence in european american and african american populations
Human Genetics, 2014Co-Authors: Shaolin Wang, Thomas J Payne, Andrew D Van Der Vaart, Chamindi Seneviratne, Ovide F Pomerleau, Cynthia S Pomerleau, Jennie ZAbstract:The direct physiological effects that promote nicotine dependence (ND) are mediated by nicotinic acetylcholine receptors (nAChRs). In line with the genetic and pharmacological basis of addiction, many previous studies have revealed significant associations between variants in the nAChR subunit genes and various measures of ND in different ethnic samples. In this study, we first examined the association of variants in nAChR subunits α2 (CHRNA2) and α6 (CHRNA6) genes on chromosome 8 with ND using a family sample consisting of 1,730 European Americans (EAs) from 495 families and 1,892 African Americans (AAs) from 424 families (defined as the discovery family sample). ND was assessed by two standard quantitative measures: smoking quantity (SQ) and the Fagerstrom Test for ND (FTND). We found nominal associations for all seven tested SNPs of the genes with at least one ND measure in the EA sample and for two SNPs in CHRNA2 in the AA sample. Of these, associations of SNPs rs3735757 with FTND (P = 0.0068) and rs2472553 with both ND measures (with a P value of 0.0043 and 0.00086 for SQ and FTND, respectively) continued to be significant in the EA sample even after correction for multiple tests. Further, we found several haplotypes that were significantly associated with ND in the EA sample in CHRNA6 and in the both EA and AA samples in CHRNA2. To confirm the associations of the two genes with ND, we conducted a replication study with an independent case–control sample from the SAGE study, which showed a significant association of the two genes with ND, although the significantly associated SNPs were not always the same in the two samples. Together, these findings indicate that both CHRNA2 and CHRNA6 play a significant role in the etiology of ND in AA and EA smokers. Further replication in additional independent samples is warranted.
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association and interaction analysis of variants in chrna5 chrna3 chrnb4 gene cluster with nicotine dependence in african and european americans
American Journal of Medical Genetics, 2009Co-Authors: Ming D Li, Thomas J Payne, Qing Xu, Jennie ZAbstract:Several previous genome-wide and targeted association studies revealed that variants in the CHRNA5–CHRNA3–CHRNB4 (CHRNA5/A3/B4) gene cluster on chromosome 15 that encode the α5, α3, and β4 subunits of the nicotinic acetylcholine receptors (nAChRs) are associated with nicotine dependence (ND) in European Americans (EAs) or others of European origin. Considering the distinct linkage disequilibrium patterns in European and other ethnic populations such as African Americans (AAs), it would be interesting to determine whether such associations exist in other ethnic populations. We performed a comprehensive association and interaction analysis of the CHRNA5/A3/B4 cluster in two ethnic samples to investigate the role of variants in the risk for ND, which was assessed by Smoking Quantity, Heaviness Smoking Index, and Fagerstrom test for ND. Using a family-based association test, we found a nominal association of single nucleotide polymorphisms (SNPs) rs1317286 and rs8040868 in CHRNA3 with ND in the AA and combined AA and EA samples. Furthermore, we found that several haplotypes in CHRNA5 and CHRNA3 are nominally associated with ND in AA, EA, and pooled samples. However, none of these associations remained significant after correction for multiple testing. In addition, we performed interaction analysis of SNPs within the CHRNA5/A3/B4 cluster using the pedigree-based generalized multifactor dimensionality reduction method and found significant interactions within CHRNA3 and among the three subunit genes in the AA and pooled samples. Together, these results indicate that variants within CHRNA3 and among CHRNA5, CHRNA3, and CHRNB4 contribute significantly to the etiology of ND through gene–gene interactions, although the association of each subunit gene with ND is weak in both the AA and EA samples. © 2009 Wiley-Liss, Inc.
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Gene-Gene Interactions Among CHRNA4, CHRNB2, BDNF, and NTRK2 in Nicotine Dependence
Biological Psychiatry, 2008Co-Authors: Xiang-yang Lou, Jennie Z, Guo-bo Chen, Robert C ElstonAbstract:Background Epidemiological data indicate that nicotine dependence (ND) are influenced by genes, environmental factors, and their interactions. Although it has been documented from molecular experiments that brain-derived neurotrophic factor ( BDNF ) exerts its functions via neurotrophic tyrosine kinase receptor 2 ( NTRK2 ) and both alpha 4 ( CHRNA4 ) and beta 2 ( CHRNB2 ) subunits are required to form functional α4β2-containing nicotinic receptors (nAChRs), no study is reported demonstrating that there exist gene-gene interactions among the four genes in affecting ND. Methods To determine if gene-gene interactions exist among the four genes, we genotyped six single nucleotide polymorphisms (SNPs) for CHRNA4 and BDNF , nine SNPs for NTRK2 , and four SNPs for CHRNB2 in a case-control sample containing 275 unrelated smokers with a Fagerstrom Test for Nicotine Dependence score of 4.0 or more and 348 unrelated nonsmokers. Results By using a generalized multifactor dimensionality reduction algorithm recently developed by us, we found highly significant gene-gene interactions for the gene pairs of CHRNA4 and CHRNB2, CHRNA4 and NTRK2, CHRNB2 and NTRK2 , and BDNF and NTRK2 ( p CHRNA4 and BDNF ( p = .031) on ND. No significant interaction was detected for CHRNB2 and BDNF ( p = .068). Conclusions Our study provides first evidence on the presence of gene-gene interaction among the four genes in affecting ND. Although CHRNB2 alone was not significantly associated with ND in several previously reported association studies on ND, we found it affects ND through interactions with CHRNA4 and NTRK2 .
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Ethnic- and gender-specific association of the nicotinic acetylcholine receptor α4 subunit gene (CHRNA4) with nicotine dependence
Human Molecular Genetics, 2005Co-Authors: Joke Beuten, Thomas J Payne, Jennie Z, Veronica Garcia, Aristeo S Duenes, Karen M Crews, Xiang-yang Lou, Robert C ElstonAbstract:We tested six single nucleotide polymorphisms (SNPs) in the alpha4 subunit gene (CHRNA4) and four SNPs in the beta2 subunit gene (CHRNB2) of nicotinic acetylcholine receptors (nAChRs) for association with nicotine dependence (ND), which was assessed by smoking quantity (SQ), the heaviness of smoking index (HSI) and the Fagerstrom test for ND (FTND) in 2037 subjects from 602 nuclear families of either European-American (EA) or African-American (AA) ancestry. Analysis of the six SNPs within CHRNA4 demonstrated that in the EA sample SNPs rs2273504 and rs1044396 are significantly associated with the adjusted SQ and FTND score, respectively. In the AA samples, SNPs rs3787137 and rs2236196 are each significantly associated with at least two adjusted ND measures. Association of rs2236196 with the adjusted HSI and FTND scores in the AA samples remained significant after correction for multiple testing. Furthermore, analysis revealed gender- and ethnic-specific associations for several SNPs with ND measures in both ethnic samples; however, only the association of SNP rs2236196 with the three adjusted ND measures remained significant after correcting for multiple testing in the AA female samples. Haplotype analysis of rs2273505-rs2273504-rs2236196 showed significant association after Bonferroni correction of a C-G-G haplotype (53.4%) with three adjusted ND measures in samples from the AA females. A similar analysis for the four SNPs within CHRNB2 did not reveal significant association with the three ND measures. In summary, our findings provide convincing evidence for the involvement of the nAChR alpha4 subunit, but not of the nAChR beta2 subunit, in nicotine addiction.