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The CHRNA5–A3–B4 gene cluster in nicotine addiction

Abstract

Nicotine addiction (NA) is a common and devastating disease, such that the annual number of deaths (world-wide) from tobacco-related diseases will double from 5 million in the year 2000 to 10 million in 2020. Nicotine is the only substance in tobacco which animals and humans will self-administer. NA, as a lifetime diagnosis, has been assessed in various approaches, including the concept of cigarettes per day (CPD). Other assessments of NA are somewhat more comprehensive, such as the Fagerstrom Test for Nicotine Dependence or the American Psychiatric Association's Diagnostic and Statistical Manual (fourth edition) diagnosis of nicotine dependence. These different measures have moderate agreement with one another. Twin, family and adoption studies have shown that these different assessments of NA have substantial heritability (that fraction of risk attributable to genetic factors). The heritability of NA has been estimated at 50–75%, depending on the definition and the population under study. DNA-based studies of NA have been somewhat successful in identifying a common haplotype, which increases risk for NA among European-origin populations. This haplotype explains a small amount of variance, accounting for 1 CPD, and it includes the α5 and the α3 nicotinic receptor subunit genes (CHRNA5 and CHRNA3). The review will focus on this implicated region. In this risk region, there is a common (among European-origin people) mis-sense single-nucleotide polymorphism in the CHRNA5 gene (D398N), which changes a conserved amino acid from aspartic acid to asparagine. The risk allele (398N) confers decreased calcium permeability and more extensive desensitization, according to in vitro cellular studies, raising the possibility that a positive allosteric modulator of the (α4β2)2α5 type of nicotinic receptor might have therapeutic potential in NA. There are other genetic influences on NA in this region, apart from the mis-sense variant, and additional biological experiments must be done to understand them.

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References

  1. World Health Statistics 2006. WHO Press, http://www.who.int/whosis.

  2. World Health Organization. WHO Report on the Global Tobacco Epidemic, 2008. <http://tobaccofreecenter.org/mpower-2008> (2008).

  3. Breslau N, Johnson EO, Hiripi E, Kessler R . Nicotine dependence in the United States. Arch Gen Psychiatry 2001; 58: 810–814.

    Article  CAS  PubMed  Google Scholar 

  4. Heatherton TF, Kozlowski LT, Frecker RC, Fagerstrom KO . The Fagerstrom test for nicotine dependence: a revision of the Fagerstrom tolerance questionnaire. Br J Addict 1991; 86: 1119–1127.

    Article  CAS  PubMed  Google Scholar 

  5. Lessov CN, Martin NG, Statham DJ, Todorov AA, Slutske WS, Bucholz KK et al. Defining nicotine dependence for genetic research: evidence from Australian twins. Psychol Med 2004; 34: 865–879.

    Article  PubMed  Google Scholar 

  6. Breslau N, Johnson EO . smoking cessation and major depression in nicotine-dependent smokers. Am J Public Health 2000; 90: 1122–1127.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Moolchan ET, Radzius A, Epstein DH, Uhl G, Gorelick DA, Cadet JL et al. The Fagerstrom test for nicotine dependence and the diagnostic interview schedule. Do they diagnose the same smokers? Addictive Behaviors 2001; 27: 101–113.

    Article  Google Scholar 

  8. Bierut LJ, Madden PA, Breslau N, Johnson EO, Hatsukami D, Pomerleau OF et al. Novel genes identified in a high-density genome wide association study for nicotine dependence. Hum Mol Genet 2007; 16: 24–35.

    CAS  PubMed  Google Scholar 

  9. Berrettini WH, Yuan X, Tozzi F, Song K, Chilcoat H, Francks C et al. Alpha-5/Alpha-3 Nicotinic Receptor Subunit Alleles Increase Risk for Heavy Smoking. Molecular Psychiatry 2008; 13: 368–373.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Hall W, Madden P, Lynskey M . The genetics of tobacco use: methods, findings and policy implications. Tob Control 2002; 11: 119–124.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Maes HH, Sullivan PF, Bulik CM, Neale MC, Prescott CA, Eaves LJ et al. A twin study of genetic and environmental influences on tobacco initiation, regular tobacco use and nicotine dependence. Psychol Med 2004; 34: 1251–1261.

    Article  PubMed  Google Scholar 

  12. Lessov-Schlaggar CN, Pang Z, Swan GE, Guo Q, Wang S, Cao W et al. Heritability of cigarette smoking and alcohol use in Chinese male twins: the Qingdao twin registry. Int J Epidemiol 2006; 35: 1278–1285.

    Article  PubMed  Google Scholar 

  13. Straub RE, Sullivan PF, Ma Y, Myakishev MV, Harris-Kerr C, Wormley B et al. Susceptibility genes for nicotine dependence: a genome scan and followup in an independent sample suggest that regions on chromosomes 2, 4, 10, 16, 17 and 18 merit further study. Mol Psychiatry 1999; 4: 129–144.

    Article  CAS  PubMed  Google Scholar 

  14. Swan GE, Hops H, Wilhelmsen KC, Lessov-Schlaggar CN, Cheng LS, Hudmon KS et al. A genome-wide screen for nicotine dependence susceptibility loci. Am J Med Genet B Neuropsychiatr Genet 2006; 141: 354–360.

    Article  Google Scholar 

  15. Li MD, Payne TJ, Ma JZ, Lou X-Y, Zhang D, Dupont RT et al. A genome-wide search finds major susceptibility loci for nicotine dependence on chromosome 10 in African Americans. Am J Hum Genet 2006; 79: 745–751.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Gelernter J, Panhuysen C, Weiss R, Brady K, Poling J, Krauthammer M et al. Genomewide linkage scan for nicotine dependence: identification of a chromosome 5 risk locus. Biol Psychiatry 2007; 61: 119–126.

    Article  CAS  PubMed  Google Scholar 

  17. Vink JM, Beem AL, Posthuma D, Neale MC, Willemsen G, Kendler KS et al. Linkage analysis of smoking initiation and quantity in Dutch sibling pairs. Pharmacogenomics J 2004; 4: 274–282, (erratum 4: 345–346).

    Article  CAS  PubMed  Google Scholar 

  18. Goode EL, Badzioch MD, Kim H, Gagnon F, Rozek LS, Edwards KL et al. Framingham Heart Study Multiple genome-wide analyses of smoking behavior in the Framingham Heart Study. BMC Genet Suppl 2003; 4: S102.

    Article  Google Scholar 

  19. Li MD, Ma JZ, Cheng R, Dupont RT, Williams NJ, Crews KM et al. Framingham Heart Study A genome-wide scan to identify loci for smoking rate in the Framingham Heart Study population. BMC Genet Suppl 2003; 4: S103.

    Article  Google Scholar 

  20. Li MD, Sun D, Lou XY, Beuten J, Payne TJ, Ma JZ . Linkage and association studies in African- and Caucasian-American populations demonstrate that SHC3 is a novel susceptibility locus for nicotine dependence. Mol Psychiatry 2007; 12: 462–473.

    Article  CAS  PubMed  Google Scholar 

  21. Saccone SF, Pergadia ML, Loukola A, Broms U, Montgomery GW, Wang JC et al. Genetic linkage to chromosome 22q12 for a heavy-smoking quantitative trait in two independent samples. Am J Hum Genet 2007; 80: 856–866.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Li MD . The genetics of nicotine dependence. Curr Psychiatry Rep 2006; 8: 158–164.

    Article  CAS  PubMed  Google Scholar 

  23. Hirschhorn JN, Altshuler D . Once and again—Issues surrounding replication in genetic association studies. J Clin Endocrinol Metab 2002; 87: 4438–4441.

    Article  CAS  PubMed  Google Scholar 

  24. Feng Y, Niu T, Xing H, Xu X, Chen C, Peng S et al. A common haplotype of the nicotine acetylcholine receptor alpha 4 subunit gene is associated with vulnerability to nicotine addiction in men. Am J Hum Genet 2004; 75: 112–121.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Li MD, Beuten J, Ma JZ, Payne TJ, Lou XY, Garcia V et al. Ethnic- and gender-specific association of the nicotinic acetylcholine receptor alphA4 subunit gene (CHRNA4) with nicotine dependence. Hum Mol Genet 2005; 14: 1211–1219.

    Article  CAS  PubMed  Google Scholar 

  26. Ma JZ, Beuten J, Payne TJ, Dupont RT, Elston RC, Li MD . Haplotype analysis indicates an association between the DOPA decarboxylase (DDC) gene and nicotine dependence. Hum Mol Genet 2005; 14: 1691–1698.

    Article  CAS  PubMed  Google Scholar 

  27. Yu Y, Panhuysen C, Kranzler H, Hesselbrock V, Rounsaville B et al. Intronic variants in the dopa decarboxylase (DDC) gene are associated with smoking behavior in European-Americans and African-Americans. Hum Mol Genet 2006; 15: 2192–2199.

    Article  CAS  PubMed  Google Scholar 

  28. Beuten J, Ma JZ, Payne TJ, Dupont RT, Crews KM, Somes G et al. Single- and multilocus allelic variants within the GABA(B) receptor subunit 2 (GABAB2) gene are significantly associated with nicotine dependence. Am J Hum Genet 2005; 76: 859–864.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Lou XY, Ma JZ, Payne TJ, Beuten J, Crew KM, Li MD . Gene-based analysis suggests association of the nicotinic acetylcholine receptor beta1 subunit (CHRNB1) and M1 muscarinic acetylcholine receptor (CHRM1) with vulnerability for nicotine dependence. Hum Genet 2006; 120: 381–389.

    Article  CAS  PubMed  Google Scholar 

  30. Beuten J, Payne TJ, Ma JZ, Li MD . Significant association of catechol-O-methyltransferase (COMT) haplotypes with nicotine dependence in male and female smokers of two ethnic populations. Neuropsychopharmacology 2006; 31: 675–684.

    Article  CAS  PubMed  Google Scholar 

  31. Thorgeirsson TE, Gudbjartsson DF, Surakka I, Vink JM, Amin N, Geller F et al. Sequence variants at CHRNB3CHRNA6 and CYP2A6 affect smoking behavior. Nature Genet 2010; 42: 448–453.

    Article  CAS  PubMed  Google Scholar 

  32. Liu JZ, Tozzi F, Waterworth DM, Pillai SG, Muglia P, Middleton L et al. Genome-wide association meta-analysis of smoking in 41 150 subjects. Nature Genetics 2010; 42: 436–440.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Tobacco and Genetics Consortium. Genome-wide meta-analyses identify multiple loci associated with smoking behavior. Nat Genet 2010; 42: 441–447.

    Article  CAS  Google Scholar 

  34. Saccone SF, Hinrichs AL, Saccone NL, Chase GA, Konvicka K, Madden PA et al. Cholinergic nicotinic receptor genes implicated in a nicotine dependence association study targeting 348 candidate genes with 3713 SNPs. Hum Mol Genet 2007; 16: 36–49.

    Article  CAS  PubMed  Google Scholar 

  35. Thorgeirsson TE, Geller F, Sulem P, Rafnar T, Wiste A, Magnusson KP et al. A variant associated with nicotine dependence, lung cancer and peripheral arterial disease. Nature 2008; 452: 638–642.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Weiss RB, Baker TB, Cannon DS, von Niederhausern A, Dunn DM, Matsunami N et al. A candidate gene approach identifies the CHRNA5-A3-B4 region as a risk factor for age-dependent nicotine addiction. PLoS Genet 2008; 4: e1000125.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Bierut LJ, Stitzel JA, Wang JC, Hinrichs AL, Grucza RA, Xuei X et al. Variants in nicotinic receptors and risk for nicotine dependence. Am J Psychiatry 2008; 165: 1163–1171.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Caporoso N, Gu F, Chatterjee N, Sheng-Chih J, Yu K, Yeager M et al. Genome-wide and candidate gene association study of cigarette smoking behaviors. PLoS ONE 2009; 4: e4653. doi:10.1371.

    Article  CAS  Google Scholar 

  39. Keskitalo K, Broms U, Heliovaara M, Ripatti S, Surakka I, Perola M et al. Association of serum cotinine level with a cluster of three nicotinic acetylcholine receptor genes (CHRNA3/CHRNA5/CHRNB4) on chromosome 15. Hum Mol Genet 2009; 18: 4007–4012.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Freathy RM, Ring SM, Shields B, Galobardes B, Knight B, Weedon MN et al. A common genetic variant in the 15q24 nicotinic acetylcholine receptor gene cluster (CHRNA5-CHRNA3-CHRNB4) is associated with a reduced ability of women to quit smoking in pregnancy. Hum Mol Genet 2009; 18: 2922–2927.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Schlaepfer IR, Hoft NR, Collins AC, Corley RP, Hewitt JK, Hopfer CJ et al. The CHRNA5/A3/B4 Gene Cluster Variability as an Important Determinant of Early Alcohol and Tobacco Initiation in Young Adults. Biol Psychiatry 2008; 63: 1039–1046.

    Article  CAS  PubMed  Google Scholar 

  42. Le Marchand L, Derby KS, Murphy SE, Hecht SS, Hatsumaki D, Carmella SG et al. Smokers with the CHRNA lung cancer-associated variants are exposed to higher levels of nicotine equivalents and a carcinogenic tobacco-specific nitrosamine. Cancer Res 2008; 68: 9137–9140.

    Article  CAS  PubMed  Google Scholar 

  43. Pillai SG, Ge D, Zhu G, Kong X, Shianna KV et al. A genome-wide association study in chronic obstructive pulmonary disease (COPD): identification of two major susceptibility loci. PLoS Genet 2009; 5: e1000421.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Saccone NL, Culverhouse RC, Schwantes-An TH, Cannon DS, Chen X, Cichon S et al. Multiple independent loci at chromosome 15q25.1 affect smoking quantity: a meta-analysis and comparison with lung cancer and COPD. PLoS Genet 2010; 6: pii, : e1001053.

    Article  CAS  Google Scholar 

  45. Saccone NL, Wang JC, Breslau N, Johnson EO, Hatsukami D et al. The CHRNA5-CHRNA3-CHRNB4 nicotinic receptor subunit gene cluster affects risk for nicotine dependence in African-Americans and in European-Americans. Cancer Res 2009; 69: 6848–6856.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Frahm S, Slimak MA, Ferrarese L, Santos-Torres J, Antolin-Fontes B, Auer S et al. Aversion to nicotine is regulated by the balanced activity of β4 and α5 nicotinic receptor subunits in the medial habenula. Neuron 2011; 70: 522–535.

    Article  CAS  PubMed  Google Scholar 

  47. Wang JC, Cruchaga C, Saccone NL, Bertelsen S, Liu P, Budde JP et al. COGEND collaborators and GELCC collaborators. Risk for nicotine dependence and lung cancer is conferred by mRNA expression levels and amino acid change in CHRNA5. Hum Mol Genet 2009A; 18: 3125–3135.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Smith RM, Alachkar H, Papp AC, Wang D, Mash DC, Wang JC et al. Nicotinic alpha5 receptor subunit mRNA expression is associated with distant 5′ upstream polymorphisms. Eur J Hum Genet 2011; 19: 76–83.

    Article  CAS  PubMed  Google Scholar 

  49. Kuryatov A, Berrettini W, Lindstrom J . AChR α5 subunit variant associated with risk for nicotine dependence and lung cancer reduces (α4β2)2α5 AChR function. Mol Pharmacol 2011; 79: 119–125.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Doyle GA, Wang M-J, Chou AD, Oleynick JU, Arnold SE, Buono RJ et al. In vitro and ex vivo analysis of CHRNA3 and CHRNA5 haplotype expression. PLoS ONE 2011; 6: e23373. doi:10.1371/journal.pone.0023373.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Hung RJ, McKay JD, Gaborieau V, Boffette P, Hashibe M, Zaridze D et al. A susceptibility locus for lung cancer maps to nicotinic acetylcholine receptor subunit genes on 15q25. Nature 2008; 452: 633–637.

    Article  CAS  PubMed  Google Scholar 

  52. Amos CI, Wu X, Broderick P, Gorlov IP, Gu J, Eisen T et al. Genome-wide association scan of tag SNPs identifies a susceptibility locus for lung cancer at 15q25.1. Nat Genet 2008; 40: 616–622.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Liu P, Vikis HG, Wang D, Lu Y, Wang Y, Schwartz AG et al. Familial aggregation of common sequence variants on 15q24-25.1 in lung cancer. J Natl Cancer Inst 2008; 100: 1326–1330.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Spitz MR, Amos CI, Dong Q, Lin J, Wu X . The CHRNA5-A3 region on chromosome 15q24-25.1 is a risk factor both for nicotine dependence and for lung cancer. J Natl Cancer Inst 2008; 100: 1552–1556.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Shiraishi K, Kohno T, Kunitoh H, Watanabe S, Goto K, Nishiwaki Y et al. Contribution of nicotine acetylcholine receptor polymorphisms to lung cancer risk in a smoking-independent manner in the Japanese. Carcinogenesis 2009; 30: 65–70.

    Article  CAS  PubMed  Google Scholar 

  56. Volkow N, Rutter J, Pollock JD, Shurtleff D, Baler R . Nicotine addiction and lung cancer susceptibility. Mol Psychiatry 2008; 13: 990–992.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Falvella FS, Galvan A, Frullanti E, Spinola M, Calabro E, Carbone A et al. Transcription deregulation at the 15q25 locus in association with lung adenocarcinoma risk. Clin Cancer Res 2009; 15: 1837–1842.

    Article  CAS  PubMed  Google Scholar 

  58. Dasgupta P, Kincade R, Joshi B, DeCook C, Haura E, Chellapan S . Nicotine inhibits apoptosis induced by chemotherapeutic drugs by up-regulating XIAP and surviving. Proc Natl Acad Sci USA 2006; 103: 6332–6337.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Paliwal A, Vaissière T, Krais A, Cuenin C, Cros MP, Zaridze D et al. Aberrant DNA methylation links cancer susceptibility locus 15q25.1 to apoptotic regulation and lung cancer. Cancer Res 2010; 70: 2779–2788.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Ray R, Tyndale RF, Lerman C . Nicotine dependence pharmacogenetics: role of genetic variation in nicotine-metabolizing enzymes. J Neurogenet 2009; 23: 252–261.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Lindstrom JM . Nicotinic acetylcholine receptors of muscles and nerves: comparison of their structures, functional roles, and vulnerability to pathology. Ann N Y Acad Sci 2003; 998: 41–52.

    Article  CAS  PubMed  Google Scholar 

  62. Gotti C, Moretti M, Gaimarri A, Zanardi A, Clementi F, Zoli M . Heterogeneity and complexity of native brain nicotinic receptors. Biochem Pharmacol 2007; 74: 1102–1111.

    Article  CAS  PubMed  Google Scholar 

  63. Klink R, de Kerchove d’Exaerde A, Zoli M, Changeux JP . Molecular and physiological diversity of nicotinic acetylcholine receptors in the midbrain dopaminergic nuclei. J Neurosci 2001; 21: 1452–1463.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Li MD, Yoon D, Lee JY, Han BG, Niu T, Payne TJ et al. Associations of variants in CHRNA5/A3/B4 gene cluster with smoking behaviors in a Korean population. PLoS ONE 2010; 5: e12183.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Wu C, Hu Z, Yu D, Huang L, Jin G, Liang J et al. Genetic variants on chromosome 15q25 associated with lung cancer risk in Chinese populations. Cancer Res 2009; 69: 5065–5072.

    Article  CAS  PubMed  Google Scholar 

  66. Xu XW, Gelber S, Orr-Urtreger A, Armstrong D, Lewis RA, Ou C et al. Megacystis, mydriasis, and ion channel defect in mice lacking the α3 neuronal nicotinic acetylcholine receptor. Proc Natl Acad Sci USA 1999; 96: 5746–5751.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Salminen O, Murphy KL, McIntosh JM, Drago J, Marks MJ, Collins AC et al. Subunit composition and pharmacology of two classes of striatal presynaptic nicotinic acetylcholine receptors mediating dopamine release in mice. Mol Pharmacol 2004; 65: 1526–1535.

    Article  CAS  PubMed  Google Scholar 

  68. Fowler C, Lu Q, Johnson PM, Marks MJ, Kenny PJ . Habenular a5 nicotinic receptor subunit signalling controls nicotine intake. Nature 2011 doi:10.1038/nature09797.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Picciotto MR, Zoli M, Rimondini R, Lena C, Marubio LM, Pich EM et al. Acetylcholine receptors containing the B2 subunit are involved in the reinforcing properties of nicotine. Nature 1998; 391: 173–177.

    Article  CAS  PubMed  Google Scholar 

  70. Tapper A, McKinney S, Nashmi R, Schwarz J, Deshpande P, Labarca C et al. Nicotine activation of A4* receptors: sufficient for reward, tolerance, and sensitization. Science 2004; 306: 1029–1032.

    Article  CAS  PubMed  Google Scholar 

  71. Buckland PR, Hoogendoorn B, Coleman SL, Guy CA, Smith SK, O’Donovan MC . Strong bias in the location of functional promoter polymorphisms. Hum Mutat 2005; 26: 214–223.

    Article  CAS  PubMed  Google Scholar 

  72. Falvella FS, Galvan A, Colombo F, Frullanti E, Pastorino U, Dragani TA . Promoter polymorphisms and transcript levels of nicotinic receptor CHRNA5. J Natl Cancer lnst 2010; 102: 1366–1370.

    Article  CAS  Google Scholar 

  73. Flora A, Schulz R, Benfante R, Battaglioli E, Terzano S, Clementi F et al. Transcriptional regulation of the human alpha5 nicotinic receptor subunit gene in neuronal and non-neuronal tissues. Eur J Pharmacol 2000; 393: 85–95.

    Article  CAS  PubMed  Google Scholar 

  74. Cardoso RA, Brozowski SJ, Chavez-Noriega LE, Harpold M, Valenzuela CF, Harris RA . Effects of ethanol on recombinant human neuronal nicotinic acetylcholine receptors expressed in Xenopus oocytes. J Pharmacol Exp Ther 1999; 289: 774–780.

    CAS  PubMed  Google Scholar 

  75. Larsson A, Engel JA . Neurochemical and behavioral studies on ethanol and nicotine interactions. Neurosci Biobehav Rev 2004; 27: 713–720.

    Article  CAS  PubMed  Google Scholar 

  76. Swan GE, Carmelli D, Rosen man RH, Fabsitz R, Christian JC . Smoking and alcohol consumption in adult male twins: genetic heritability and shared environmental influences. J Subst Abuse 1990; 2: 39–50.

    Article  CAS  PubMed  Google Scholar 

  77. Steensland P, Simms JA, Holgate J, Richards JK, Bartlett SE . Varenicline, an alpha4beta2 nicotinic acetylcholine receptor partial agonist, selectively decreases ethanol consumption and seeking. Proc Natl Acad Sci USA 2007; 104: 12518–12523.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Wang JC, Grucza R, Cruchaga C, Hinrichs AL, Bertelsen S, Budde JP et al. Genetic variation in the CHRNA5 gene affects mRNA levels and is associated with risk for alcohol dependence. Mol Psychiatry 2009B; 14: 501–510.

    Article  CAS  PubMed  Google Scholar 

  79. Joslyn G, Brush G, Robertson M, Smith TL, Kalmijn J, Schuckit M et al. Chromosome 15q25.1 genetic markers associated with level of response to alcohol in humans. Proc Natl Acad Sci USA 2008; 105: 20368–20373.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Chatterjee S, Steensland P, Simms JA, Holgate J, Coe JW, Hurst RS et al. Partial agonists of the α3β4* neuronal nicotinic acetylcholine receptor reduce ethanol consumption and seeking in rats. Neuropsychopharmacology 2011; 36: 603–615.

    Article  CAS  PubMed  Google Scholar 

  81. McKee SA, Harrison EL, O’Malley SS, Krishnan-Sarin S, Shi J, Tetrault JM et al. Varenicline reduces alcohol self-administration in heavy-drinking smokers. Biol Psychiatry 2009; 66: 185–190.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Uhl GR, Liu QR, Drgon T, Johnson C, Walther D, Rose JE . Molecular genetics of nicotine dependence and abstinence: whole genome association using 520 000 SNPs. BMC Genet 2007; 8: 10–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Uhl GR, Drgon T, Johnson C, Ramoni MF, Behm FM, Rose JE . Genome-wide association for smoking cessation success in a trial of precessation nicotine replacement. Mol Med 2010; 16: 513–526.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Breitling LP, Dahmen N, Mittelstrass K, Illig T, Rujescu D, Raum E et al. Smoking cessation and variations in nicotinic acetylcholine receptor subunits alpha-5, alpha-3, and beta-4 genes. Biol Psychiatry 2009; 65: 691–695.

    Article  CAS  PubMed  Google Scholar 

  85. Thorgeirsson TE, Stefansson K . Commentary: Gene-environment interactions and smoking–related cancers. Int J Epidemiol 2010B; 39: 577.

    Article  PubMed  Google Scholar 

  86. Heitjan DF, Guo M, Ray R, Wileyto EP, Epstein LH, Lerman C . Identification of pharmacogenetic markers in smoking cessation therapy. Am J Med Genet B Neuropsychiatr Genet 2008; 147B: 712–719.

    Article  PubMed  PubMed Central  Google Scholar 

  87. Conti DV, Lee W, Li D, Liu J, Van Den Berg D, Thomas PD et al. Pharmacogenetics of Nicotine Addiction and Treatment Consortium. Nicotinic acetylcholine receptor beta2 subunit gene implicated in a systems-based candidate gene study of smoking cessation. Hum Mol Genet 2008; 17: 2834–2848.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Uhl GR, Liu QR, Drgon T, Johnson C, Walther D, Rose JE et al. Molecular genetics of successful smoking cessation: convergent genome-wide association study results. Arch Gen Psychiatry 2008; 65: 683–693.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Sarginson JE, Killen JD, Lazzeroni LC, Fortmann SP, Ryan HS, Schatzberg AF et al. Markers in the 15q24 nicotinic receptor subunit gene cluster (CHRNA5-A3-B4) predict severity of nicotine addiction and response to smoking cessation therapy. Am J Med Genet B Neuropsychiatr Genet 2011 doi:10.1002/ajmg.b.31155.

    Article  Google Scholar 

  90. Dale LC, Glover ED, Sachs DP, Schroeder DR, Offord KP, Croghan IT et al. Bupropion for smoking cessation: predictors of successful outcome. Chest 2001; 119: 1357–1364.

    Article  CAS  PubMed  Google Scholar 

  91. Berrettini WH, Wileyto EP, Epstein L, Restine S, Hawk L, Niaura R et al. Catechol-O-Methyltransferase (COMT) gene variants predict response to bupropion therapy for tobacco dependence. Biol Psychiatry 2007; 61: 111–118.

    Article  CAS  PubMed  Google Scholar 

  92. Barrett JC, Fry B, Maller J, Daly MJ . Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 2005; 21: 263–265.

    Article  CAS  PubMed  Google Scholar 

  93. Gabriel SB, Schaffner SF, Nguyen H, Moore JM, Roy J, Blumenstiel B et al. The structure of haplotype blocks in the human genome. Science 2002; 296: 2225–2229.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors would like to thank Jon Lindstrom, PhD, Professor of Neuroscience, University of Pennsylvania School of Medicine, for his insights into the CHRNA5 N398D variants. This paper was written with the support of R01 DA 025201, P20 DA 025995, P60 DA 05186 and the VISN 4 Mental Illness Research, Education and Clinical Center (MIRECC, David Oslin, PI) of the Veterans Administration.

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Berrettini, W., Doyle, G. The CHRNA5–A3–B4 gene cluster in nicotine addiction. Mol Psychiatry 17, 856–866 (2012). https://doi.org/10.1038/mp.2011.122

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