Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Expert Review
  • Published:

Converging findings from linkage and association analyses on susceptibility genes for smoking and other addictions

Molecular Psychiatry volume 21, pages 992–1008 (2016)Cite this article

Subjects

Abstract

Experimental approaches to genetic studies of complex traits evolve with technological advances. How do discoveries using different approaches advance our knowledge of the genetic architecture underlying complex diseases/traits? Do most of the findings of newer techniques, such as genome-wide association study (GWAS), provide more information than older ones, for example, genome-wide linkage study? In this review, we address these issues by developing a nicotine dependence (ND) genetic susceptibility map based on the results obtained by the approaches commonly used in recent years, namely, genome-wide linkage, candidate gene association, GWAS and targeted sequencing. Converging and diverging results from these empirical approaches have elucidated a preliminary genetic architecture of this intractable psychiatric disorder and yielded new hypotheses on ND etiology. The insights we obtained by putting together results from diverse approaches can be applied to other complex diseases/traits. In sum, developing a genetic susceptibility map and keeping it updated are effective ways to keep track of what we know about a disease/trait and what the next steps may be with new approaches.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1

Similar content being viewed by others

References

  1. Lim SS, Vos T, Flaxman AD, Danaei G, Shibuya K, Adair-Rohani H et al. A comparative risk assessment of burden of disease and injury attributable to 67 risk factors and risk factor clusters in 21 regions, 1990-2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 2012; 380: 2224–2260.

    Article  PubMed  PubMed Central  Google Scholar 

  2. USDHHS The Health Consequences of Smoking—50 Years of Progress. A Report of the Surgeon General. US Department of Health & Human Services, Center for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promortion: Atlanta, GA: USA, 2014.

  3. Gunby P . Surgeon General emphasizes nicotine addiction in annual report on tobacco use, consequences. JAMA 1988; 259: 2811.

    Article  CAS  PubMed  Google Scholar 

  4. Carmelli D, Swan GE, Robinette D, Fabsitz R . Genetic influence on smoking—a study of male twins. N Engl J Med 1992; 327: 829–833.

    Article  CAS  PubMed  Google Scholar 

  5. Li MD, Cheng R, Ma JZ, Swan GE . A meta-analysis of estimated genetic and environmental effects on smoking behavior in male and female adult twins. Addiction 2003; 98: 23–31.

    Article  PubMed  Google Scholar 

  6. Berrettine W, Yuan X, Tozzi F, Song K, Francks C, Chilcoat H et al. Alpha-5/alpha-3 nicotinic receptor subunit alleles increase risk for heavy smoking. Mol Psychiatr 2008; 13: 368–373.

    Article  CAS  Google Scholar 

  7. 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 

  8. Chen LS, Saccone NL, Culverhouse RC, Bracci PM, Chen CH, Dueker N et al. Smoking and genetic risk variation across populations of European, Asian, and African American ancestry—a meta-analysis of chromosome 15q25. Genet Epidemiol 2012; 36: 340–351.

    Article  PubMed  PubMed Central  Google Scholar 

  9. 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 

  10. Li MD, Xu Q, Lou XY, Payne TJ, Niu T, Ma JZ . Association and interaction analysis of variants in CHRNA5/CHRNA3/CHRNB4 gene cluster with nicotine dependence in African and European Americans. Am J Med Genet B Neuropsychiatr Genet 2010; 153B: 745–756.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. 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 

  12. Liu JZ, Tozzi F, Waterworth DM, Pillai SG, Muglia P, Middleton L et al. Meta-analysis and imputation refines the association of 15q25 with smoking quantity. Nat Genet 2010; 42: 436–440.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. 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 

  14. 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 

  15. Saccone NL, Schwantes-An TH, Wang JC, Grucza RA, Breslau N, Hatsukami D et al. Multiple cholinergic nicotinic receptor genes affect nicotine dependence risk in African and European Americans. Genes Brain Behav 2010; 9: 741–750.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. TAG. Genome-wide meta-analyses identify multiple loci associated with smoking behavior. Nat Genet 2010; 42: 441–447.

    Article  CAS  Google Scholar 

  17. 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 

  18. Thorgeirsson TE, Gudbjartsson DF, Surakka I, Vink JM, Amin N, Geller F et al. Sequence variants at CHRNB3-CHRNA6 and CYP2A6 affect smoking behavior. Nat Genet 2010; 42: 448–453.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. David SP, Hamidovic A, Chen GK, Bergen AW, Wessel J, Kasberger JL et al. Genome-wide meta-analyses of smoking behaviors in African Americans. Transl Psychiatry 2012; 2: e119.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Wen L, Jiang K, Yuan W, Cui W, Li MD . Contribution of variants in CHRNA5/A3/B4 gene cluster on chromosome 15 to tobacco smoking: from genetic association to mechanism. Mol Neurobiol 2016; 53: 472–484.

    Article  CAS  PubMed  Google Scholar 

  21. Cui WY, Wang S, Yang J, Yi SG, Yoon D, Kim YJ et al. Significant association of CHRNB3 variants with nicotine dependence in multiple ethnic populations. Mol Psychiatry 2013; 18: 1149–1151.

    Article  CAS  PubMed  Google Scholar 

  22. Culverhouse RC, Johnson EO, Breslau N, Hatsukami DK, Sadler B, Brooks AI et al. Multiple distinct CHRNB3-CHRNA6 variants are genetic risk factors for nicotine dependence in African Americans and European Americans. Addiction 2014; 109: 814–822.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Hoft NR, Corley RP, McQueen MB, Schlaepfer IR, Huizinga D, Ehringer MA . Genetic association of the CHRNA6 and CHRNB3 genes with tobacco dependence in a nationally representative sample. Neuropsychopharmacology 2009; 34: 698–706.

    Article  CAS  PubMed  Google Scholar 

  24. Zeiger JS, Haberstick BC, Schlaepfer I, Collins AC, Corley RP, Crowley TJ et al. The neuronal nicotinic receptor subunit genes (CHRNA6 and CHRNB3) are associated with subjective responses to tobacco. Hum Mol Genet 2008; 17: 724–734.

    Article  CAS  PubMed  Google Scholar 

  25. Rice JP, Hartz SM, Agrawal A, Almasy L, Bennett S, Breslau N et al. CHRNB3 is more strongly associated with Fagerstrom test for cigarette dependence-based nicotine dependence than cigarettes per day: phenotype definition changes genome-wide association studies results. Addiction 2012; 107: 2019–2028.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Kumasaka N, Aoki M, Okada Y, Takahashi A, Ozaki K, Mushiroda T et al. Haplotypes with copy number and single nucleotide polymorphisms in CYP2A6 locus are associated with smoking quantity in a Japanese population. PLoS One 2012; 7: e44507.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Chen LS, Bloom AJ, Baker TB, Smith SS, Piper ME, Martinez M et al. Pharmacotherapy effects on smoking cessation vary with nicotine metabolism gene (CYP2A6). Addiction 2014; 109: 128–137.

    Article  PubMed  Google Scholar 

  28. Bloom AJ, Baker TB, Chen LS, Breslau N, Hatsukami D, Bierut LJ et al. Variants in two adjacent genes, EGLN2 and CYP2A6, influence smoking behavior related to disease risk via different mechanisms. Hum Mol Genet 2014; 23: 555–561.

    Article  CAS  PubMed  Google Scholar 

  29. Chanock SJ, Manolio T, Boehnke M, Boerwinkle E, Hunter DJ, Thomas G et al. Replicating genotype-phenotype associations. Nature 2007; 447: 655–660.

    Article  CAS  PubMed  Google Scholar 

  30. Yang J, Benyamin B, McEvoy BP, Gordon S, Henders AK, Nyholt DR et al. Common SNPs explain a large proportion of the heritability for human height. Nat Genet 2010; 42: 565–569.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Lee SH, DeCandia TR, Ripke S, Yang J, Sullivan PF, Goddard ME et al. Estimating the proportion of variation in susceptibility to schizophrenia captured by common SNPs. Nat Genet 2012; 44: 247–250.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Ott J, Wang J, Leal SM . Genetic linkage analysis in the age of whole-genome sequencing. Nat Rev Genet 2015; 16: 275–284.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Gelernter J . Genetics of complex traits in psychiatry. Biol Psychiatry 2015; 77: 36–42.

    Article  CAS  PubMed  Google Scholar 

  34. Li MD . Identifying susceptibility loci for nicotine dependence: 2008 update based on recent genome-wide linkage analyses. Hum Genet 2008; 123: 119–131.

    Article  CAS  PubMed  Google Scholar 

  35. Hardin J, He Y, Javitz HS, Wessel J, Krasnow RE, Tildesley E et al. Nicotine withdrawal sensitivity, linkage to chr6q26, and association of OPRM1 SNPs in the SMOking in FAMilies (SMOFAM) sample. Cancer Epidemiol Biomarkers Prev 2009; 18: 3399–3406.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. 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 

  37. Han S, Gelernter J, Luo X, Yang BZ . Meta-analysis of 15 genome-wide linkage scans of smoking behavior. Biol Ppsychiatry 2010; 67: 12–19.

    Article  CAS  Google Scholar 

  38. Sullivan PF, Daly MJ, O'Donovan M . Genetic architectures of psychiatric disorders: the emerging picture and its implications. Nat Rev Genet 2012; 13: 537–551.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Yu A, Zhao C, Fan Y, Jang W, Mungall AJ, Deloukas P et al. Comparison of human genetic and sequence-based physical maps. Nature 2001; 409: 951–953.

    Article  CAS  PubMed  Google Scholar 

  40. Dani JA . Roles of dopamine signaling in nicotine addiction. Mol Psychiatry 2003; 8: 255–256.

    Article  CAS  PubMed  Google Scholar 

  41. 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 

  42. Neville MJ, Johnstone EC, Walton RT . Identification and characterization of ANKK1: a novel kinase gene closely linked to DRD2 on chromosome band 11q23.1. Hum Mutat 2004; 23: 540–545.

    Article  CAS  PubMed  Google Scholar 

  43. David SP, Mezuk B, Zandi PP, Strong D, Anthony JC, Niaura R et al. Sex differences in TTC12/ANKK1 haplotype associations with daily tobacco smoking in Black and White Americans. Nicotine Tob Res 2010; 12: 251–262.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Gelernter J, Yu Y, Weiss R, Brady K, Panhuysen C, Yang BZ et al. Haplotype spanning TTC12 and ANKK1, flanked by the DRD2 and NCAM1 loci, is strongly associated to nicotine dependence in two distinct American populations. Hum Mol Genet 2006; 15: 3498–3507.

    Article  CAS  PubMed  Google Scholar 

  45. Huang W, Payne TJ, Ma JZ, Beuten J, Dupont RT, Inohara N et al. Significant association of ANKK1 and detection of a functional polymorphism with nicotine dependence in an African-American sample. Neuropsychopharmacology 2009; 34: 319–330.

    Article  CAS  PubMed  Google Scholar 

  46. Ducci F, Kaakinen M, Pouta A, Hartikainen AL, Veijola J, Isohanni M et al. TTC12-ANKK1-DRD2 and CHRNA5-CHRNA3-CHRNB4 influence different pathways leading to smoking behavior from adolescence to mid-adulthood. Biol Psychiatry 2011; 69: 650–660.

    Article  CAS  PubMed  Google Scholar 

  47. Ma Y, Yuan W, Jiang X, Cui WY, Li MD . Updated findings of the association and functional studies of DRD2/ANKK1 variants with addictions. Mol Neurobiol 2015; 51: 281–299.

    Article  CAS  PubMed  Google Scholar 

  48. Huang W, Ma JZ, Payne TJ, Beuten J, Dupont RT, Li MD . Significant association of DRD1 with nicotine dependence. Hum Genet 2008; 123: 133–140.

    Article  CAS  PubMed  Google Scholar 

  49. David SP, Munafo MR, Murphy MF, Proctor M, Walton RT, Johnstone EC . Genetic variation in the dopamine D4 receptor (DRD4) gene and smoking cessation: follow-up of a randomised clinical trial of transdermal nicotine patch. Pharmacogenomics J 2008; 8: 122–128.

    Article  CAS  PubMed  Google Scholar 

  50. Ellis JA, Olsson CA, Moore E, Greenwood P, Van De Ven MO, Patton GC . A role for the DRD4 exon III VNTR in modifying the association between nicotine dependence and neuroticism. Nicotine Tob Res 2011; 13: 64–69.

    Article  CAS  PubMed  Google Scholar 

  51. Das D, Tan X, Easteal S . Effect of model choice in genetic association studies: DRD4 exon III VNTR and cigarette use in young adults. Am J Med Genet B Neuropsychiatr Genet 2011; 156B: 346–351.

    Article  CAS  PubMed  Google Scholar 

  52. Leventhal AM, Lee W, Bergen AW, Swan GE, Tyndale RF, Lerman C et al. Nicotine dependence as a moderator of genetic influences on smoking cessation treatment outcome. Drug Alcohol Depend 2014; 138: 109–117.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Ella E, Sato N, Nishizawa D, Kageyama S, Yamada H, Kurabe N et al. Association between dopamine beta hydroxylase rs5320 polymorphism and smoking behaviour in elderly Japanese. J Hum Genet 2012; 57: 385–390.

    Article  CAS  PubMed  Google Scholar 

  54. Yu Y, Panhuysen C, Kranzler HR, Hesselbrock V, Rounsaville B, Weiss R 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 

  55. 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 

  56. Berrettini WH, Wileyto EP, Epstein L, Restine S, Hawk L, Shields P 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 

  57. Amstadter AB, Nugent NR, Koenen KC, Ruggiero KJ, Acierno R, Galea S et al. Association between COMT, PTSD, and increased smoking following hurricane exposure in an epidemiologic sample. Psychiatry 2009; 72: 360–369.

    Article  PubMed  Google Scholar 

  58. Nedic G, Nikolac M, Borovecki F, Hajnsek S, Muck-Seler D, Pivac N . Association study of a functional catechol-O-methyltransferase polymorphism and smoking in healthy Caucasian subjects. Neurosci Lett 2010; 473: 216–219.

    Article  CAS  PubMed  Google Scholar 

  59. 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 

  60. Omidvar M, Stolk L, Uitterlinden AG, Hofman A, Van Duijn CM, Tiemeier H . The effect of catechol-O-methyltransferase Met/Val functional polymorphism on smoking cessation: retrospective and prospective analyses in a cohort study. Pharmacogenet Genomics 2009; 19: 45–51.

    Article  CAS  PubMed  Google Scholar 

  61. Munafo MR, Freathy RM, Ring SM St, Pourcain B, Smith GD . Association of COMT Val(108/158)Met genotype and cigarette smoking in pregnant women. Nicotine Tob Res 2011; 13: 55–63.

    Article  CAS  PubMed  Google Scholar 

  62. Huang W, Payne TJ, Ma JZ, Li MD . A functional polymorphism, rs6280, in DRD3 is significantly associated with nicotine dependence in European-American smokers. Am J Med Genet B Neuropsychiatr Genet 2008; 147B: 1109–1115.

    Article  CAS  PubMed  Google Scholar 

  63. Stapleton JA, Sutherland G, O'Gara C . Association between dopamine transporter genotypes and smoking cessation: a meta-analysis. Addict Biol 2007; 12: 221–226.

    Article  CAS  PubMed  Google Scholar 

  64. Ling D, Niu T, Feng Y, Xing H, Xu X . Association between polymorphism of the dopamine transporter gene and early smoking onset: an interaction risk on nicotine dependence. J Hum Genet 2004; 49: 35–39.

    Article  CAS  PubMed  Google Scholar 

  65. Farris SP, Harris RA, Ponomarev I . Epigenetic modulation of brain gene networks for cocaine and alcohol abuse. Front Neurosci 2015; 9: 176.

    Article  PubMed  PubMed Central  Google Scholar 

  66. Ramchandani VA, Umhau J, Pavon FJ, Ruiz-Velasco V, Margas W, Sun H et al. A genetic determinant of the striatal dopamine response to alcohol in men. Mol Psychiatry 2011; 16: 809–817.

    Article  CAS  PubMed  Google Scholar 

  67. Domino EF, Evans CL, Ni L, Guthrie SK, Koeppe RA, Zubieta JK . Tobacco smoking produces greater striatal dopamine release in G-allele carriers with mu opioid receptor A118G polymorphism. Prog Neuropsychopharmacol Biol Psychiatry 2012; 38: 236–240.

    Article  CAS  PubMed  Google Scholar 

  68. Huang S, Cook DG, Hinks LJ, Chen XH, Ye S, Gilg JA et al. CYP2A6, MAOA, DBH, DRD4, and 5HT2A genotypes, smoking behaviour and cotinine levels in 1518 UK adolescents. Pharmacogenet Genomics 2005; 15: 839–850.

    Article  CAS  PubMed  Google Scholar 

  69. Ton TG, Rossing MA, Bowen DJ, Srinouanprachan S, Wicklund K, Farin FM . Genetic polymorphisms in dopamine-related genes and smoking cessation in women: a prospective cohort study. Behav Brain Funct 2007; 3: 22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Breitling LP, Dahmen N, Illig T, Rujescu D, Nitz B, Raum E et al. Variants in COMT and spontaneous smoking cessation: retrospective cohort analysis of 925 cessation events. Pharmacogenet Genomics 2009; 19: 657–659.

    Article  CAS  PubMed  Google Scholar 

  71. Marteau TM, Aveyard P, Munafo MR, Prevost AT, Hollands GJ, Armstrong D et al. Effect on adherence to nicotine replacement therapy of informing smokers their dose is determined by their genotype: a randomised controlled trial. PLoS One 2012; 7: e35249.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Munafo MR, Johnstone EC, Aveyard P, Marteau T . Lack of association of OPRM1 genotype and smoking cessation. Nicotine Tob Res 2013; 15: 739–744.

    Article  CAS  PubMed  Google Scholar 

  73. 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 

  74. Lou XY, Ma JZ, Sun D, Payne TJ, Li MD . Fine mapping of a linkage region on chromosome 17p13 reveals that GABARAP and DLG4 are associated with vulnerability to nicotine dependence in European-Americans. Hum Mol Genet 2007; 16: 142–153.

    Article  CAS  PubMed  Google Scholar 

  75. Agrawal A, Pergadia ML, Saccone SF, Hinrichs AL, Lessov-Schlaggar CN, Saccone NL et al. Gamma-aminobutyric acid receptor genes and nicotine dependence: evidence for association from a case-control study. Addiction 2008; 103: 1027–1038.

    Article  PubMed  Google Scholar 

  76. Agrawal A, Pergadia ML, Balasubramanian S, Saccone SF, Hinrichs AL, Saccone NL et al. Further evidence for an association between the gamma-aminobutyric acid receptor A, subunit 4 genes on chromosome 4 and Fagerstrom Test for Nicotine Dependence. Addiction 2009; 104: 471–477.

    Article  PubMed  PubMed Central  Google Scholar 

  77. Cui WY, Seneviratne C, Gu J, Li MD . Genetics of GABAergic signaling in nicotine and alcohol dependence. Hum Genet 2012; 131: 843–855.

    Article  CAS  PubMed  Google Scholar 

  78. Iordanidou M, Tavridou A, Petridis I, Kyroglou S, Kaklamanis L, Christakidis D et al. Association of polymorphisms of the serotonergic system with smoking initiation in Caucasians. Drug Alcohol Depend 2010; 108: 70–76.

    Article  CAS  PubMed  Google Scholar 

  79. Yang Z, Seneviratne C, Wang S, Ma JZ, Payne TJ, Wang J et al. Serotonin transporter and receptor genes significantly impact nicotine dependence through genetic interactions in both European American and African American smokers. Drug Alcohol Depend 2013; 129: 217–225.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Kremer I, Bachner-Melman R, Reshef A, Broude L, Nemanov L, Gritsenko I et al. Association of the serotonin transporter gene with smoking behavior. Am J Psychiatry 2005; 162: 924–930.

    Article  PubMed  Google Scholar 

  81. Daw J, Boardman JD, Peterson R, Smolen A, Haberstick BC, Ehringer MA et al. The interactive effect of neighborhood peer cigarette use and 5HTTLPR genotype on individual cigarette use. Addict Behav 2014; 39: 1804–1810.

    Article  PubMed  PubMed Central  Google Scholar 

  82. Bidwell LC, Garrett ME, McClernon FJ, Fuemmeler BF, Williams RB, Ashley-Koch AE et al. A preliminary analysis of interactions between genotype, retrospective ADHD symptoms, and initial reactions to smoking in a sample of young adults. Nicotine Tob Res 2012; 14: 229–233.

    Article  CAS  PubMed  Google Scholar 

  83. Trummer O, Koppel H, Wascher TC, Grunbacher G, Gutjahr M, Stanger O et al. The serotonin transporter gene polymorphism is not associated with smoking behavior. Pharmacogenomics J 2006; 6: 397–400.

    Article  CAS  PubMed  Google Scholar 

  84. David SP, Johnstone EC, Murphy MF, Aveyard P, Guo B, Lerman C et al. Genetic variation in the serotonin pathway and smoking cessation with nicotine replacement therapy: new data from the Patch in Practice trial and pooled analyses. Drug Alcohol Depend 2008; 98: 77–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Li MD, Payne TJ, Ma JZ, Lou XY, Zhang D, Dupont RT et al. A genomewide 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 

  86. do Prado-Lima PA, Chatkin JM, Taufer M, Oliveira G, Silveira E, Neto CA et al. Polymorphism of 5HT2A serotonin receptor gene is implicated in smoking addiction. Am J Med Genet B Neuropsychiatr Genet 2004; 128B: 90–93.

    Article  CAS  PubMed  Google Scholar 

  87. Vink JM, Smit AB, de Geus EJ, Sullivan P, Willemsen G, Hottenga JJ et al. Genome-wide association study of smoking initiation and current smoking. Am J Hum Genet 2009; 84: 367–379.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Li MD, Ma JZ, Payne TJ, Lou XY, Zhang D, Dupont RT et al. Genome-wide linkage scan for nicotine dependence in European Americans and its converging results with African Americans in the Mid-South Tobacco Family sample. Mol Psychiatry 2008; 13: 407–416.

    Article  CAS  PubMed  Google Scholar 

  89. Ma JZ, Payne TJ, Li MD . Significant association of glutamate receptor, ionotropic N-methyl-D-aspartate 3A (GRIN3A), with nicotine dependence in European- and African-American smokers. Hum Genet 2010; 127: 503–512.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Grucza RA, Johnson EO, Krueger RF, Breslau N, Saccone NL, Chen LS et al. Incorporating age at onset of smoking into genetic models for nicotine dependence: evidence for interaction with multiple genes. Addict Biol 2010; 15: 346–357.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Li X, Semenova S, D'Souza MS, Stoker AK, Markou A . Involvement of glutamatergic and GABAergic systems in nicotine dependence: implications for novel pharmacotherapies for smoking cessation. Neuropharmacology 2014; 76 Pt B: 554–565.

    Article  CAS  PubMed  Google Scholar 

  92. 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 

  93. Nussbaum J, Xu Q, Payne TJ, Ma JZ, Huang W, Gelernter J et al. Significant association of the neurexin-1 gene (NRXN1) with nicotine dependence in European- and African-American smokers. Hum Mol Genet 2008; 17: 1569–1577.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Sato N, Kageyama S, Chen R, Suzuki M, Tanioka F, Kamo T et al. Association between neurexin 1 (NRXN1) polymorphisms and the smoking behavior of elderly Japanese. Psychiatr Genet 2010; 20: 135–136.

    PubMed  Google Scholar 

  95. Docampo E, Ribases M, Gratacos M, Bruguera E, Cabezas C, Sanchez-Mora C et al. Association of neurexin 3 polymorphisms with smoking behavior. Genes Brain Behav 2012; 11: 704–711.

    Article  CAS  PubMed  Google Scholar 

  96. Liu QR, Drgon T, Walther D, Johnson C, Poleskaya O, Hess J et al. Pooled association genome scanning: validation and use to identify addiction vulnerability loci in two samples. Proc Natl Acad Sci USA 2005; 102: 11864–11869.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Feng Y, Niu TH, Xing HX, Xu X, Chen CZ, Peng SJ 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 Human Genet 2004; 75: 112–121.

    Article  CAS  Google Scholar 

  98. 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 

  99. Breitling LP, Dahmen N, Mittelstrass K, Rujescu D, Gallinat J, Fehr C et al. Association of nicotinic acetylcholine receptor subunit alpha 4 polymorphisms with nicotine dependence in 5500 Germans. Pharmacogenomics J 2009; 9: 219–224.

    Article  CAS  PubMed  Google Scholar 

  100. Kamens HM, Corley RP, McQueen MB, Stallings MC, Hopfer CJ, Crowley TJ et al. Nominal association with CHRNA4 variants and nicotine dependence. Genes Brain Behav 2013; 12: 297–304.

    Article  CAS  PubMed  Google Scholar 

  101. 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 

  102. Ehringer MA, Clegg HV, Collins AC, Corley RP, Crowley T, Hewitt JK et al. Association of the neuronal nicotinic receptor beta 2 subunit gene (CHRNB2) with subjective responses to alcohol and nicotine. Am J Med Genet B 2007; 144B: 596–604.

    Article  CAS  Google Scholar 

  103. Wang S, DvdV A, Xu Q, Seneviratne C, Pomerleau OF, Pomerleau CS et al. Significant associations of CHRNA2 and CHRNA6 with nicotine dependence in European American and African American populations. Hum Genet 2014; 133: 575–586.

    Article  CAS  PubMed  Google Scholar 

  104. 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 

  105. Johnstone E, Benowitz N, Cargill A, Jacob R, Hinks L, Day I et al. Determinants of the rate of nicotine metabolism and effects on smoking behavior. Clin Pharmacol Ther 2006; 80: 319–330.

    Article  CAS  PubMed  Google Scholar 

  106. Chen LS, Baker TB, Grucza R, Wang JC, Johnson EO, Breslau N et al. Dissection of the phenotypic and genotypic associations with nicotinic dependence. Nicotine Tob Res 2012; 14: 425–433.

    Article  CAS  PubMed  Google Scholar 

  107. Carter B, Long T, Cinciripini P . A meta-analytic review of the CYP2A6 genotype and smoking behavior. Nicotine Tob Res 2004; 6: 221–227.

    Article  CAS  PubMed  Google Scholar 

  108. Zhang XY, Chen da C, Xiu MH, Luo X, Zuo L, Haile CN et al. BDNF Val66Met variant and smoking in a Chinese population. PLoS One 2012; 7: e53295.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Beuten J, Ma JZ, Payne TJ, Dupont RT, Quezada P, Huang W et al. Significant association of BDNF haplotypes in European-American male smokers but not in European-American female or African-American smokers. Am J Med Genet B Neuropsychiatr Genet 2005; 139: 73–80.

    Article  CAS  Google Scholar 

  110. Beuten J, Ma JZ, Payne TJ, Dupont RT, Lou XY, Crews KM et al. Association of specific haplotypes of neurotrophic tyrosine kinase receptor 2 gene (NTRK2) with vulnerability to nicotine dependence in African-Americans and European-Americans. Biol Psychiatry 2006; 61: 48–55.

    Article  CAS  PubMed  Google Scholar 

  111. Sun D, Ma JZ, Payne TJ, Li MD . Beta-arrestins 1 and 2 are associated with nicotine dependence in European American smokers. Mol Psychiatry 2008; 13: 398–406.

    Article  CAS  PubMed  Google Scholar 

  112. 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 

  113. Xu Q, Huang W, Payne TJ, Ma JZ, Li MD . Detection of genetic association and a functional polymorphism of dynamin 1 gene with nicotine dependence in European and African Americans. Neuropsychopharmacology 2009; 34: 1351–1359.

    Article  CAS  PubMed  Google Scholar 

  114. Mangold JE, Payne TJ, Ma JZ, Chen G, Li MD . Bitter taste receptor gene polymorphisms are an important factor in the development of nicotine dependence in African Americans. J Med Genet 2008; 45: 578–582.

    Article  CAS  PubMed  Google Scholar 

  115. Chen GB, Payne TJ, Lou XY, Ma JZ, Zhu J, Li MD . Association of amyloid precursor protein-binding protein, family B, member 1 with nicotine dependence in African and European American smokers. Hum Genet 2008; 124: 393–398.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Zhang L, Kendler KS, Chen X . Association of the phosphatase and tensin homolog gene (PTEN) with smoking initiation and nicotine dependence. Am J Med Genet B Neuropsychiatr Genet 2006; 141B: 10–14.

    Article  PubMed  Google Scholar 

  117. Turner JR, Ray R, Lee B, Everett L, Xiang J, Jepson C et al. Evidence from mouse and man for a role of neuregulin 3 in nicotine dependence. Mol Psychiatry 2014; 19: 801–810.

    Article  CAS  PubMed  Google Scholar 

  118. Li CY, Mao X, Genes Wei L . Gene and (common) pathways underlying drug addiction. PLoS Comput Biol 2008; 4: e2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Risch N, Merikangas K . The future of genetic studies of complex human diseases. Science 1996; 273: 1516–1517.

    CAS  PubMed  Google Scholar 

  120. Klein RJ, Zeiss C, Chew EY, Tsai JY, Sackler RS, Haynes C et al. Complement factor H polymorphism in age-related macular degeneration. Science 2005; 308: 385–389.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Nees F, Witt SH, Lourdusamy A, Vollstadt-Klein S, Steiner S, Poustka L et al. Genetic risk for nicotine dependence in the cholinergic system and activation of the brain reward system in healthy adolescents. Neuropsychopharmacology 2013; 38: 2081–2089.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Chen LS, Baker TB, Piper ME, Breslau N, Cannon DS, Doheny KF et al. Interplay of genetic risk factors (CHRNA5-CHRNA3-CHRNB4) and cessation treatments in smoking cessation success. Am J Psychiatry 2012; 169: 735–742.

    Article  PubMed  PubMed Central  Google Scholar 

  123. Munafo MR, Johnstone EC, Walther D, Uhl GR, Murphy MF, Aveyard P . CHRNA3 rs1051730 genotype and short-term smoking cessation. Nicotine Tob Res 2011; 13: 982–988.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Bergen AW, Javitz HS, Krasnow R, Nishita D, Michel M, Conti DV et al. Nicotinic acetylcholine receptor variation and response to smoking cessation therapies. Pharmacogenet Genomics 2013; 23: 94–103.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. 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 

  126. 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 

  127. Saccone NL, Saccone SF, Hinrichs AL, Stitzel JA, Duan W, Pergadia ML et al. Multiple distinct risk loci for nicotine dependence identified by dense coverage of the complete family of nicotinic receptor subunit (CHRN) genes. Am J Med Genet B Neuropsychiatr Genet 2009; 150B: 453–466.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Lee CT, Fuemmeler BF, McClernon FJ, Ashley-Koch A, Kollins SH . Nicotinic receptor gene variants interact with attention deficient hyperactive disorder symptoms to predict smoking trajectories from early adolescence to adulthood. Addictive behaviors 2013; 38: 2683–2689.

    Article  PubMed  Google Scholar 

  129. Bar-Shira A, Gana-Weisz M, Gan-Or Z, Giladi E, Giladi N, Orr-Urtreger A . CHRNB3 c.-57A>G functional promoter change affects Parkinson's disease and smoking. Neurobiol Aging 2014; 35: 2179.e2171–2176.

    Article  CAS  Google Scholar 

  130. Loukola A, Buchwald J, Gupta R, Palviainen T, Hallfors J, Tikkanen E et al. A genome-wide association study of a biomarker of nicotine metabolism. PLoS Genet 2015; 11: e1005498.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Cirulli ET, Goldstein DB . Uncovering the roles of rare variants in common disease through whole-genome sequencing. Nat Rev Genet 2010; 11: 415–425.

    Article  CAS  PubMed  Google Scholar 

  132. Sham PC, Purcell SM . Statistical power and significance testing in large-scale genetic studies. Nat Rev Genet 2014; 15: 335–346.

    Article  CAS  PubMed  Google Scholar 

  133. Wessel J, McDonald SM, Hinds DA, Stokowski RP, Javitz HS, Kennemer M et al. Resequencing of nicotinic acetylcholine receptor genes and association of common and rare variants with the Fagerstrom test for nicotine dependence. Neuropsychopharmacology 2010; 35: 2392–2402.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Xie P, Kranzler HR, Krauthammer M, Cosgrove KP, Oslin D, Anton RF et al. Rare nonsynonymous variants in alpha-4 nicotinic acetylcholine receptor gene protect against nicotine dependence. Biol Psychiatry 2011; 70: 528–536.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Haller G, Druley T, Vallania FL, Mitra RD, Li P, Akk G et al. Rare missense variants in CHRNB4 are associated with reduced risk of nicotine dependence. Hum Mol Genet 2012; 21: 647–655.

    Article  CAS  PubMed  Google Scholar 

  136. Slimak MA, Ables JL, Frahm S, Antolin-Fontes B, Santos-Torres J, Moretti M et al. Habenular expression of rare missense variants of the beta4 nicotinic receptor subunit alters nicotine consumption. Front Human Neurosci 2014; 8: 12.

    Article  CAS  Google Scholar 

  137. Doyle GA, Chou AD, Saung WT, Lai AT, Lohoff FW, Berrettini WH . Identification of CHRNA5 rare variants in African-American heavy smokers. Psychiatric Genet 2014; 24: 102–109.

    Article  CAS  Google Scholar 

  138. Yang J, Wang S, Yang Z, Hodgkinson CA, Iarikova P, Ma JZ et al. The contribution of rare and common variants in 30 genes to risk nicotine dependence. Mol Psychiatry 2014; 20: 1467–1478.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Munafo MR, Clark TG, Johnstone EC, Murphy FG, Walton RT . The genetics basis for smoking behavior: a systematic review and meta-analysis. Nicotine Tob Res 2004; 6: 583–597.

    Article  CAS  PubMed  Google Scholar 

  140. Piper ME, McCarthy DE, Baker TB . Assessing tobacco dependence: a guide to measure evaluation and selection. Nicotine Tob Res 2006; 8: 339–351.

    Article  PubMed  Google Scholar 

  141. Egan MF, Kojima M, Callicott JH, Goldberg TE, Kolachana BS, Bertolino A et al. The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function. Cell 2003; 112: 257–269.

    Article  CAS  PubMed  Google Scholar 

  142. Ducci F, Goldman D . The genetic basis of addictive disorders. Psychiatr Clin North Am 2012; 35: 495–519.

    Article  PubMed  PubMed Central  Google Scholar 

  143. Yudkin P, Munafo M, Hey K, Roberts S, Welch S, Johnstone E et al. Effectiveness of nicotine patches in relation to genotype in women versus men: randomised controlled trial. BMJ 2004; 328: 989–990.

    Article  PubMed  PubMed Central  Google Scholar 

  144. Johnstone EC, Yudkin PL, Hey K, Roberts SJ, Welch SJ, Murphy MF et al. Genetic variation in dopaminergic pathways and short-term effectiveness of the nicotine patch. Pharmacogenetics 2004; 14: 83–90.

    Article  CAS  PubMed  Google Scholar 

  145. Lerman C, Jepson C, Wileyto EP, Epstein LH, Rukstalis M, Patterson F et al. Role of functional genetic variation in the dopamine D2 receptor (DRD2) in response to bupropion and nicotine replacement therapy for tobacco dependence: results of two randomized clinical trials. Neuropsychopharmacology 2006; 31: 231–242.

    Article  CAS  PubMed  Google Scholar 

  146. Comings DE, Ferry L, Bradshaw-Robinson S, Burchette R, Chiu C, Muhleman D . The dopamine D2 receptor (DRD2) gene: a genetic risk factor in smoking. Pharmacogenetics 1996; 6: 73–79.

    Article  CAS  PubMed  Google Scholar 

  147. Liu YZ, Pei YF, Guo YF, Wang L, Liu XG, Yan H et al. Genome-wide association analyses suggested a novel mechanism for smoking behavior regulated by IL15. Mol Psychiatry 2009; 14: 668–680.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Beuten J, Ma JZ, Lou XY, Payne TJ, Li MD . Association analysis of the protein phosphatase 1 regulatory subunit 1B (PPP1R1B) gene with nicotine dependence in European- and African-American smokers. Am J Med Genet B Neuropsychiatr Genet 2007; 144: 285–290.

    Article  CAS  Google Scholar 

  149. Munafo MR, Elliot KM, Murphy MF, Walton RT, Johnstone EC . Association of the mu-opioid receptor gene with smoking cessation. Pharmacogenomics J 2007; 7: 353–361.

    Article  CAS  PubMed  Google Scholar 

  150. Falcone M, Jepson C, Benowitz N, Bergen AW, Pinto A, Wileyto EP et al. Association of the nicotine metabolite ratio and CHRNA5/CHRNA3 polymorphisms with smoking rate among treatment-seeking smokers. Nicotine Tob Res 2011; 13: 498–503.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Polina ER, Rovaris DL, de Azeredo LA, Mota NR, Vitola ES, Silva KL et al. ADHD diagnosis may influence the association between polymorphisms in nicotinic acetylcholine receptor genes and tobacco smoking. Neuromol Med 2014; 16: 389–397.

    CAS  Google Scholar 

  152. Rodriguez S, Cook DG, Gaunt TR, Nightingale CM, Whincup PH, Day IN . Combined analysis of CHRNA5, CHRNA3 and CYP2A6 in relation to adolescent smoking behaviour. J Psychopharmacol 2011; 25: 915–923.

    Article  CAS  PubMed  Google Scholar 

  153. Chen X, Chen J, Williamson VS, An SS, Hettema JM, Aggen SH et al. Variants in nicotinic acetylcholine receptors alpha5 and alpha3 increase risks to nicotine dependence. Am J Med Genet B Neuropsychiatr Genet 2009; 150B: 926–933.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Johnson EO, Chen LS, Breslau N, Hatsukami D, Robbins T, Saccone NL et al. Peer smoking and the nicotinic receptor genes: an examination of genetic and environmental risks for nicotine dependence. Addiction 2010; 105: 2014–2022.

    Article  PubMed  PubMed Central  Google Scholar 

  155. Xie P, Kranzler HR, Zhang H, Oslin D, Anton RF, Farrer LA et al. Childhood adversity increases risk for nicotine dependence and interacts with alpha5 nicotinic acetylcholine receptor genotype specifically in males. Neuropsychopharmacology 2011; 37: 669–676.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Saccone NL, Wang JC, Breslau N, Johnson EO, Hatsukami D, Saccone SF 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 

  157. Stevens VL, Bierut LJ, Talbot JT, Wang JC, Sun J, Hinrichs AL et al. Nicotinic receptor gene variants influence susceptibility to heavy smoking. Cancer Epidemiol Biomark Prev 2008; 17: 3517–3525.

    Article  CAS  Google Scholar 

  158. Sorice R, Bione S, Sansanelli S, Ulivi S, Athanasakis E, Lanzara C et al. Association of a variant in the CHRNA5-A3-B4 gene cluster region to heavy smoking in the Italian population. Eur J Human Genet 2011; 19: 593–596.

    Article  CAS  Google Scholar 

  159. Maes HH, Neale MC, Chen X, Chen J, Prescott CA, Kendler KS . A twin association study of nicotine dependence with markers in the CHRNA3 and CHRNA5 genes. Behav Genet 2011; 41: 680–690.

    Article  PubMed  PubMed Central  Google Scholar 

  160. Rode L, Bojesen SE, Weischer M, Nordestgaard BG . High tobacco consumption is causally associated with increased all-cause mortality in a general population sample of 55,568 individuals, but not with short telomeres: a Mendelian randomization study. Int J Epidemiol 2014; 43: 1473–1483.

    Article  PubMed  Google Scholar 

  161. Hartz SM, Short SE, Saccone NL, Culverhouse R, Chen L, Schwantes-An TH et al. Increased genetic vulnerability to smoking at CHRNA5 in early-onset smokers. Arch Gen Psychiatry 2012; 69: 854–860.

    Article  PubMed  PubMed Central  Google Scholar 

  162. 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: e1001053.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Cannon DS, Baker TB, Piper ME, Scholand MB, Lawrence DL, Drayna DT et al. Associations between phenylthiocarbamide gene polymorphisms and cigarette smoking. Nicotine Tob Res 2005; 7: 853–858.

    Article  CAS  PubMed  Google Scholar 

  164. Gelernter J, Kranzler HR, Sherva R, Almasy L, Herman AI, Koesterer R et al. Genome-wide association study of nicotine dependence in American populations: identification of novel risk loci in both African-Americans and European-Americans. Biol Psychiatry 2015; 77: 493–503.

    Article  CAS  PubMed  Google Scholar 

  165. Hoft NR, Stitzel JA, Hutchison KE, Ehringer MA . CHRNB2 promoter region: association with subjective effects to nicotine and gene expression differences. Genes Brain Behav 2011; 10: 176–185.

    Article  CAS  PubMed  Google Scholar 

  166. Domino EF, Hirasawa-Fujita M, Ni L, Guthrie SK, Zubieta JK . Regional brain [(11)C]carfentanil binding following tobacco smoking. Prog Neuropsychopharmacol Biol Psychiatry 2015; 59: 100–104.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Ray R, Ruparel K, Newberg A, Wileyto EP, Loughead JW, Divgi C et al. Human mu opioid receptor (OPRM1 A118G) polymorphism is associated with brain mu-opioid receptor binding potential in smokers. Proc Natl Acad Sci USA 2011; 108: 9268–9273.

    Article  PubMed  PubMed Central  Google Scholar 

  168. Dash B, Li MD . Two rare variations, D478N and D478E, that occur at the same amino acid residue in nicotinic acetylcholine receptor (nAChR) alpha2 subunit influence nAChR function. Neuropharmacology 2014; 85: 471–481.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Dash B, Lukas RJ, Li MD . A signal peptide missense mutation associated with nicotine dependence alters alpha2*-nicotinic acetylcholine receptor function. Neuropharmacology 2014; 79: 715–725.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Kamens HM, Miyamoto J, Powers MS, Ro K, Soto M, Cox R et al. The beta3 subunit of the nicotinic acetylcholine receptor: modulation of gene expression and nicotine consumption. Neuropharmacology 2015; 99: 639–649.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Xu X, Clark US, David SP, Mulligan RC, Knopik VS, McGeary J et al. Effects of nicotine deprivation and replacement on BOLD-fMRI response to smoking cues as a function of DRD4 VNTR genotype. Nicotine Tob Res 2014; 16: 939–947.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Hong LE, Hodgkinson CA, Yang Y, Sampath H, Ross TJ, Buchholz B et al. A genetically modulated, intrinsic cingulate circuit supports human nicotine addiction. Proc Natl Acad Sci USA 2010; 107: 13509–13514.

    Article  PubMed  PubMed Central  Google Scholar 

  173. Kuryatov A, Berrettini W, Lindstrom J . Acetylcholine receptor (AChR) alpha5 subunit variant associated with risk for nicotine dependence and lung cancer reduces (alpha4beta2)(2)alpha5 AChR function. Mol Pharmacol 2011; 79: 119–125.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Hu XZ, Lipsky RH, Zhu G, Akhtar LA, Taubman J, Greenberg BD et al. Serotonin transporter promoter gain-of-function genotypes are linked to obsessive-compulsive disorder. Am J Hum Genet 2006; 78: 815–826.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Little KY, McLauglin DP, Ranc J, Gilmore J, Lopez JF, Watson SJ et al. Serotonin transporter binding sites and mRNA levels in depressed persons committing suicide. Biol Psychiatry 1997; 41: 1156–1164.

    Article  CAS  PubMed  Google Scholar 

  176. Heinz A, Jones DW, Mazzanti C, Goldman D, Ragan P, Hommer D et al. A relationship between serotonin transporter genotype and in vivo protein expression and alcohol neurotoxicity. Biol Psychiatry 2000; 47: 643–649.

    Article  CAS  PubMed  Google Scholar 

  177. Tricker AR . Nicotine metabolism, human drug metabolism polymorphisms, and smoking behaviour. Toxicology 2003; 183: 151–173.

    Article  CAS  PubMed  Google Scholar 

  178. Eggert M, Winterer G, Wanischeck M, Hoda JC, Bertrand D, Steinlein O . The nicotinic acetylcholine receptor alpha 4 subunit contains a functionally relevant SNP Haplotype. BMC Genet 2015; 16: 46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Chen J, Lipska BK, Halim N, Ma QD, Matsumoto M, Melhem S et al. Functional analysis of genetic variation in catechol-O-methyltransferase (COMT): effects on mRNA, protein, and enzyme activity in postmortem human brain. Am J Hum Genet 2004; 75: 807–821.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The preparation of this communication was supported by US National Institutes of Health grant DA012844 to MDL. We thank Dr David L Bronson for his excellent editing of this report.

Author information

Authors and Affiliations

  1. State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China

    J Yang & M D Li

  2. Department of Psychiatry and Neurobehavioral Sciences, University of Virginia, Charlottesville, VA, USA

    J Yang & M D Li

  3. Center for Air Pollution and Health, Zhejiang University, Hangzhou, China

    M D Li

Authors
  1. J Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M D Li
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to M D Li.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies the paper on the Molecular Psychiatry website

Supplementary information

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yang, J., Li, M. Converging findings from linkage and association analyses on susceptibility genes for smoking and other addictions. Mol Psychiatry 21, 992–1008 (2016). https://doi.org/10.1038/mp.2016.67

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/mp.2016.67

This article is cited by

Search

Advanced search

Quick links