Genetics of Nicotine Addiction


Diseases associated with addiction to nicotine, the key reinforcing constituent of tobacco, remain the largest cause of preventable death worldwide. Although twin studies indicate a large genetic contribution to the variation in smoking‐related behaviours, the polymorphisms underlying this heritability remain largely unidentified. Candidate gene studies have investigated several pathways, but thus far only those few genetic loci identified in unbiased genome‐wide association studies have been consistently replicated; these are the direct targets of nicotine in the nervous system, the nicotinic acetylcholine receptor subunit genes CHRNA5–CHRNA3–CHRNB4 and the primary nicotine metabolism gene CYP2A6. These variants may differ in their influences regarding different aspects of smoking behaviour, and their frequencies vary widely among different ethnic populations. Use of more‐targeted phenotypes including biomarkers of smoke exposure such as cotinine, nicotine's major metabolite, and exhaled carbon monoxide, may provide the key to detecting further genetic correlates of nicotine dependence and related diseases.

Key Concepts:

  • Variation in nicotine addiction‐related traits have large genetic components.

  • Genetic studies of nicotine addiction seek to identify drug targets for smoking cessation treatment and to improve treatments using genotype‐based personalised medicine.

  • Candidate gene studies have focussed on the nicotinic acetylcholine receptors and genes in the nicotine metabolism, dopaminergic, serotonergic, GABAergic, and opioid pathways, but few associations have been convincingly replicated.

  • Unbiased genome‐wide studies have identified very few consistent genetic associations with smoking‐related phenotypes.

  • A functional variant in the CHRNA5–CHRNA3–CHRNB4 gene cluster is robustly associated with multiple smoking behaviours and related disease risk.

  • Functional variation in the CYP2A6 nicotine metabolism gene is associated with cigarette consumption and related disease risk.

  • Genetic factors contributing to nicotine addiction vary by ethnic population.

  • Genotype–environment and genotype–treatment interactions are important factors determining smoking initiation, dependence and cessation outcomes.

  • Use of biomarkers and other endophenotypes may provide greater power to identify genetic correlates of nicotine dependence.

Keywords: Nicotine; addiction; genetics; polymorphism; smoking; tobacco; CHRNA5; CYP2A6

Figure 1.

Neurotransmitters and nAChRs in the mesolimbic system. The dopaminergic projection from the VTA to the NAc; and glutamatergic (Glut), cholinergic (ACh), gamma‐aminobutyric acid (GABA)‐ergic and opioid projections to both structures. CHRNA and CHRNB subunit genes expressed in both structures.

Figure 2.

Stages of smoking behaviour, related phenotypes and genes with strong evidence for association. Brain‐Derived Neurotrophic Factor (BDNF), Dopamine Beta Hydroxylase (DBH), Cytochrome P450 2A6 and 2B6 (CYP2A6 and CYP2B6), nicotinic acetylcholine receptor α (CHRNA3,5,6) and β (CHRNB3,4,6) subunit genes.



Berlin I and Covey LS (2006) Pre‐cessation depressive mood predicts failure to quit smoking: the role of coping and personality traits. Addiction 101(12): 1814–1821.

Bierut LJ, Stitzel JA, Wang JC et al. (2008) Variants in nicotinic receptors and risk for nicotine dependence. American Journal of Psychiatry 165(9): 1163–1171.

Bloom AJ, Baker TB, Chen LS et al. (2014a) Variants in two adjacent genes, EGLN2 and CYP2A6, influence smoking behavior related to disease risk via different mechanisms. Human Molecular Genetics 23(2): 555–561.

Bloom AJ, Harari O, Martinez M et al. (2012) Use of a predictive model derived from in vivo endophenotype measurements to demonstrate associations with a complex locus, CYP2A6. Human Molecular Genetics 21(13): 3050–3062.

Bloom AJ, Hartz S, Baker TB et al. (2014b) Carbon monoxide level captures an important genetic aspect of cigarette smoke exposure. Annals of the American Thoracic Society. in press.

Bloom J, Hinrichs AL, Wang JC et al. (2011) The contribution of common CYP2A6 alleles to variation in nicotine metabolism among European‐Americans. Pharmacogenet Genomics 21(7): 403–416.

Broms U, Silventoinen K, Madden PA, Heath AC and Kaprio J (2006) Genetic architecture of smoking behavior: a study of Finnish adult twins. Twin Research and Human Genetics 9(1): 64–72.

Button KS, Ioannidis JP, Mokrysz C et al. (2013) Power failure: why small sample size undermines the reliability of neuroscience. Nature Reviews Neuroscience 14(5): 365–376.

CDC (2010) Smoking‐attributable mortality, years of potential life lost, and productivity losses – United States, 2000–2004. Morbidity and Mortality Weekly Report 57: 1226–1228.

Chen LS, Baker TB, Grucza R et al. (2012) Dissection of the phenotypic and genotypic associations with nicotinic dependence. Nicotine & Tobacco Research 14(4): 425–433.

Chen LS, Bloom AJ, Baker TB et al. (2014) Pharmacotherapy effects on smoking cessation vary with nicotine metabolism gene (CYP2A6). Addiction 109(1): 128–137.

Dani JA and Harris RA (2005) Nicotine addiction and comorbidity with alcohol abuse and mental illness. Nature Neuroscience 8(11): 1465–1470.

David SP, Hamidovic A, Chen GK et al. (2012) Genome‐wide meta‐analyses of smoking behaviors in African Americans. Translational Psychiatry 2: e119.

Etter JF and Perneger TV (2001) Measurement of self reported active exposure to cigarette smoke. Journal of Epidemiology and Community Health 55(9): 674–680.

Etter JF, Vu Duc T and Perneger TV (2000) Saliva cotinine levels in smokers and nonsmokers. American Journal of Epidemiology 151(3): 251–258.

Fowler CD, Arends MA and Kenny PJ (2008) Subtypes of nicotinic acetylcholine receptors in nicotine reward, dependence, and withdrawal: evidence from genetically modified mice. Behavioural Pharmacology 19(5–6): 461–484.

Fowler CD, Lu Q, Johnson PM, Mark MJ and Kenny PJ (2011) Habenular alpha5 nicotinic receptor subunit signalling controls nicotine intake. Nature 471(7340): 597–601.

Franklin TR, Lohoff FW, Wang Z et al. (2009) DAT genotype modulates brain and behavioral responses elicited by cigarette cues. Neuropsychopharmacology 34(3): 717–728.

Grant BF, Hasin DS, Chou SP, Stinson FS and Dawson DA (2004) Nicotine dependence and psychiatric disorders in the United States: results from the national epidemiologic survey on alcohol and related conditions. Archives of General Psychiatry 61(11): 1107–1115.

Haller G, Druley T, Vallania FL et al. (2012) Rare missense variants in CHRNB4 are associated with reduced risk of nicotine dependence. Human Molecular Genetics 21(3): 647–655.

Jackson KJ, Marks MJ, Vann RE et al. (2010) Role of alpha5 nicotinic acetylcholine receptors in pharmacological and behavioral effects of nicotine in mice. Journal of Pharmacology and Experimental Therapeutics 334(1): 137–146.

Jonsson EG, Nothen MM, Grunhage F et al. (1999) Polymorphisms in the dopamine D2 receptor gene and their relationships to striatal dopamine receptor density of healthy volunteers. Molecular Psychiatry 4(3): 290–296.

Keskitalo K, Broms U, Heliovaara M et al. (2009) Association of serum cotinine level with a cluster of three nicotinic acetylcholine receptor genes (CHRNA3/CHRNA5/CHRNB4) on chromosome 15. Human Molecular Genetics 18(20): 4007–4012.

King DP, Paciga S, Pickering E et al. (2012) Smoking cessation pharmacogenetics: analysis of varenicline and bupropion in placebo‐controlled clinical trials. Neuropsychopharmacology 37(3): 641–650.

Klungsoyr O, Nygard JF, Sorensen T and Sandanger I (2006) Cigarette smoking and incidence of first depressive episode: an 11‐year, population‐based follow‐up study. American Journal of Epidemiology 163(5): 421–432.

Koopmans JR, Slutske WS, Heath AC, Neale MC and Boomsma DI (1999) The genetics of smoking initiation and quantity smoked in Dutch adolescent and young adult twins. Behavior Genetics 29(6): 383–393.

Li MD, Cheng R, Ma JZ and Swan GE (2003) A meta‐analysis of estimated genetic and environmental effects on smoking behavior in male and female adult twins. Addiction 98(1): 23–31.

Loughead J, Wileyto EP, Valdez JN et al. (2009) Effect of abstinence challenge on brain function and cognition in smokers differs by COMT genotype. Molecular Psychiatry 14(8): 820–826.

Maes HH, Sullivan PF, Bulik CM et al. (2004) A twin study of genetic and environmental influences on tobacco initiation, regular tobacco use and nicotine dependence. Psychological Medicine 34(7): 1251–1261.

Malaiyandi V, Sellers EM and Tyndale RF (2005) Implications of CYP2A6 genetic variation for smoking behaviors and nicotine dependence. Clinical Pharmacology & Therapeutics 77(3): 145–158.

McClernon FJ, Hutchison KE, Rose JE and Kozink RV (2007) DRD4 VNTR polymorphism is associated with transient fMRI‐BOLD responses to smoking cues. Psychopharmacology (Berlin) 194(4): 433–441.

Munafo MR, Johnstone EC, Aveyard P and Marteau T (2013) Lack of association of OPRM1 genotype and smoking cessation. Nicotine & Tobacco Research 15(3): 739–744.

Munafo MR, Timofeeva MN, Morris RW et al. (2012) Association between genetic variants on chromosome 15q25 locus and objective measures of tobacco exposure. Journal of the National Cancer Institute 104(10): 740–748.

Munafo MR, Timpson NJ, David SP, Ebrahim S and Lawlor DA (2009) Association of the DRD2 gene Taq1A polymorphism and smoking behavior: a meta‐analysis and new data. Nicotine & Tobacco Research 11(1): 64–76.

Perez‐Stable EJ, Benowitz NL and Marin G (1995) Is serum cotinine a better measure of cigarette smoking than self‐report? Preventive Medicine 24(2): 171–179.

Rice JP, Hartz SM, Agrawal A et al. (2012) 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 107(11): 2019–2028.

Saccone NL, Wang JC, Breslau N et al. (2009) The CHRNA5‐CHRNA3‐CHRNB4 nicotinic receptor subunit gene cluster affects risk for nicotine dependence in African‐Americans and in European‐Americans. Cancer Research 69(17): 6848–6856.

Schoedel KA, Hoffmann EB, Rao Y, Sellers EM and Tyndale RF (2004) Ethnic variation in CYP2A6 and association of genetically slow nicotine metabolism and smoking in adult Caucasians. Pharmacogenetics 14(9): 615–626.

Siedlinski M, Cho MH, Bakke P et al. (2011) Genome‐wide association study of smoking behaviours in patients with COPD. Thorax 66(10): 894–902.

Stapleton JA, Sutherland G and O'Gara C (2007) Association between dopamine transporter genotypes and smoking cessation: a meta‐analysis. Addiction Biology 12(2): 221–226.

Sullivan PF and Kendler KS (1999) The genetic epidemiology of smoking. Nicotine & Tobacco Research 1(suppl. 2): S51–S57 (Discussion S69–S70).

TAG‐Consortium (2010) Genome‐wide meta‐analyses identify multiple loci associated with smoking behavior. Nature Genetics 42(5): 441–447.

Tammimaki AE and Mannisto PT (2010) Are genetic variants of COMT associated with addiction? Pharmacogenetics and Genomics 20(12): 717–741.

Thorgeirsson TE, Gudbjartsson DF, Surakka I et al. (2010) Sequence variants at CHRNB3‐CHRNA6 and CYP2A6 affect smoking behavior. Nature Genetics 42(5): 448–453.

Tsuang MT, Francis T, Minor K, Thomas A and Stone WS (2012) Genetics of smoking and depression. Human Genetics 131(6): 905–915.

Vink JM, Smit AB, de Geus EJ et al. (2009) Genome‐wide association study of smoking initiation and current smoking. American Journal of Human Genetics 84(3): 367–379.

Wang JC, Cruchaga C, Saccone NL et al. (2009) Risk for nicotine dependence and lung cancer is conferred by mRNA expression levels and amino acid change in CHRNA5. Human Molecular Genetics 18(16): 3125–3135.

Wang S, Yang Z, Ma JZ, Payne TJ and Li MD (2013) Introduction to deep sequencing and its application to drug addiction research with a focus on rare variants. Molecular Neurobiology 49(1): 601–614.

World Health Organization (2010) Global burden of disease. Available at: (accessed on 01 Oct 2013).

Xian H, Scherrer JF, Madden PA et al. (2003) The heritability of failed smoking cessation and nicotine withdrawal in twins who smoked and attempted to quit. Nicotine & Tobacco Research 5(2): 245–254.

Further Reading

Bodmer W and Bonilla C (2008) Common and rare variants in multifactorial susceptibility to common diseases. Nature Genetics 40(6): 695–701.

Fowler CD and Kenny PJ (2012) Utility of genetically modified mice for understanding the neurobiology of substance use disorders. Human Genetics 131(6): 941–957.

Leslie FM, Mojica CY and Reynaga DD (2013) Nicotinic receptors in addiction pathways. Molecular Pharmacology 83(4): 753–758.

Picciotto MR and Kenny PJ (2013) Molecular mechanisms underlying behaviors related to nicotine addiction. Cold Spring Harbor Perspectives in Medicine 3(1): a012112.

Tsuang MT, Francis T, Minor K, Thomas A and Stone WS (2012) Genetics of smoking and depression. Human Genetics 131(6): 905–915.

Ware JJ, van den Bree M and Munafo MR (2012) From men to mice: CHRNA5/CHRNA3, smoking behavior and disease. Nicotine & Tobacco Research 14(11): 1291–1299.

Ware JJ, van den Bree MB and Munafo MR (2011) Association of the CHRNA5‐A3‐B4 gene cluster with heaviness of smoking: a meta‐analysis. Nicotine & Tobacco Research 13(12): 1167–1175.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Bloom, A Joseph, and Goate, Alison M(Apr 2014) Genetics of Nicotine Addiction. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0024636]