Abstract
Smoking is a common risk factor for many diseases1. We conducted genome-wide association meta-analyses for the number of cigarettes smoked per day (CPD) in smokers (n = 31,266) and smoking initiation (n = 46,481) using samples from the ENGAGE Consortium. In a second stage, we tested selected SNPs with in silico replication in the Tobacco and Genetics (TAG) and Glaxo Smith Kline (Ox-GSK) consortia cohorts (n = 45,691 smokers) and assessed some of those in a third sample of European ancestry (n = 9,040). Variants in three genomic regions associated with CPD (P < 5 × 10−8), including previously identified SNPs at 15q25 represented by rs1051730[A] (effect size = 0.80 CPD, P = 2.4 × 10−69), and SNPs at 19q13 and 8p11, represented by rs4105144[C] (effect size = 0.39 CPD, P = 2.2 × 10−12) and rs6474412-T (effect size = 0.29 CPD, P = 1.4 × 10−8), respectively. Among the genes at the two newly associated loci are genes encoding nicotine-metabolizing enzymes (CYP2A6 and CYP2B6) and nicotinic acetylcholine receptor subunits (CHRNB3 and CHRNA6), all of which have been highlighted in previous studies of smoking and nicotine dependence2,3,4. Nominal associations with lung cancer were observed at both 8p11 (rs6474412[T], odds ratio (OR) = 1.09, P = 0.04) and 19q13 (rs4105144[C], OR = 1.12, P = 0.0006).
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
WHO Report on the Global Tobacco Epidemic, 2008. 8 http://tobaccofreecenter.org/mpower-2008 (2008).
Bierut, L.J. et al. Novel genes identified in a high-density genome wide association study for nicotine dependence. Hum. Mol. Genet. 16, 24–35 (2007).
Saccone, S.F. et al. Cholinergic nicotinic receptor genes implicated in a nicotine dependence association study targeting 348 candidate genes with 3713 SNPs. Hum. Mol. Genet. 16, 36–49 (2007).
Ray, R., Tyndale, R.F. & Lerman, C. Nicotine dependence pharmacogenetics: role of genetic variation in nicotine-metabolizing enzymes. J. Neurogenet. 23, 252–261 (2009).
Rose, R., Broms, U., Korhonen, T., Dick, D. & Kaprio, J. Genetics of Smoking Behavior. in Handbook of Behavior Genetics (ed. Kim, Y.) Part IV, 411–432 (Springer Science+Business Media, 2009).
Li, M.D., Cheng, R., Ma, J.Z. & Swan, G.E. A meta-analysis of estimated genetic and environmental effects on smoking behavior in male and female adult twins. Addiction 98, 23–31 (2003).
Koopmans, J.R., Slutske, W.S., Heath, A.C., Neale, M.C. & Boomsma, D.I. The genetics of smoking initiation and quantity smoked in Dutch adolescent and young adult twins. Behav. Genet. 29, 383–393 (1999).
Thorgeirsson, T.E. et al. A variant associated with nicotine dependence, lung cancer and peripheral arterial disease. Nature 452, 638–642 (2008).
Berrettini, W. et al. Alpha-5/alpha-3 nicotinic receptor subunit alleles increase risk for heavy smoking. Mol. Psychiatry 13, 368–373 (2008).
Amos, C.I. et al. Genome-wide association scan of tag SNPs identifies a susceptibility locus for lung cancer at 15q25.1. Nat. Genet. 40, 616–622 (2008).
Hung, R.J. et al. A susceptibility locus for lung cancer maps to nicotinic acetylcholine receptor subunit genes on 15q25. Nature 452, 633–637 (2008).
Pillai, S.G. et al. A genome-wide association study in chronic obstructive pulmonary disease (COPD): identification of two major susceptibility loci. PLoS Genet. 5, e1000421 (2009).
Tobacco and Genetics Consortium. Genome-wide meta-analyses identify multiple loci associated with smoking behavior. Nat. Genet. 42, 441–447 (2010).
Liu, J. et al. Meta-analysis and imputation refines the association of 15q25 with smoking quantity. Nat. Genet. 42, 436–440 (2010).
Stevens, V.L. et al. Nicotinic receptor gene variants influence susceptibility to heavy smoking. Cancer Epidemiol. Biomarkers Prev. 17, 3517–3525 (2008).
Collins, A.C., Salminen, O., Marks, M.J., Whiteaker, P. & Grady, S.R. The road to discovery of neuronal nicotinic cholinergic receptor subtypes. Handb. Exp. Pharmacol. 192, 85–112 (2009).
Mineur, Y.S. & Picciotto, M.R. Genetics of nicotinic acetylcholine receptors: relevance to nicotine addiction. Biochem. Pharmacol. 75, 323–333 (2008).
West, K.A. et al. Rapid Akt activation by nicotine and a tobacco carcinogen modulates the phenotype of normal human airway epithelial cells. J. Clin. Invest. 111, 81–90 (2003).
Miksys, S., Lerman, C., Shields, P.G., Mash, D.C. & Tyndale, R.F. Smoking, alcoholism and genetic polymorphisms alter CYP2B6 levels in human brain. Neuropharmacology 45, 122–132 (2003).
Keskitalo, K. 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. 18, 4007–4012 (2009).
Uhl, G.R. et al. Molecular genetics of successful smoking cessation: convergent genome-wide association study results. Arch. Gen. Psychiatry 65, 683–693 (2008).
Uhl, G.R. et al. Molecular genetics of nicotine dependence and abstinence: whole genome association using 520,000 SNPs. BMC Genet. 8, 10 (2007).
Chanock, S.J. & Hunter, D.J. Genomics: when the smoke clears. Nature 452, 537–538 (2008).
Thorgeirsson, T.E. & Stefansson, K. Genetics of smoking behavior and its consequences: the role of nicotinic acetylcholine receptors. Biol. Psychiatry 64, 919–921 (2008).
Spitz, M.R., Amos, C.I., 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. 100, 1552–1556 (2008).
Lips, E.H. et al. Association between a 15q25 gene variant, smoking quantity and tobacco-related cancers among 17000 individuals. Int. J. Epidemiol. 39, 563–577 (2010).
Thorgeirsson, T.E. & Stefansson, K. Commentary: gene-environment interactions and smoking-related cancers. Int. J. Epidemiol. 39, 577–579 (2010).
Krestyaninova, M. et al. A System for Information Management in BioMedical Studies–SIMBioMS. Bioinformatics 25, 2768–2769 (2009).
International HapMap Consortium. A haplotype map of the human genome. Nature 437, 1299–1320 (2005).
Marchini, J., Howie, B., Myers, S., McVean, G. & Donnelly, P. A new multipoint method for genome-wide association studies by imputation of genotypes. Nat. Genet. 39, 906–913 (2007).
Li, Y., Willer, C., Sanna, S. & Abecasis, G. Genotype imputation. Annu. Rev. Genomics Hum. Genet. 10, 387–406 (2009).
Kutyavin, I.V. et al. A novel endonuclease IV post-PCR genotyping system. Nucleic Acids Res. 34, e128 (2006).
Gretarsdottir, S. et al. The gene encoding phosphodiesterase 4D confers risk of ischemic stroke. Nat. Genet. 35, 131–138 (2003).
Rice, J.A. Mathematical Statistics and Data Analysis. 299–330 (Wadsworth, Belmont, California, USA, 1995).
Higgins, J.P. & Thompson, S. Quantifying heterogeneity in a meta-analysis. Stat. Med. 21, 1539–1558 (2002).
Devlin, B. & Roeder, K. Genomic control for association studies. Biometrics 55, 997–1004 (1999).
Acknowledgements
We thank all the participants in the genetic studies whose contributions made this work possible. This work was supported in part by the US National Institutes of Health (R01-DA017932) and the European Commission's Sixth Framework Program, Integrated Project GENADDICT (LSHM-CT-2004-005166). The ENGAGE smoking consortium was formed through a component of the Integrated Project ENGAGE, supported by the European Commission's Seventh Framework Program, grant agreement HEALTH-F4-2007- 201413. ENGAGE projects have benefited from the SIMBioMS platform28, which has greatly facilitated data exchange and annotation. Further acknowledgments are listed in the Supplementary Note online.
Author information
Authors and Affiliations
Consortia
Contributions
The study was designed by and the results interpreted by T.E.T., D.F.G., F.G., J.R.G., U.T., K.S., L.P. and M.I.M. The meta-analysis was performed by D.F.G. and F.G., and D.F.G., F.G., I.S., J.M.V., P.S., N.A., T.E., S.W., C.G., R.R., M.M., I.P., R.M., J. Kettunen, Y.S.A., N.S. and J.J.H. were responsible for data analysis in each of the ENGAGE samples. Stage 3 and smoking-related disease samples were coordinated by I.H.G., H.S., S.G. and T.R. Those responsible for case and control ascertainment, recruitment and phenotypic information and project management at the study sites are: J.R.T., W.A.F., H.W., G.W.M., A.C.H., N.G.M., P.A.F.M., K.K.A., M.d.H., L.A.K., G.T.J., A.M.v.R., T.M., B.D., M.H., S.J., T.R., S.E.M., S.G., A.M.V., C.S., A.G.U., A.H., A.T., P.K., G.W., N.V., A. Dirksen, N.D., B.N., M.L.P., B.S., S.R., M.P., J. Kettunen, A.-L.H., A.P., J.L., M.I., A.S.H., T.E.T., H.O., T.T., V.D.D., V.L., M.D.G.-P., J.I.M., A. Döring, H.A., J.S.L., J.H.P., I.G., D.R., M.-R.J., V.S., M.S., T.D.S., H.-E.W., A.M., M.N., N.J.S., B.W.P., B.A.O., D.I.B., H.T., C.M.v.D., J. Kaprio, J.R.G., M.I.M., L.P., U.T. and K.S. Data submission coordination was provided by S.H.-Y., M.A. and M.K. Authors T.E.T., D.F.G. and U.T. wrote the first draft of the paper. All authors contributed to the final version of the paper.
Corresponding authors
Ethics declarations
Competing interests
Authors whose affiliations are listed as deCODE genetics are employees of deCODE genetics, a biotechnology company.
Additional information
A full list of members is provided in the Supplementary Note.
Supplementary information
Supplementary Text and Figures
Supplementary Figures 1–3, Supplementary Tables 1–4 and Supplementary Note (PDF 215 kb)
Rights and permissions
About this article
Cite this article
Thorgeirsson, T., Gudbjartsson, D., Surakka, I. et al. Sequence variants at CHRNB3–CHRNA6 and CYP2A6 affect smoking behavior. Nat Genet 42, 448–453 (2010). https://doi.org/10.1038/ng.573
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/ng.573
This article is cited by
-
Tobacco and nicotine use
Nature Reviews Disease Primers (2022)
-
Sex-specific nicotine sensitization and imprinting of self-administration in rats inform GWAS findings on human addiction phenotypes
Neuropsychopharmacology (2021)
-
Association Study of Opioid Receptor Delta-Type 1 (OPRD1) Gene Variants with Nicotine Dependence in an Iranian Population
Journal of Molecular Neuroscience (2021)
-
Clarifying the Genetic Influences on Nicotine Dependence and Quantity of Use in Cigarette Smokers
Behavior Genetics (2021)
-
Nicotinic acetylcholine gene cluster CHRNA5-A3-B4 variants influence smoking status in a Bangladeshi population
Pharmacological Reports (2021)