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.

Sequence variants at CHRNB3CHRNA6 and CYP2A6 affect smoking behavior

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

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: Regional plots of the CPD loci.

References

  1. WHO Report on the Global Tobacco Epidemic, 2008. 8 http://tobaccofreecenter.org/mpower-2008 (2008).

  2. 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).

    Article  CAS  Google Scholar 

  3. 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).

    Article  CAS  Google Scholar 

  4. Ray, R., Tyndale, R.F. & Lerman, C. Nicotine dependence pharmacogenetics: role of genetic variation in nicotine-metabolizing enzymes. J. Neurogenet. 23, 252–261 (2009).

    Article  CAS  Google Scholar 

  5. 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).

  6. 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).

    Article  Google Scholar 

  7. 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).

    Article  CAS  Google Scholar 

  8. Thorgeirsson, T.E. et al. A variant associated with nicotine dependence, lung cancer and peripheral arterial disease. Nature 452, 638–642 (2008).

    Article  CAS  Google Scholar 

  9. Berrettini, W. et al. Alpha-5/alpha-3 nicotinic receptor subunit alleles increase risk for heavy smoking. Mol. Psychiatry 13, 368–373 (2008).

    Article  CAS  Google Scholar 

  10. 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).

    Article  CAS  Google Scholar 

  11. 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).

    Article  CAS  Google Scholar 

  12. 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).

    Article  Google Scholar 

  13. Tobacco and Genetics Consortium. Genome-wide meta-analyses identify multiple loci associated with smoking behavior. Nat. Genet. 42, 441–447 (2010).

  14. Liu, J. et al. Meta-analysis and imputation refines the association of 15q25 with smoking quantity. Nat. Genet. 42, 436–440 (2010).

    Article  CAS  Google Scholar 

  15. Stevens, V.L. et al. Nicotinic receptor gene variants influence susceptibility to heavy smoking. Cancer Epidemiol. Biomarkers Prev. 17, 3517–3525 (2008).

    Article  CAS  Google Scholar 

  16. 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).

    Article  CAS  Google Scholar 

  17. Mineur, Y.S. & Picciotto, M.R. Genetics of nicotinic acetylcholine receptors: relevance to nicotine addiction. Biochem. Pharmacol. 75, 323–333 (2008).

    Article  CAS  Google Scholar 

  18. 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).

    Article  CAS  Google Scholar 

  19. 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).

    Article  CAS  Google Scholar 

  20. 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).

    Article  CAS  Google Scholar 

  21. Uhl, G.R. et al. Molecular genetics of successful smoking cessation: convergent genome-wide association study results. Arch. Gen. Psychiatry 65, 683–693 (2008).

    Article  CAS  Google Scholar 

  22. Uhl, G.R. et al. Molecular genetics of nicotine dependence and abstinence: whole genome association using 520,000 SNPs. BMC Genet. 8, 10 (2007).

    Article  Google Scholar 

  23. Chanock, S.J. & Hunter, D.J. Genomics: when the smoke clears. Nature 452, 537–538 (2008).

    Article  CAS  Google Scholar 

  24. Thorgeirsson, T.E. & Stefansson, K. Genetics of smoking behavior and its consequences: the role of nicotinic acetylcholine receptors. Biol. Psychiatry 64, 919–921 (2008).

    Article  CAS  Google Scholar 

  25. 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).

    Article  CAS  Google Scholar 

  26. 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).

    Article  Google Scholar 

  27. Thorgeirsson, T.E. & Stefansson, K. Commentary: gene-environment interactions and smoking-related cancers. Int. J. Epidemiol. 39, 577–579 (2010).

    Article  Google Scholar 

  28. Krestyaninova, M. et al. A System for Information Management in BioMedical Studies–SIMBioMS. Bioinformatics 25, 2768–2769 (2009).

    Article  CAS  Google Scholar 

  29. International HapMap Consortium. A haplotype map of the human genome. Nature 437, 1299–1320 (2005).

  30. 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).

    Article  CAS  Google Scholar 

  31. Li, Y., Willer, C., Sanna, S. & Abecasis, G. Genotype imputation. Annu. Rev. Genomics Hum. Genet. 10, 387–406 (2009).

    Article  CAS  Google Scholar 

  32. Kutyavin, I.V. et al. A novel endonuclease IV post-PCR genotyping system. Nucleic Acids Res. 34, e128 (2006).

    Article  Google Scholar 

  33. Gretarsdottir, S. et al. The gene encoding phosphodiesterase 4D confers risk of ischemic stroke. Nat. Genet. 35, 131–138 (2003).

    Article  CAS  Google Scholar 

  34. Rice, J.A. Mathematical Statistics and Data Analysis. 299–330 (Wadsworth, Belmont, California, USA, 1995).

    Google Scholar 

  35. Higgins, J.P. & Thompson, S. Quantifying heterogeneity in a meta-analysis. Stat. Med. 21, 1539–1558 (2002).

    Article  Google Scholar 

  36. Devlin, B. & Roeder, K. Genomic control for association studies. Biometrics 55, 997–1004 (1999).

    Article  CAS  Google Scholar 

Download references

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

Authors

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

Correspondence to Unnur Thorsteinsdottir or Kari Stefansson.

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

Reprints and Permissions

About this article

Cite this article

Thorgeirsson, T., Gudbjartsson, D., Surakka, I. et al. Sequence variants at CHRNB3CHRNA6 and CYP2A6 affect smoking behavior. Nat Genet 42, 448–453 (2010). https://doi.org/10.1038/ng.573

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng.573

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing