Sequence variants at CHRNB3CHRNA6 and CYP2A6 affect smoking behavior

Journal name:
Nature Genetics
Year published:
Published online

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).


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Author information


  1. deCODE Genetics, Reykjavik, Iceland.

    • Thorgeir E Thorgeirsson,
    • Daniel F Gudbjartsson,
    • Frank Geller,
    • Patrick Sulem,
    • Thorunn Rafnar,
    • Iris H Gudjonsdottir,
    • Solveig Gretarsdottir,
    • Hreinn Stefansson,
    • Jeffrey R Gulcher,
    • Unnur Thorsteinsdottir &
    • Kari Stefansson
  2. Center for Biomolecular Science and Engineering, Jack Baskin School of Engineering, University of California, Santa Cruz, California, USA.

    • Thorgeir E Thorgeirsson
  3. Institute for Molecular Medicine (FIMM), University of Helsinki, Finland.

    • Ida Surakka,
    • Samuli Ripatti,
    • Shen Huei-Yi,
    • Jaakko Kaprio &
    • Leena Peltonen
  4. National Institute for Health and Welfare, Helsinki, Finland.

    • Ida Surakka,
    • Samuli Ripatti,
    • Markus Perola,
    • Shen Huei-Yi &
    • Veikko Salomaa
  5. Department of Biological Psychology, Vrije Universiteit (VU) Amsterdam, Amsterdam, The Netherlands.

    • Jacqueline M Vink,
    • Jouke Jan Hottenga,
    • Gonneke Willemsen &
    • Dorret I Boomsma
  6. Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands.

    • Najaf Amin,
    • Stefan Walter,
    • Yurii S Aulchenko,
    • André G Uitterlinden,
    • Albert Hofman,
    • Henning Tiemeier &
    • Cornelia M van Duijn
  7. Estonian Genome Project of University of Tartu, Tartu, Estonia.

    • Tõnu Esko,
    • Mari Nelis &
    • Andres Metspalu
  8. Estonian Biocentre, Tartu, Estonia.

    • Tõnu Esko,
    • Mari Nelis &
    • Andres Metspalu
  9. Institute of Epidemiology, Helmholtz Zentrum München, Neuherberg, Germany.

    • Christian Gieger,
    • Rajesh Rawal,
    • Angela Döring,
    • Barbara Nitz &
    • H-Erich Wichmann
  10. Department of Twin Research and Genetic Epidemiology, King's College London, St. Thomas' Hospital Campus, London, UK.

    • Massimo Mangino,
    • Nicole Soranzo,
    • Ana M Valdes,
    • Claire Steves &
    • Tim D Spector
  11. Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK.

    • Inga Prokopenko,
    • Reedik Mägi,
    • Maxine Allen &
    • Mark I McCarthy
  12. Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.

    • Inga Prokopenko,
    • Reedik Mägi &
    • Mark I McCarthy
  13. Department of Public Health, University of Helsinki, Helsinki, Finland.

    • Kaisu Keskitalo &
    • Jaakko Kaprio
  14. Department of Health Sciences and Genetics, University of Leicester, Leicester, UK.

    • John R Thompson
  15. Radboud University Nijmegen Medical Centre, Department of Epidemiology, Biostatistics and Health Technology Assessment, Nijmegen, The Netherlands.

    • Katja K Aben,
    • Martin den Heijer &
    • Lambertus A Kiemeney
  16. Comprehensive Cancer Centre East, Nijmegen, The Netherlands.

    • Katja K Aben &
    • Lambertus A Kiemeney
  17. Radboud University Nijmegen Medical Centre, Department of Endocrinology, Nijmegen, The Netherlands.

    • Martin den Heijer
  18. Department of Pulmonary Medicine, Gentofte University Hospital, Hellerup, Denmark.

    • Asger Dirksen &
    • Haseem Ashraf
  19. Wellcome Trust Sanger Institute, Hinxton, UK.

    • Nicole Soranzo,
    • Johannes Kettunen &
    • Leena Peltonen
  20. Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands.

    • André G Uitterlinden
  21. Department of Medicine, University of Leipzig, Leipzig, Germany.

    • Anke Tönjes &
    • Michael Stumvoll
  22. Coordination Centre for Clinical Trials, University of Leipzig, Leipzig, Germany.

    • Anke Tönjes
  23. Interdisciplinary Centre for Clinical Research, University of Leipzig, Leipzig, Germany.

    • Peter Kovacs
  24. Department of Psychiatry, VU University Medical Center, Amsterdam, The Netherlands.

    • Nicole Vogelzangs &
    • Brenda W Penninx
  25. Department of Psychiatry, University of Mainz, Mainz, Germany.

    • Norbert Dahmen
  26. Washington University School of Medicine, Department of Psychiatry, St. Louis, Missouri, USA.

    • Michele L Pergadia,
    • Andrew C Heath &
    • Pamela A F Madden
  27. Instituto de Nanotecnología de Aragón, Zaragoza, Spain.

    • Berta Saez
  28. Division of Dermatology, Hospital San Pedro, Logroño, Spain.

    • Veronica De Diego &
    • Victoria Lezcano
  29. Division of Pathology, San Jorge Hospital, Huesca, Spain.

    • Maria D Garcia-Prats
  30. Institute of Clinical Medicine, University of Oulu, Oulu, Finland.

    • Anna-Liisa Hartikainen &
    • Matti Isohanni
  31. Lifecourse and Service Department, National Institute of Health and Welfare, Oulu, Finland.

    • Anneli Pouta &
    • Marjo-Riitta Järvelin
  32. Finnish Institute of Occupational Health, Oulu, Finland.

    • Jaana Laitinen
  33. European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK.

    • Maria Krestyaninova
  34. Multidisciplinary Cardiovascular Research Centre (MCRC), Leeds Institute of Genetics, Health and Therapeutics (LIGHT), University of Leeds, Leeds, UK.

    • Alistair S Hall
  35. Vascular Research Group, Otago Medical School, Dunedin, New Zealand.

    • Gregory T Jones &
    • Andre M van Rij
  36. Department of Laboratory Medicine, Konventhospital Barmherzige Brueder Linz, Linz, Austria.

    • Thomas Mueller,
    • Benjamin Dieplinger &
    • Meinhard Haltmayer
  37. Landspitali University Hospital, Department of Medicine, Reykjavik, Iceland.

    • Steinn Jonsson
  38. University of Iceland, Faculty of Medicine, Reykjavik, Iceland.

    • Stefan E Matthiasson,
    • Unnur Thorsteinsdottir &
    • Kari Stefansson
  39. Therapeia, Reykjavik, Iceland.

    • Hogni Oskarsson
  40. National Center of Addiction Medicine, Vogur Hospital, Reykjavik, Iceland.

    • Thorarinn Tyrfingsson
  41. Radboud University Nijmegen Medical Centre, Department of Urology, Nijmegen, The Netherlands.

    • Lambertus A Kiemeney
  42. University of Zaragoza, Zaragoza, Spain.

    • Jose I Mayordomo
  43. Vascular Research Unit, Viborg Hospital, Viborg, Denmark.

    • Jes S Lindholt
  44. Department of Cardiothoracic Surgery, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.

    • Jesper Holst Pedersen
  45. Department of Pathology, University of Colorado Denver, Aurora, Colorado, USA.

    • Wilbur A Franklin
  46. Community and Behavioral Health, Colorado School of Public Health, University of Colorado Denver, Aurora, Colorado, USA.

    • Holly Wolf
  47. Queensland Institute of Medical Research, Queensland, Australia.

    • Grant W Montgomery &
    • Nicholas G Martin
  48. Department of Psychiatry, University of Munich (LMU), Munich, Germany.

    • Ina Giegling &
    • Dan Rujescu
  49. Department of Epidemiology and Public Health, Imperial College, Faculty of Medicine, London, UK.

    • Marjo-Riitta Järvelin
  50. Institute of Health Sciences, University of Oulu, Oulu, Finland.

    • Marjo-Riitta Järvelin
  51. Biocenter Oulu, University of Oulu, Oulu, Finland.

    • Marjo-Riitta Järvelin
  52. Institute of Medical Informatics, Biometry and Epidemiology, Ludwig-Maximilians-Universität, Munich, Germany.

    • H-Erich Wichmann
  53. Klinikum Grosshadern, Munich, Germany.

    • H-Erich Wichmann
  54. Department of Cardiovascular Sciences, University of Leicester, Clinical Sciences Wing, Glenfield Hospital, Leicester, UK.

    • Nilesh J Samani
  55. Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands.

    • Ben A Oostra
  56. Department of Mental Health and Alcohol Abuse Services, National Institute for Health and Welfare, Helsinki, Finland.

    • Jaakko Kaprio
  57. A full list of members is provided in the Supplementary Note.

    • The ENGAGE Consortium


  1. The ENGAGE Consortium


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.

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Authors whose affiliations are listed as deCODE genetics are employees of deCODE genetics, a biotechnology company.

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