Letter | Published:

Genome-wide meta-analyses identify multiple loci associated with smoking behavior

Nature Genetics volume 42, pages 441447 (2010) | Download Citation

Abstract

Consistent but indirect evidence has implicated genetic factors in smoking behavior1,2. We report meta-analyses of several smoking phenotypes within cohorts of the Tobacco and Genetics Consortium (n = 74,053). We also partnered with the European Network of Genetic and Genomic Epidemiology (ENGAGE) and Oxford-GlaxoSmithKline (Ox-GSK) consortia to follow up the 15 most significant regions (n > 140,000). We identified three loci associated with number of cigarettes smoked per day. The strongest association was a synonymous 15q25 SNP in the nicotinic receptor gene CHRNA3 (rs1051730[A], β = 1.03, standard error (s.e.) = 0.053, P = 2.8 × 10−73). Two 10q25 SNPs (rs1329650[G], β = 0.367, s.e. = 0.059, P = 5.7 × 10−10; and rs1028936[A], β = 0.446, s.e. = 0.074, P = 1.3 × 10−9) and one 9q13 SNP in EGLN2 (rs3733829[G], β = 0.333, s.e. = 0.058, P = 1.0 × 10−8) also exceeded genome-wide significance for cigarettes per day. For smoking initiation, eight SNPs exceeded genome-wide significance, with the strongest association at a nonsynonymous SNP in BDNF on chromosome 11 (rs6265[C], odds ratio (OR) = 1.06, 95% confidence interval (Cl) 1.04–1.08, P = 1.8 × 10−8). One SNP located near DBH on chromosome 9 (rs3025343[G], OR = 1.12, 95% Cl 1.08–1.18, P = 3.6 × 10−8) was significantly associated with smoking cessation.

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Acknowledgements

This work was funded by the University of North Carolina Lineberger Comprehensive Cancer Center University Cancer Research Fund Award and by US National Cancer Institute K07 CA118412 to H.F. Statistical analyses were carried out on the Genetic Cluster Computer (see URLs), which is supported by the Netherlands Scientific Organization (NWO 480-05-003). Acknowledgments for studies included in TAG are listed in the Supplementary Note.

Author information

Affiliations

  1. Department of Genetics, University of North Carolina, Chapel Hill, North Carolina, USA.

    • Helena Furberg
    • , YunJung Kim
    • , Jennifer Dackor
    • , Karen L Mohlke
    •  & Patrick F Sullivan
  2. University of North Carolina Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina, USA.

    • Helena Furberg
    • , Karen L Mohlke
    •  & Patrick F Sullivan
  3. Human Genetics Center and Institute for Molecular Medicine, University of Texas Health Science Center, Houston, Texas, USA.

    • Eric Boerwinkle
  4. Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina, USA.

    • Nora Franceschini
  5. Division of Cardiology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy.

    • Diego Ardissino
  6. Statistical Laboratory, Centre for Mathematical Sciences, University of Cambridge, Cambridge, UK.

    • Luisa Bernardinelli
  7. Department of Applied Health Sciences, University of Pavia, Pavia, Italy.

    • Luisa Bernardinelli
  8. Department of Internal Medicine and Medical Specialties, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico, Ospedale Maggiore, Mangiagalli e Regina Elena, University of Milan, Milan, Italy.

    • Pier M Mannucci
  9. Department of Cardiology, Azienda Ospedaliera Niguarda Ca' Granda, Milan, Italy.

    • Francesco Mauri
    •  & Piera A Merlini
  10. HudsonAlpha Institute for Biotechnology, Huntsville, Alabama, USA.

    • Devin Absher
  11. Cardiovascular Medicine, Stanford University, Stanford, California, USA.

    • Themistocles L Assimes
    • , Joshua W Knowles
    •  & Thomas Quertermous
  12. Stanford Prevention Research Center, Stanford University, Stanford, California, USA.

    • Stephen P Fortmann
  13. Kaiser Permanente Northern California Division of Research, Oakland, California, USA.

    • Carlos Iribarren
  14. National Institute on Aging, Baltimore, Maryland, USA.

    • Luigi Ferrucci
  15. Medstart Research Institute, National Institute on Aging, Baltimore, Maryland, USA.

    • Toshiko Tanaka
  16. Cardiovascular Health Research Unit, University of Washington, Seattle, Washington, USA.

    • Joshua C Bis
    • , Barbara McKnight
    • , Bruce M Psaty
    • , Evan L Thacker
    •  & Stephen M Schwartz
  17. Department of Medicine, University of Washington, Seattle, Washington, USA.

    • Joshua C Bis
    •  & Bruce M Psaty
  18. Division of Public Health Sciences, Wake Forest University Health Sciences, Winston-Salem, North Carolina, USA.

    • Curt D Furberg
  19. Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.

    • Talin Haritunians
    •  & Kent D Taylor
  20. Department of Biostatistics, University of Washington, Seattle, Washington, USA.

    • Barbara McKnight
  21. Department of Epidemiology and Health Services, University of Washington, Seattle, Washington, USA.

    • Bruce M Psaty
  22. Group Health Research Institute, Seattle, Washington, USA.

    • Bruce M Psaty
  23. Department of Epidemiology, University of Washington, Seattle, Washington, USA.

    • Evan L Thacker
  24. Department of Clinical Sciences, Diabetes and Endocrinology Unit, Lund University, Malmö, Sweden.

    • Peter Almgren
    • , Leif Groop
    •  & Claes Ladenvall
  25. Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, Michigan, USA.

    • Michael Boehnke
    • , Anne U Jackson
    •  & Heather M Stringham
  26. Hjelt Institute, Department of Public Health, University of Helsinki, Helsinki, Finland.

    • Jaakko Tuomilehto
    •  & Jaakko Kaprio
  27. Diabetes Prevention Unit, National Institute for Health and Welfare, Helsinki, Finland.

    • Jaakko Tuomilehto
  28. Finland South Ostrobothnia Central Hospital, Seinäjoki, Finland.

    • Jaakko Tuomilehto
  29. Boston University School of Medicine, Boston, Massachusetts, USA.

    • Emelia J Benjamin
    •  & Ramachandran S Vasan
  30. Boston University School of Public Health, Boston, Massachusetts, USA.

    • Emelia J Benjamin
  31. Center for Population Studies, National Heart, Lung, and Blood Institute, Bethesda, Maryland, USA.

    • Shih-Jen Hwang
    •  & Sarah Rosner Preis
  32. Department of Medicine, Sections of Preventive Medicine and Cardiology, Boston University School of Medicine, Boston, Massachusetts, USA.

    • Daniel Levy
    •  & Ramachandran S Vasan
  33. Center for Psychiatric Genetics, NorthShore University HealthSystem Research Institute, Evanston, Illinois, USA.

    • Jubao Duan
    • , Pablo V Gejman
    •  & Alan R Sanders
  34. Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, California, USA.

    • Douglas F Levinson
  35. Biostatistics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA.

    • Jianxin Shi
  36. International Agency for Research on Cancer (IARC), Lyon, France.

    • Esther H Lips
    • , James D McKay
    •  & Paul Brennan
  37. Institut Català d'Oncologia, Barcelona, Spain.

    • Antonio Agudo
    •  & Xavier Castellsagué
  38. General Hospital, Pordenone, Italy.

    • Luigi Barzan
  39. Institute of Hygiene and Epidemiology, First Faculty of Medicine, Charles University, Prague, Czech Republic.

    • Vladimir Bencko
    •  & Ivana Holcátová
  40. Institut National de la santé et de la Recherche Medicalé (INSERM) U794, Paris, France.

    • Simone Benhamou
  41. Institut Gustave Roussy, Villejuif, France.

    • Simone Benhamou
  42. Department of Environmental Medicine and Public Health, University of Padua, Padua, Italy.

    • Cristina Canova
  43. University of Glasgow Medical Faculty Dental School, Glasgow, UK.

    • David I Conway
  44. Specialized Institute of Hygiene and Epidemiology, Banska Bystrica, Slovakia.

    • Eleonora Fabianova
  45. Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute, Brno, Czech Republic.

    • Lenka Foretova
  46. Palacky University, Olomouc, Czech Republic.

    • Vladimir Janout
  47. Trinity College School of Dental Science, Dublin, Ireland.

    • Claire M Healy
  48. Cancer Registry of Norway, Oslo, Norway.

    • Kristina Kjaerheim
  49. University of Athens School of Medicine, Athens, Greece.

    • Pagona Lagiou
  50. Department of Cancer Epidemiology and Prevention, Maria Sklodowska-Curie Cancer Center and Institute of Oncology, Warsaw, Poland.

    • Jolanta Lissowska
  51. University of Newcastle Dental School, Newcastle, UK.

    • Ray Lowry
  52. University of Aberdeen School of Medicine, Aberdeen, UK.

    • Tatiana V Macfarlane
  53. Institute of Public Health, Bucharest, Romania.

    • Dana Mates
  54. Center for Experimental Research and Medical Studies, University of Turin, Turin, Italy.

    • Lorenzo Richiardi
  55. National Institute of Environmental Health, Budapest, Hungary.

    • Peter Rudnai
  56. Department of Epidemiology, Institute of Occupational Medicine, Lodz, Poland.

    • Neonilia Szeszenia-Dabrowska
  57. Institute of Carcinogenesis, Cancer Research Centre, Moscow, Russia.

    • David Zaridze
  58. Croatian National Cancer Registry, Zagreb, Croatia.

    • Ariana Znaor
  59. Centre National de Genotypage, Institut Genomique, Comissariat à l'énergie Atomique, Evry, France.

    • Mark Lathrop
  60. Fondation Jean Dausset-Centre d'Étude du Polymorphisme Humain (CEPH), Paris, France.

    • Mark Lathrop
  61. Geriatric Unit, Azienda Sanitaria di Firenze, Florence, Italy.

    • Stefania Bandinelli
  62. Genetics of Complex Traits, Peninsula Medical School, The University of Exeter, Exeter, UK.

    • Timothy M Frayling
    •  & John R B Perry
  63. Laboratory of Epidemiology, Demography and Biometry, National Institute on Aging, Bethesda, Maryland, USA.

    • Jack M Guralnik
  64. Tuscany Health Regional Agency, Florence, Italy.

    • Yuri Milaneschi
  65. Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.

    • David Altshuler
    •  & Sek Kathiresan
  66. Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts, USA.

    • David Altshuler
  67. Diabetes Unit, Massachusetts General Hospital, Boston, Massachusetts, USA.

    • David Altshuler
  68. Center for Human Genetics Research, Massachusetts General Hospital, Boston, Massachusetts, USA.

    • David Altshuler
    •  & Sek Kathiresan
  69. Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.

    • David Altshuler
  70. Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.

    • David Altshuler
  71. Cardiovascular Epidemiology and Genetics, Institut Municipal d'Investigacio Medica, Barcelona, Spain.

    • Roberto Elosua
    •  & Gavin Lucas
  72. Harvard Medical School, Boston, Massachusetts, USA.

    • Sek Kathiresan
  73. Department of Clinical Sciences, Hypertension and Cardiovascular Diseases, University Hospital Malmö, Lund University, Malmö, Sweden.

    • Olle Melander
  74. National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, Massachusetts, USA.

    • Christopher J O'Donnell
  75. National Institute for Health and Welfare (THL), Helsinki, Finland.

    • Veikko Salomaa
    •  & Jaakko Kaprio
  76. Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.

    • Benjamin F Voight
  77. EMGO Institute, Vrije Universiteit (VU) Medical Center, Amsterdam, The Netherlands.

    • Brenda W Penninx
    • , Johannes H Smit
    •  & Nicole Vogelzangs
  78. Department of Psychiatry, VU University Medical Center, Amsterdam, The Netherlands.

    • Brenda W Penninx
    • , Johannes H Smit
    •  & Nicole Vogelzangs
  79. Biological Psychology, VU University Amsterdam, Amsterdam, The Netherlands.

    • Dorret I Boomsma
    • , Eco J C de Geus
    • , Jacqueline M Vink
    •  & Gonneke Willemsen
  80. Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA.

    • Stephen J Chanock
  81. Program in Molecular and Genetic Epidemiology, Department of Epidemiology, Harvard University, Boston, Massachusetts, USA.

    • Fangyi Gu
    • , David J Hunter
    •  & Peter Kraft
  82. Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.

    • Susan E Hankinson
  83. Department of Epidemiology, Erasmus Medical Center, Member of the Netherlands Consortium on Healthy Aging, Rotterdam, The Netherlands.

    • Albert Hofman
    • , Henning Tiemeier
    • , Andre G Uitterlinden
    • , Cornelia M van Duijn
    •  & Stefan Walter
  84. Department of Child and Adolescent Psychiatry, Erasmus Medical Center, Rotterdam, The Netherlands.

    • Henning Tiemeier
  85. Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.

    • Andre G Uitterlinden
  86. Centre for Medical Systems Biology, Erasmus Medical Center, Rotterdam, The Netherlands.

    • Cornelia M van Duijn
  87. Department of Public Health, Erasmus Medical Center, Rotterdam, The Netherlands.

    • Stefan Walter
  88. Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.

    • Daniel I Chasman
    • , Brendan M Everett
    • , Guillaume Paré
    •  & Paul M Ridker
  89. Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.

    • Brendan M Everett
    •  & Paul M Ridker
  90. Department of Psychiatry and Neurobehavioural Sciences, University of Virginia, Charlottesville, Virginia, USA.

    • Ming D Li
  91. Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, Virginia, USA.

    • Hermine H Maes
  92. Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia, USA.

    • Hermine H Maes
  93. Department of Psychiatry, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

    • Janet Audrain-McGovern
    •  & Caryn Lerman
  94. Department of Functional Genomics, VU Amsterdam, Amsterdam, The Netherlands.

    • Danielle Posthuma
  95. Department of Medical Genomics, VU University Medical Center Amsterdam, Amsterdam, The Netherlands.

    • Danielle Posthuma
  96. Department of Psychiatry, University of North Carolina, Chapel Hill, North Carolina, USA.

    • Laura M Thornton
  97. Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

    • Caryn Lerman
  98. Institute for Molecular Medicine, University of Helsinki, Helsinki, Finland.

    • Jaakko Kaprio
  99. Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, North Carolina, USA.

    • Jed E Rose
  100. Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece.

    • John P A Ioannidis
  101. Tufts Clinical and Translational Science Institute, Tufts University School of Medicine, Boston, Massachusetts, USA.

    • John P A Ioannidis
  102. Center for Genetic Epidemiology and Modeling, Institute for Clinical Research and Health Policy Studies, Tufts Medical Center, Boston, Massachusetts, USA.

    • John P A Ioannidis
  103. Department of Biostatistics, University of North Carolina, Chapel Hill, North Carolina, USA.

    • Dan-Yu Lin

Consortia

  1. The Tobacco and Genetics Consortium

Authors

    Contributions

    TAG: study conception, design, management: H.F., P.F.S., Y.K., J. Dackor; TAG Statistical Working Group: D.-Y.L., P.K., J.P.A.I., D.P., H.F., Y.K., J. Dackor, S.P.F., N.F., E.H.L., J.D.M., J.M.V., D.I.B., D.L., B.M.E., E.L.T., B. McKnight, P.F.S., D. Absher; TAG Phenotype Working Group: C. Lerman, J.K., H.H.M., L.M.T., J.A.-M., E.H.L., J.E.R., M.D.L., J.M.V., H.F., Y.K., J. Dackor, S.P.F., P.F.S., E.L.T.; data analysis: Y.K., D.M.A., F.G., E.H.L., J.D.M., J.M.V., A.U.J., L. Bernardinelli, S.R.P., S.-J.H., B.M.E., C. Ladenvall, J.R.B.P., T.T., E.L.T., J.C.B., G.L., S.W.; TAG Manuscript Writing Group: H.F., Y.K., J. Dackor, P.F.S., C. Lerman, M.D.L., J.K., J.A.-M., P.K. All authors reviewed and approved the final version of the manuscript. The corresponding authors had access to the full data set of summary results contributed by each study.

    ARIC: study conception, design, management: E.B.; phenotype collection, data management: N.F.; sample processing and genotyping: N.F.; data analysis: Y.K., N.F.

    Atherosclerosis Thrombosis and Vascular Biology Italian Study Group: study conception, design, management: L. Bernardinelli, P.M.M., P.A.M., D. Ardissino; phenotype collection, data management: F.M., L. Bernandinelli; data analysis: L. Bernandinelli.

    ADVANCE: study conception, design, management: S.P.F., D. Absher, T.Q., C.I., T.L.A., J.W.K.; phenotype collection, data management: S.P.F., T.Q., C.I., T.L.A., J.W.K.; sample processing and genotyping: D. Absher, T.Q.; data analysis: S.P.F., D. Absher, T.L.A., J.W.K.

    Baltimore Longitudinal Study of Aging: study conception, design, management: L. Ferrucci; phenotype collection, data management: L. Ferrucci; data analysis: T.T.

    CHS: study conception, design, management: B.M.P., J.C.B., C.D.F.; phenotype collection, data management: B.M.P.; sample processing and genotyping: T.H., K.D.T.; data analysis: B.M.P., E.L.T., J.C.B., B. McKnight.

    DGI: study conception, design, management: L.G.; phenotype collection, data management: P.A.; data analysis: P.A., C. Ladenvall.

    FUSION: study conception, design, management: K.L.M., M.B.; phenotype collection, data management: H.M.S., J.T.; data analysis: H.M.S., A.U.J.

    Framingham Heart Study: study conception, design, management: R.S.V., E.J.B., D.L.; phenotype collection, data management: S.R.P., R.S.V., S.-J.H., E.J.B., D.L.; data analysis: S.R.P., S.-J.H.

    GAIN: study conception, design, management: D.F.L., P.V.G.; phenotype collection, data management: A.R.S., D.F.L., J. Duan, J.S., P.V.G.; sample processing and genotyping: J. Duan, P.V.G.; data analysis: A.R.S., D.F.L., J. Duan, J.S., P.V.G.

    IARC/ARCAGE/Central European GWAS: phenotype collection, data management: D.Z., N.S.-D., J.L., P.R., E.F., D.M., V.B., L. Foretova, V.J., S. Benhamou, P.L., I.H., L.R., K.K., A.A., X.C., T.V.M., L. Barzan, C.C., R.L., D.I. Conway, A.Z., C.M.H., P.B.; sample processing and genotyping: J.D.M., M.L., P.B.; data analysis: E.H.L., J.D.M.

    InCHIANTI: study conception, design, management: T.M.F., J.M.G., S. Bandinelli; phenotype collection, data management: Y.M.; data analysis: J.R.B.P.

    MIGEN: study conception, design, management: R.E., V.S., O.M., C.J.O., D. Altshuler; phenotype collection, data management: G.L., S.M.S., R.E., V.S., B.F.V., O.M., S.K., C.J.O.; sample processing and genotyping: S.K., D. Altshuler; data analysis: G.L., B.F.V., D. Altshuler

    NESDA: study conception, design, management: B.W.P., J.H.S.; phenotype collection, data management: B.W.P., J.H.S., N.V.; sample processing and genotyping: B.W.P., J.H.S.; data analysis: N.V.

    NTR: study conception, design, management: D.I.B., G.W., E.J.C.d.G.; phenotype collection, data management: D.I.B., G.W., E.J.C.d.G., J.M.V.; sample processing and genotyping: D.I.B., G.W., E.J.C.d.G.; data analysis: J.M.V.

    NHS: phenotype collection, data management: S.E.H., D.J.H., P.K., F.G.; sample processing and genotyping: S.J.C., S.E.H., D.J.H., P.K.; data analysis: S.J.C., F.G., P.K.

    Rotterdam: study conception, design, management: A.H.; phenotype collection, data management: H.T., A.G.U.; sample processing and genotyping: H.T., A.G.U.; data analysis: H.T., A.G.U., S.W., C.M.v.D.

    WGHS: study conception, design, management: B.M.E., G.P., D.I. Chasman, P.M.R.; phenotype collection, data management: B.M.E., G.P., D.I. Chasman, P.M.R.; sample processing and genotyping: G.P., D.I. Chasman; data analysis: B.M.E., G.P., D.I. Chasman.

    Competing interests

    The author declare no competing financial interests.

    Corresponding authors

    Correspondence to Helena Furberg or Patrick F Sullivan.

    Supplementary information

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      Supplementary Text and Figures

      Supplementary Tables 1–5, Supplementary Figures 1 and 2 and Supplementary Note

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      Supplementary Table 6

      Association testing for CPD on chromosome 15, conditional on rs1051730

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    DOI

    https://doi.org/10.1038/ng.571

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