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Meta-analysis and imputation refines the association of 15q25 with smoking quantity

Nature Genetics volume 42, pages 436440 (2010) | Download Citation


Smoking is a leading global cause of disease and mortality1. We established the Oxford-GlaxoSmithKline study (Ox-GSK) to perform a genome-wide meta-analysis of SNP association with smoking-related behavioral traits. Our final data set included 41,150 individuals drawn from 20 disease, population and control cohorts. Our analysis confirmed an effect on smoking quantity at a locus on 15q25 (P = 9.45 × 10−19) that includes CHRNA5, CHRNA3 and CHRNB4, three genes encoding neuronal nicotinic acetylcholine receptor subunits. We used data from the 1000 Genomes project to investigate the region using imputation, which allowed for analysis of virtually all common SNPs in the region and offered a fivefold increase in marker density over HapMap2 (ref. 2) as an imputation reference panel. Our fine-mapping approach identified a SNP showing the highest significance, rs55853698, located within the promoter region of CHRNA5. Conditional analysis also identified a secondary locus (rs6495308) in CHRNA3.

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GlaxoSmithKline (GSK), a pharmaceuticals company that is interested in developing new cessation therapies for smoking, funded a postdoctoral fellowship for J.Z.L. at Oxford University. GSK also funded the collection, characterization, and, in some cases, the genotyping and genotype data preparation for several of the cohorts used in this study. A. Roses and P. Matthews played crucial roles in establishing and funding the Medical Genetics activities at GSK. Acknowledgments that are specific to individual cohorts are given in the Supplementary Note.

Author information


  1. Department of Statistics, University of Oxford, Oxford, UK.

    • Jason Z Liu
    •  & Jonathan Marchini
  2. Genetics Division, GlaxoSmithKline, Verona, Italy.

    • Federica Tozzi
    • , Pierandrea Muglia
    •  & Clyde Francks
  3. Genetics Division, GlaxoSmithKline, Upper Merion, Pennsylvania, USA.

    • Dawn M Waterworth
    • , Sreekumar G Pillai
    • , Xin Yuan
    •  & Vincent Mooser
  4. Division of Neurosciences and Mental Health, Imperial College London, UK.

    • Lefkos Middleton
  5. Department of Psychiatry, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.

    • Wade Berrettini
  6. Genetics Division, GlaxoSmithKline, Research Triangle Park, North Carolina, USA.

    • Christopher W Knouff
  7. University Hospital Center, University of Lausanne, Lausanne, Switzerland.

    • Gérard Waeber
    • , Peter Vollenweider
    •  & Martin Preisig
  8. Department of Internal Medicine, University of Lausanne, Lausanne, Switzerland.

    • Gérard Waeber
    •  & Peter Vollenweider
  9. Department of Psychiatry, University of Lausanne, Lausanne, Switzerland.

    • Martin Preisig
  10. Medical Research Council Epidemiology Unit, Institute of Metabolic Science, Cambridge, UK.

    • Nicholas J Wareham
    • , Jing Hua Zhao
    •  & Ruth J F Loos
  11. Wellcome Trust Sanger Institute, Hinxton, UK.

    • Inês Barroso
    •  & Carl A Anderson
  12. Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.

    • Kay-Tee Khaw
  13. Center for Human Nutrition, University of Texas Southwestern Medical Center, Dallas, Texas, USA.

    • Scott Grundy
  14. The Heart Research Institute, Sydney, New South Wales, Australia.

    • Philip Barter
  15. Gladstone Institute of Cardiovascular Disease, University of California, San Francisco, California, USA.

    • Robert Mahley
  16. American Hospital, Istanbul, Turkey.

    • Robert Mahley
  17. Department of Internal Medicine, University of Oulu, Oulu, Finland.

    • Antero Kesaniemi
  18. Biocenter Oulu, University of Oulu, Oulu, Finland.

    • Antero Kesaniemi
  19. Division of Cardiology, University of Ottawa Heart Institute, Ottawa, Ontario, Canada.

    • Ruth McPherson
  20. Centre for Addiction and Mental Health, University of Toronto, Toronto, Ontario, Canada.

    • John B Vincent
    • , John Strauss
    •  & James L Kennedy
  21. Medical Research Council Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King′s College London, London, UK.

    • Anne Farmer
    •  & Peter McGuffin
  22. Center for Neuroscience, Division of Medical Sciences, University of Dundee, Dundee, UK.

    • Richard Day
    •  & Keith Matthews
  23. Institute of Medicine, University of Bergen, Bergen, Norway.

    • Per Bakke
    •  & Amund Gulsvik
  24. Max Planck Institute of Psychiatry, Munich, Germany.

    • Susanne Lucae
    • , Marcus Ising
    • , Tanja Brueckl
    •  & Sonja Horstmann
  25. Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.

    • H-Erich Wichmann
    • , Rajesh Rawal
    •  & Claudia Lamina
  26. Institute of Medical Informatics, Biometry and Epidemiology, Ludwig-Maximilians-Universität, Munich, Germany.

  27. Klinikum Grosshadern, Munich, Germany.

    • H-Erich Wichmann
  28. Psychiatrische Klinik und Poliklinik University of Mainz, Mainz, Germany.

    • Norbert Dahmen
  29. Division of Genetic Epidemiology, Department of Medical Genetics, Molecular and Clinical Pharmacology, Innsbruck Medical University, Innsbruck, Austria.

    • Claudia Lamina
  30. School of Public Health, School of Medicine, University of Zagreb, Croatia.

    • Ozren Polasek
    •  & Ivana Kolcic
  31. Centre for Population Health Sciences, University of Edinburgh, Edinburgh, UK.

    • Lina Zgaga
    • , James F Wilson
    • , Sarah H Wild
    • , Harry Campbell
    •  & Igor Rudan
  32. Institute of Genetics and Molecular Medicine, MRC Human Genetics Unit, Edinburgh, UK.

    • Jennifer Huffman
    • , Susan Campbell
    • , Veronique Vitart
    • , Caroline Hayward
    •  & Alan F Wright
  33. National Heart and Lung Institute, Imperial College London, London, UK.

    • Jaspal Kooner
  34. Division of Epidemiology, Imperial College London, London, UK.

    • John C Chambers
  35. Cardiovascular Research Institute, MedStar Research Institute, Washington Hospital Center, Washington DC, USA.

    • Mary Susan Burnett
    • , Joseph M Devaney
    • , Augusto D Pichard
    • , Kenneth M Kent
    • , Lowell Satler
    • , Joseph M Lindsay
    • , Ron Waksman
    •  & Stephen Epstein
  36. The Cardiovascular Institute, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

    • Muredach P Reilly
    • , Robert Wilensky
    • , William Matthai
    •  & Daniel J Rader
  37. The Institute for Translational Medicine and Therapeutics, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

    • Muredach P Reilly
    •  & Daniel J Rader
  38. Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

    • Mingyao Li
    •  & Liming Qu
  39. The Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.

    • Hakon H Hakonarson
  40. Institute of Clinical Molecular Biology, Christian-Albrechts-University, Kiel, Germany.

    • Andre Franke
    • , Michael Wittig
    •  & Arne Schäfer
  41. Istituto di Neurogenetica e Neurofarmacologia, Consiglio Nazionale delle Ricerche, Monserrato, Cagliari, Italy.

    • Manuela Uda
    •  & Fabio Busonero
  42. National Institute on Aging, Baltimore, Maryland, USA.

    • Antonio Terracciano
    •  & David Schlessinger
  43. Department of Epidemiology, University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA.

    • Xiangjun Xiao
    •  & Paul Scheet
  44. Department of Mental Health, University of Aberdeen, Aberdeen, UK.

    • David St Clair
  45. Division of Molecular and Clinical Neurobiology, Department of Psychiatry, Ludwig-Maximilians-University, Munich, Germany.

    • Dan Rujescu
  46. Center for Statistical Genetics, Department of Biostatistics, University of Michigan, Ann Arbor, Michigan, USA.

    • Gonçalo R Abecasis
  47. Department of Psychiatry and Psychotherapy, University of Greifswald, Greifswald, Germany.

    • Hans Jörgen Grabe
  48. Interfacultary Institute for Genetics and Functional Genomics, University of Greifswald, Greifswald, Germany.

    • Alexander Teumer
  49. Institute for Community Medicine, University of Greifswald, Greifswald, Germany.

    • Henry Völzke
  50. Institute of Clinical Chemistry and Laboratory Medicine, University of Greifswald, Greifswald, Germany.

    • Astrid Petersmann
  51. Department of Social Medicine and Epidemiology, University of Greifswald, Greifswald, Germany.

    • Ulrich John
  52. Croatian Centre for Global Health, University of Split, Split, Croatia.

    • Igor Rudan
  53. Department of Health Sciences, University of Leicester, Leicester, UK.

    • Benjamin J Wright
    •  & John R Thompson
  54. Mulitdisciplinary Cardiovascular Research Centre (MCRC), Leeds Institute of Genetics, Health and Therapeutics (LIGHT), University of Leeds, Leeds, UK.

    • Anthony J Balmforth
    •  & Alistair S Hall
  55. Department of Cardiovascular Sciences, University of Leicester, Glenfield Hospital, Leicester, UK.

    • Nilesh J Samani
  56. Peninsula College of Medicine and Dentistry, Exeter, UK.

    • Tariq Ahmad
  57. Department of Medical and Molecular Genetics, King's College London School of Medicine, Guy's Hospital, London, UK.

    • Christopher G Mathew
  58. Gastroenterology Research Unit, Addenbrooke's Hospital, Cambridge, UK.

    • Miles Parkes
  59. Gastrointestinal Unit, Molecular Medicine Centre, University of Edinburgh, Western General Hospital, Edinburgh, UK.

    • Jack Satsangi
  60. Clinical Pharmacology and Barts and the London Genome Centre, William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University of London, London, UK.

    • Mark Caulfield
    •  & Patricia B Munroe
  61. Department of Cardiovascular Medicine, University of Oxford, Wellcome Trust Centre for Human Genetics, Oxford, UK.

    • Martin Farrall
  62. British Heart Foundation Glasgow Cardiovascular Research Centre, Division of Cardiovascular and Medical Sciences, University of Glasgow, Western Infirmary, Glasgow, UK.

    • Anna Dominiczak
  63. arc Epidemiology Research Unit, School of Translational Medicine, Faculty of Medical and Human Sciences, University of Manchester, UK.

    • Jane Worthington
    • , Wendy Thomson
    • , Steve Eyre
    •  & Anne Barton
  64. Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.

    • Clyde Francks


  1. The Wellcome Trust Case Control Consortium

    A full list of members is provided in the Supplementary Note.


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J.Z.L. carried out most of the analysis for this study. J.M. and C.F. conceived and directed this study and wrote the manuscript. F.T., D.M.W. and V.M. were involved in study design and helped to coordinate the inclusion of many of the GSK cohorts. S.G.P., P. Muglia, L.M., W.B., C.W.K., X.Y., G.W., P.V., M. Preisig, N.J.W., J.H.Z., R.J.F.L., I.B., K.-T.K., S.G., P. Barter, R. Mahley, A.K., R. McPherson, J.B.V., J. Strauss, J.L.K., A. Farmer, P. McGuffin, R.D., K.M., P. Bakke, A.G., S.L., M.I., T.B., S.H., H.-E.W., R.R., N.D., C.L., O.P., L.Z., J.H., S.C., J.K., J.C.C., M.S.B., J.M.D., A.D.P., K.M.K.. L.S., J.M.L., R. Waksman, S. Epstein, J.F.W., S.H.W., H.C., V.V., M.P.R., M.L., L.Q., R. Wilensky, W.M., H.H.H., D.J.R., A. Franke, M.W., A.S., M.U., A. Terracciano, X.X., F.B., P.S., D.S., D.St.C., D.R., G.R.A., H.J.G., A. Teumer, H.V., A.P., U.J., I.R., C.H., A.F.W., I.K., B.J.W., J.R.T., A.J.B., A.S.H., N.J.S., C.A.A., T.A., C.G.M., M. Parkes, J. Satsangi, M.C., P.B.M., M.F., A.D., J.W., W.T., S. Eyre, A.B. and W.T.C.C.C. prepared and shared data sets and, in some cases, cohort-specific results from their own primary analysis.

Competing interests

F.T., C.F., D.M.W., V.M., P.M., S.G.P. and C.W.K either are or were full-time employees of the company GlaxoSmithKline (GSK). GSK also funded several aspects of the study as detailed in the ACKNOWLEDGMENTS section.

Corresponding authors

Correspondence to Clyde Francks or Jonathan Marchini.

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