Genome-wide association and large-scale follow up identifies 16 new loci influencing lung function

Journal name:
Nature Genetics
Volume:
43,
Pages:
1082–1090
Year published:
DOI:
doi:10.1038/ng.941
Received
Accepted
Published online

Abstract

Pulmonary function measures reflect respiratory health and are used in the diagnosis of chronic obstructive pulmonary disease. We tested genome-wide association with forced expiratory volume in 1 second and the ratio of forced expiratory volume in 1 second to forced vital capacity in 48,201 individuals of European ancestry with follow up of the top associations in up to an additional 46,411 individuals. We identified new regions showing association (combined P < 5 × 10−8) with pulmonary function in or near MFAP2, TGFB2, HDAC4, RARB, MECOM (also known as EVI1), SPATA9, ARMC2, NCR3, ZKSCAN3, CDC123, C10orf11, LRP1, CCDC38, MMP15, CFDP1 and KCNE2. Identification of these 16 new loci may provide insight into the molecular mechanisms regulating pulmonary function and into molecular targets for future therapy to alleviate reduced lung function.

At a glance

Figures

  1. Study design.
    Figure 1: Study design.

    We followed up in stage 2 a total of 34 SNPs showing new evidence of association (P < 3 × 10−6) with FEV1 and/or FEV1/FVC in a meta-analysis of the stage 1 studies. Studies with a combined total of 24,737 individuals undertook genotyping and association testing of the top ten SNPs. Seven studies (marked with an asterisk) with a combined total of 11,275 individuals had genome-wide association data and provided results for up to 34 SNPs. Researchers from GS: SFHS (marked with #) undertook genotyping on a 32-SNP multiplex genotyping platform and so included the 32 top ranking SNPs (including proxies and both SNPs from regions that showed association with both FEV1 and FEV1/FVC). This assay failed for one SNP (rs3769124), which was subsequently replaced with the thirty-third SNP (rs4762767). We excluded rs2284746 because of poor clustering. Although rs3743563 was chosen as proxy for rs12447804, which had an effective N < 80% in the stage 1 meta-analysis, researchers from BHS2 were unable to genotype rs3743563 and so undertook genotyping for rs12447804 instead. See Table 1 for definitions of all study abbreviations.

  2. Manhattan plots of association results for FEV1/FVC and FEV1 (analysis stage 1).
    Figure 2: Manhattan plots of association results for FEV1/FVC and FEV1 (analysis stage 1).

    The Manhattan plots for FEV1/FVC (a) and FEV1 (b) are ordered by chromosome position. SNPs for which −log10 P > 5 are indicated in red. Newly associated regions that reached genome-wide significance after meta-analysis of stages 1 and 2 are labeled.

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Author information

  1. These authors contributed equally to this work.

    • María Soler Artigas,
    • Daan W Loth,
    • Louise V Wain,
    • Sina A Gharib,
    • Ma'en Obeidat,
    • Wenbo Tang,
    • Bruno H Ch Stricker,
    • Paul Elliott,
    • George T O'Connor,
    • David P Strachan,
    • Stephanie J London,
    • Ian P Hall,
    • Vilmundur Gudnason &
    • Martin D Tobin

Affiliations

  1. Department of Health Sciences, University of Leicester, Leicester, UK.

    • María Soler Artigas,
    • Louise V Wain &
    • Martin D Tobin
  2. Department of Genetics, University of Leicester, Leicester, UK.

    • María Soler Artigas,
    • Louise V Wain &
    • Martin D Tobin
  3. Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands.

    • Daan W Loth,
    • Mark Eijgelsheim,
    • Albert Hofman,
    • Fernando Rivadeneira,
    • André G Uitterlinden &
    • Bruno H Ch Stricker
  4. Inspectorate of Healthcare, The Hague, The Netherlands.

    • Daan W Loth &
    • Bruno H Ch Stricker
  5. Center for Lung Biology, University of Washington, Seattle, Washington, USA.

    • Sina A Gharib
  6. Department of Medicine, University of Washington, Seattle, Washington, USA.

    • Sina A Gharib,
    • Kristin D Marciante &
    • Bruce M Psaty
  7. Division of Therapeutics and Molecular Medicine, Nottingham Respiratory Biomedical Research Unit, University Hospital of Nottingham, Nottingham, London, UK.

    • Ma'en Obeidat,
    • Khalid A Al Balushi,
    • John D Blakey,
    • Amanda Henry,
    • Ian Sayers &
    • Ian P Hall
  8. Division of Nutritional Sciences, Cornell University Ithaca, New York, USA.

    • Wenbo Tang &
    • Patricia A Cassano
  9. Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.

    • Guangju Zhai,
    • Christopher J Hammond,
    • Pirro G Hysi,
    • Massimo Mangino &
    • Tim D Spector
  10. Discipline of Genetics, Faculty of Medicine, Memorial University of Newfoundland, St. John's, Newfoundland, Canada.

    • Guangju Zhai
  11. Medical Research Council (MRC) Epidemiology Unit, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK.

    • Jing Hua Zhao,
    • Ruth J F Loos &
    • Nicholas J Wareham
  12. Icelandic Heart Association, Kopavogur, Iceland.

    • Albert Vernon Smith,
    • Thor Aspelund,
    • Gudny Eiriksdottir,
    • Gauti Kjartan Gislason &
    • Vilmundur Gudnason
  13. University of Iceland, Reykjavik, Iceland.

    • Albert Vernon Smith,
    • Thor Aspelund &
    • Vilmundur Gudnason
  14. MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh, UK.

    • Jennifer E Huffman,
    • Veronique Vitart,
    • Alan F Wright &
    • Caroline Hayward
  15. Institute of Genetic Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.

    • Eva Albrecht &
    • Christian Gieger
  16. School of Medicine, University of St. Andrews, St. Andrews, Scotland, UK.

    • Catherine M Jackson
  17. MRC Centre for Causal Analyses in Translational Epidemiology, School of Social and Community Medicine, University of Bristol, Bristol, UK.

    • David M Evans,
    • George Davey Smith &
    • Debbie A Lawlor
  18. Genetic Epidemiology and Biostatistics Platform, Ontario Institute for Cancer Research, Toronto, Ontario, Canada.

    • Gemma Cadby &
    • Lyle J Palmer
  19. Prosserman Centre for Health Research, Samuel Lunenfeld Research Institute, Toronto, Ontario, Canada.

    • Gemma Cadby,
    • Lyle J Palmer &
    • Nicole M Warrington
  20. Brown Foundation Institute of Molecular Medicine, University of Texas at Houston, Houston, Texas, USA.

    • Myriam Fornage &
    • Xiangjun Gu
  21. Human Genetics Center, School of Public Health, University of Texas at Houston, Houston, Texas, USA.

    • Myriam Fornage &
    • Alanna C Morrison
  22. Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia, USA.

    • Ani Manichaikul &
    • Stephen S Rich
  23. Department of Public Health Sciences, Division of Biostatistics and Epidemiology, University of Virginia, Charlottesville, Virginia, USA.

    • Ani Manichaikul
  24. Centre for Cognitive Ageing and Cognitive Epidemiology, The University of Edinburgh, Edinburgh, UK.

    • Lorna M Lopez,
    • Ian J Deary,
    • Sarah E Harris &
    • John M Starr
  25. Department of Psychology, The University of Edinburgh, Edinburgh, UK.

    • Lorna M Lopez &
    • Ian J Deary
  26. Clinical Pharmacology and the Genome Centre, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.

    • Toby Johnson
  27. Department of Thoracic Surgery, Vanderbilt University, Nashville, Tennessee, USA.

    • Melinda C Aldrich
  28. Division of Epidemiology, Vanderbilt University, Nashville, Tennessee, USA.

    • Melinda C Aldrich
  29. Wellcome Trust Sanger Institute, Genome Campus, Hinxton, Cambridge, UK.

    • Inês Barroso &
    • So-Youn Shin
  30. University of Cambridge Metabolic Research Labs, Institute of Metabolic Science Addenbrooke's Hospital, Cambridge, UK.

    • Inês Barroso
  31. Centre for Population Health Sciences, The University of Edinburgh, Edinburgh, UK.

    • Harry Campbell,
    • Igor Rudan,
    • Sarah H Wild,
    • Lina Zgaga &
    • James F Wilson
  32. Department of Biostatistics, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, North Carolina, USA.

    • David J Couper
  33. Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, North Carolina, USA.

    • Nora Franceschini,
    • Laura R Loehr &
    • Kari E North
  34. Laboratory of Epidemiology, Demography, and Biometry, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA.

    • Melissa Garcia,
    • Tamara B Harris &
    • Lenore J Launer
  35. Croatian Centre for Global Health, The University of Split Medical School, Split, Croatia.

    • Ivica Grkovic,
    • Stipan Jankovic &
    • Igor Rudan
  36. Epidemiology Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina, USA.

    • Dana B Hancock,
    • Bonnie R Joubert &
    • Stephanie J London
  37. Behavioral Health Epidemiology Program, Research Triangle Institute International, Research Triangle Park, North Carolina, USA.

    • Dana B Hancock
  38. Respiratory Epidemiology and Public Health, Imperial College London, London, UK.

    • Adaikalavan Ramasamy &
    • Deborah L Jarvis
  39. Department of Epidemiology and Biostatistics, Imperial College London, London, UK.

    • Adaikalavan Ramasamy,
    • Marjo-Riitta Järvelin &
    • Paul Elliott
  40. Department of Medical and Molecular Genetics, King's College London, Guy's Hospital, London, UK.

    • Adaikalavan Ramasamy
  41. Cardiovascular Health Research Unit, University of Washington, Seattle, Washington, USA.

    • Susan R Heckbert,
    • Kristin D Marciante &
    • Bruce M Psaty
  42. Department of Epidemiology, University of Washington, Seattle, Washington, USA.

    • Susan R Heckbert &
    • Bruce M Psaty
  43. Group Health Research Institute, Group Health Cooperative, Seattle, Washington, USA.

    • Susan R Heckbert &
    • Bruce M Psaty
  44. National Institute for Health and Welfare, Helsinki, Finland.

    • Markku Heliövaara &
    • Jaakko Kaprio
  45. Interfaculty Institute for Genetics and Functional Genomics, Department of Functional Genomics, University of Greifswald, Greifswald, Germany.

    • Georg Homuth
  46. Department of Pulmonary Physiology and Sleep Medicine/West Australian Sleep Disorders Research Institute, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia.

    • Alan L James
  47. The School of Medicine and Pharmacology, University of Western Australia, Perth, Western Australia, Australia.

    • Alan L James &
    • Arthur W Musk
  48. Busselton Population Medical Research Foundation, Department of Respiratory Medicine, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia.

    • Alan L James,
    • Jennie Hui,
    • Michael L Hunter &
    • Arthur W Musk
  49. Institute and Outpatient Clinic for Occupational, Social and Environmental Medicine, Ludwig-Maximilians-University, Munich, Germany.

    • Stefan Karrasch
  50. Unit for Molecular Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.

    • Norman Klopp
  51. Department of Internal Medicine B, University Hospital Greifswald, Greifswald, Germany.

    • Beate Koch
  52. Sticht Center on Aging, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.

    • Stephen B Kritchevsky
  53. Epidemiology, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.

    • Yongmei Liu
  54. Department of Biostatistical Sciences, Division of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA.

    • Kurt Lohman
  55. Department of Statistics, University of Auckland, Auckland, New Zealand.

    • Thomas Lumley
  56. School of Women's and Infants' Health, The University of Western Australia, Perth, Western Australia, Australia.

    • Wei Q Ang,
    • Nicole M Warrington &
    • Craig E Pennell
  57. Department of Medicine, Columbia University Medical Center, New York, New York, USA.

    • R Graham Barr
  58. Department of Surgery and Pathology, University of Western Australia, Nedlands, Western Australia, Australia.

    • John Beilby
  59. PathWest Laboratory Medicine of Western Australia, Queen Elizabeth II Medical Centre, Nedlands, Western Australia, Australia.

    • John Beilby &
    • Jennie Hui
  60. Faculty of Medicine, University of Split, Croatia, Split, Croatia.

    • Mladen Boban,
    • Vesna Boraska,
    • Ivana Kolcic,
    • Ozren Polas breveek &
    • Tatijana Zemunik
  61. Occupational and Environmental Medicine, Department of Public Health and Community Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

    • Jonas Brisman,
    • Santosh Dahgam,
    • Anna-Carin Olin &
    • Fredrik Nyberg
  62. Division of Epidemiology and Public Health, School of Community Health Sciences and Nottingham Respiratory Biomedical Research Unit, University of Nottingham, Nottingham, UK.

    • John R Britton &
    • Tricia McKeever
  63. Department of Respiratory Medicine, Ghent University Hospital, Ghent, Belgium.

    • Guy G Brusselle
  64. MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton, UK.

    • Cyrus Cooper,
    • Karen A Jameson &
    • Avan Aihie Sayer
  65. Chronic Disease Epidemiology, Swiss Tropical and Public Health (TPH) Institute, Basel, Switzerland.

    • Ivan Curjuric,
    • Medea Imboden &
    • Nicole Probst-Hensch
  66. University of Basel, Switzerland.

    • Ivan Curjuric,
    • Medea Imboden &
    • Nicole Probst-Hensch
  67. Non-Communicable Diseases Epidemiology Unit, Department of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, UK.

    • Shah Ebrahim
  68. South Asia Centre for Chronic Disease, New Delhi, India.

    • Shah Ebrahim
  69. Max Planck Institute for Psycholinguistics, Nijmegen, The Netherlands.

    • Clyde Francks
  70. MRC Unit for Lifelong Health and Ageing, London, UK.

    • Darya Gaysina,
    • Rebecca Hardy,
    • Andrew Wong &
    • Diana Kuh
  71. School of Social and Community Medicine, University of Bristol, Bristol, UK.

    • Raquel Granell,
    • John Henderson,
    • Susan M Ring &
    • Wendy L McArdle
  72. Hankinson Consulting, Inc, Athens, Georgia, USA.

    • John L Hankinson
  73. Medical Genetics Section, The University of Edinburgh, Edinburgh, UK.

    • Sarah E Harris
  74. Department of Epidemiology and Public Health, University College London, London, UK.

    • Aroon D Hingorani
  75. Netherlands Genomics Initiative (NGI)-sponsored Netherlands Consortium for Healthy Aging (NCHA), The Netherlands.

    • Albert Hofman,
    • Fernando Rivadeneira,
    • André G Uitterlinden &
    • Bruno H Ch Stricker
  76. Telethon Institute for Child Health Research and Centre for Child Health Research, The University of Western Australia, Perth, Western Australia, Australia.

    • Patrick G Holt &
    • Peter D Sly
  77. School of Pathology and Laboratory Medicine, The University of Western Australia, Nedlands, Western Australia, Australia.

    • Jennie Hui
  78. School of Population Health, University of Western Australia, Nedlands, Western Australia, Australia.

    • Jennie Hui,
    • Michael L Hunter &
    • Arthur W Musk
  79. Molecular Medicine Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.

    • Shona M Kerr &
    • David J Porteous
  80. Division of Genetic Epidemiology, Department of Medical Genetics, Molecular and Clinical Pharmacology, Innsbruck Medical University, Innsbruck, Austria.

    • Florian Kronenberg
  81. Department of Statistics, University of Oxford, Oxford, UK.

    • Jason Z Liu &
    • Jonathan Marchini
  82. Medical Research Institute, The University of Dundee, Dundee, UK.

    • Andrew D Morris
  83. Department of Pulmonology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

    • Dirkje S Postma
  84. Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands.

    • Fernando Rivadeneira,
    • André G Uitterlinden &
    • Bruno H Ch Stricker
  85. Division of Pulmonary Medicine, University Hospitals of Geneva, Geneva, Switzerland.

    • Thierry Rochat
  86. Department of Medicine, University of New Mexico, Albuquerque, New Mexico, USA.

    • Akshay Sood
  87. Geriatric Medicine Unit, The University of Edinburgh, Edinburgh, UK.

    • John M Starr
  88. Department of Epidemiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

    • Judith M Vonk &
    • H Marike Boezen
  89. Department of Primary Care and Population Health, University College London, London, UK.

    • S Goya Wannamethee &
    • Richard W Morris
  90. Division of Population Health Sciences and Education, St. George's University of London, London, UK.

    • Peter H Whincup,
    • Alicja R Rudnicka &
    • David P Strachan
  91. Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

    • Cisca Wijmenga
  92. Division of Preventive Medicine, University of Alabama at Birmingham, Birmingham, USA.

    • O Dale Williams
  93. College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee, USA.

    • Bernd Meibohm
  94. Centre for Clinical Research, Haukeland University Hospital, Bergen, Norway.

    • Ernst Omenaas
  95. Obesity Research Unit, Department of Medicine, Division of Internal Medicine, Helsinki University Central Hospital, Helsinki, Finland.

    • Kirsi H Pietiläinen
  96. Hjelt Institute, Department of Public Health, University of Helsinki, Helsinki, Finland.

    • Kirsi H Pietiläinen &
    • Jaakko Kaprio
  97. Institute for Molecular Medicine, University of Helsinki, Helsinki, Finland.

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    • Jaakko Kaprio
  98. Pédiatrie, Centre Hospitalier Universitaire (CHU), Grenoble, France.

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  100. Université Joseph Fourier, Grenoble, France.

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  101. Gen-Info Ltd, Zagreb, Croatia.

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    • Igor Rudan
  102. Department of Children, Young People and Families, National Institute for Health and Welfare, Oulu, Finland.

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  103. Institute of Clinical Medicine, University of Oulu, Oulu, Finland.

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  104. Gerontology Research Centre, Department of Health Sciences, University of Jyväskylä, Jyväskylä, Finland.

    • Taina Rantanen
  105. Public Health Genomics Unit, Department Of Chronic Disease Prevention, The National Institute for Health and Welfare, Helsinki, Finland.

    • Samuli Ripatti &
    • Ida Surakka
  106. Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.

    • Jerome I Rotter
  107. Institute of Epidemiology I, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.

    • Holger Schulz,
    • H-Erich Wichmann &
    • Joachim Heinrich
  108. Institute for Community Medicine, Study of Health In Pomerania (SHIP)/Clinical Epidemiological Research, University of Greifswald, Greifswald, Germany.

    • Henry Völzke
  109. Institute of Medical Informatics, Biometry and Epidemiology, Chair of Epidemiology, Ludwig-Maximilians-Universität, Munich, Germany.

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

    • H-Erich Wichmann
  111. Division of Aging, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.

    • Jemma B Wilk
  112. Institute of Lung Biology and Disease, Comprehensive Pneumology Center, Helmholtz Zentrum München, Neuherberg, Germany.

    • Matthias Wjst
  113. Institute for Medical Statistics and Epidemiology (IMSE), Technical University Munich, Munich, Germany.

    • Matthias Wjst
  114. Andrija Stampar School of Public Health, Faculty of Medicine, University of Zagreb, Zagreb, Croatia.

    • Lina Zgaga
  115. AstraZeneca Research and Development, Mölndal, Sweden.

    • Fredrik Nyberg
  116. Human Development and Health, Faculty of Medicine, University of Southampton, Southampton, UK.

    • John W Holloway
  117. Infection, Inflammation and Immunity, Faculty of Medicine, University of Southampton, Southampton, UK.

    • John W Holloway
  118. Department of Clinical Physiology, University of Tampere and Tampere University Hospital, Tampere, Finland.

    • Mika Kähönen
  119. Department of Respiratory Medicine, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia.

    • Arthur W Musk
  120. MRC Health Protection Agency (HPA) Centre for Environment and Health, Imperial College London, London, UK.

    • Deborah L Jarvis,
    • Marjo-Riitta Järvelin &
    • Paul Elliott
  121. University Hospital Greifswald, Department of Internal Medicine B, Greifswald, Germany.

    • Sven Gläser
  122. Institute of Health Sciences, University of Oulu, Oulu, Finland.

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

    • Marjo-Riitta Järvelin
  124. Department of Medical Informatics, Erasmus Medical Center, Rotterdam, The Netherlands.

    • Bruno H Ch Stricker
  125. Pulmonary Center, Boston University School of Medicine, Boston, Massachusetts, USA.

    • George T O'Connor
  126. The National Heart, Lung and Blood Institute's Framingham Heart Study, Framingham, Massachusetts, USA.

    • George T O'Connor
  127. A full list of members is provided in the Supplementary Note.

    • $affiliationAuthor

Consortia

  1. The International Lung Cancer Consortium

  2. GIANT consortium

Contributions

Author contributions are listed in alphabetical order. See Supplementary Note for definitions of study acronyms.

Project conception, design and management. Stage 1 GWAS, AGES: G.E., M.G., V.G., T.B.H., L.J.L. ARIC: S.J.L., N.F., L.R.L., D.J.C., D.B.H., B.R.J., A.C.M., K.E.N. B58C-T1DGC: D.P.S. B58C -WTCCC: D.P.S. BHS1: A.L.J., A.W.M., L.J.P. CHS: S.A.G., S.R.H., T.L., B.M.P. CROATIA-Korcula: H.C., I.G., S.J., I.R., A.F.W., L.Z. CROATIA-Vis: H.C., C.H., O.P., I.R., A.F.W. ECRHS: D.L.J., E.O., I.P., M.W. EPIC: N.J.W. FHS: J.B.W., G.T.O. FTC: J.K., K.H.P., T. Rantanen. Health ABC: M.C.A., P.A.C., T.B.H., S.B.K., Y.L., B.M. Health 2000: M.H., M.K. KORA F4: J. Heinrich. KORA S3: C.G., H.-E.W. NFBC1966: P.E., A.-L.H., M.-R.J., A.P. ORCADES: H.C., S.H.W., J.F.W., A.F.W. RS: A. Hofman. SHIP: S.G., G.H., B.K., H.V. TwinsUK: T.D.S., G.Z. Stage 2 follow up, ADONIX: J. Brisman., A.-C.O. BHS2: J. Beilby. BRHS: R.W.M., S.G.W., P.H.W. BWHHS: G.D.S., S.E., D.A.L., P.H.W. CARDIA: A.S. CROATIA-Split: M.B., I.K., T.Z. GS: SFHS: C.M.J., S.M.K., A.D.M., D.J.P. HCS: C.C., J.W.H., A.A.S. LBC1936: I.J.D., S.E.H., J.M.S. LifeLines: H.M.B., D.S.P., J.M.V., C.W. MESA-Lung: R.G.B., J.L.H. Nottingham smokers: I.P.H. NSHD: R.H., D.K. SAPALDIA: N.P.-H., T. Rochat. Look-up studies, ALSPAC: R.G., J. Henderson. ILCCO: ILCCO data. Ox-GSK: C.F., J.M.

Phenotype collection and data management. Stage 1 GWAS, AGES: T.A. ARIC: D.J.C., N.F., L.R.L., A.C.M., K.E.N. B58C-T1DGC: A.R.R., D.P.S. B58C -WTCCC: A.R.R., D.P.S. BHS1: A.L.J., A.W.M., L.J.P. CHS: S.A.G., S.R.H., T.L., B.M.P. CROATIA-Korcula: I.G., S.J., O.P., I.R., L.Z. CROATIA-Vis: H.C., C.H., O.P., I.R., A.F.W. ECRHS: D.L.J., E.O., I.P., M.W. EPIC: N.J.W. FHS: J.B.W., G.T.O. FTC: J.K., K.H.P., T. Rantanen. Health ABC: P.A.C., B.M., W.T. Health 2000: M.H., M.K. KORA F4: S.K., H.S. KORA S3: N.P.-H. NFBC1966: P.E., A.-L.H., M.-R.J., A.P. ORCADES: H.C., S.H.W., J.F.W. RS: G.G.B., M.E., D.W.L., B.H.Ch.S. SHIP: S.G., B.K., H.V. TwinsUK: C.J.H., P.G. Hysi, M.M., T.D.S., G.Z. Stage 2 follow up, ADONIX: J. Brisman, A.-C.O. BHS2: J. Beilby, M.L.H. BRHS: R.W.M., S.G.W., P.H.W. BWHHS: G.D.S., S.E., D.A.L., P.H.W. CARDIA: O.D.W. CROATIA-Split: M.B., I.K., T.Z. GS: SFHS: C.M.J., A.D.M. HCS: C.C., K.A.J., A.A.S. LBC1936: I.J.D., L.M.L., J.M.S. LifeLines: D.S.P., J.M.V. MESA-Lung: R.G.B., J.L.H. Nottingham smokers: K.A.A.B., J.D.B., I.P.H., A. Henry, M.O., I. Sayers. NSHD: R.H., D.K. SAPALDIA: N.P.-H. Look-up studies, ALSPAC: R.G., J. Henderson. ILCCO: ILCCO. Raine: W.Q.A., P.G. Holt, C.E.P., P.D.S.

Genotyping. Stage 1 GWAS, B58C-T1DGC: W.L.M. B58C-WTCCC: W.L.M. BHS1: A.L.J., A.W.M., L.J.P. CHS: S.R.H., B.M.P., J.I.R. CROATIA-Vis: C.H., I.R., A.F.W. ECRHS: M.W. EPIC: I.B., R.J.F.L., J.H.Z. FTC: J.K. Health ABC: Y.L., K.L. Health 2000: S.R., I. Surakka. KORA F4: N.K. KORA S3: C.G. NFBC1966: P.E., A.-L.H., M.-R.J., A.P., A.R. ORCADES: H.C., J.F.W. RS: F.R., A.G.U. SHIP: G.H. TwinsUK: C.J.H., S.-Y.S. Stage 2 follow up, ADONIX: S.D., F.N., A.-C.O. BHS2: J. Beilby, G.C., J.H. BRHS: A.D.H., R.W.M. BWHHS: S.E., D.A.L. CARDIA: M.F., X.G. CROATIA-Split: V.B., T.Z. Gedling: J.R.B., T.M. GS: SFHS: C.M.J., S.M.K., D.J.P. HCS: J.W.H. LBC1936: I.J.D., S.E.H., L.M.L., J.M.S. LifeLines: C.W. MESA-Lung: S.S.R. NSHD: D.K., A.W. SAPALDIA: M.I., F.K. Look-up studies, ALSPAC: S.M.R., W.L.M. ILCCO: ILCCO. Raine: W.Q.A., C.E.P.

Data analysis. Stage 1 GWAS, AGES: G.K.G., A.V.S. ARIC: N.F., D.B.H., L.R.L. B58C–T1DGC: A.R.R., D.P.S. B58C -WTCCC: A.R.R., D.P.S. BHS1: N.M.W. CHS: K.D.M., J.I.R. CROATIA-Korcula: C.H., J.E.H., V.V. CROATIA-Vis: C.H., V.V. ECRHS: D.L.J., A.R. EPIC: J.H.Z. FHS: J.B.W. FTC: I. Surakka. Health ABC: P.A.C., Y.L., K.L., W.T. Health 2000: M.K., S.R., I. Surakka. KORA S3: E.A. NFBC1966: A.R. ORCADES: C.H., V.V. RS: M.E., D.W.L. SHIP: S.G., G.H., B.K., H.V. TwinsUK: M.M., G.Z. Stage 2 follow-up studies, ADONIX: S.D., F.N. BHS2: G.C. BRHS: R.W.M. BWHHS: D.A.L. CARDIA: M.F., X.G. HCS: J.W.H., K.A.J. LBC1936: L.M.L. LifeLines: H.M.B. MESA-Lung: A.M., S.S.R. Nottingham smokers: I. Sayers, A. Henry. NSHD: D.G., R.H. SAPALDIA: I.C., M.I. Look-up studies, ALSPAC: D.M.E. ILCCO: ILCCO. Ox-GSK: J.Z.L. Raine: W.Q.A.

Analysis group: SpiroMeta consortium: I.P.H., T.J., M.S.A., M.D.T., L.V.W. CHARGE consortium: N.F., S.J.L., D.W.L., K.D.M., A.V.S., W.T., J.B.W.

Expression profiling and bioinformatics group: SpiroMeta consortium: I.P.H., M.O., I. Sayers, M.S.A., M.D.T., L.V.W. CHARGE consortium: S.A.G., D.W.L.

Writing group: SpiroMeta consortium: P.E., I.P.H., M.O., M.S.A., D.P.S., M.D.T., L.V.W. CHARGE consortium: S.J.L., D.W.L., S.A.G., G.T.O., V.G., B.H.Ch.S., W.T.

Competing financial interests

I.B. and spouse own stock in Incyte Ltd and GlaxoSmithKline. F.N. is employed by AstraZeneca R&D, 431 83 Mölndal, Sweden. D.S.P. has received unrestricted research grants from and has been a consultant to AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Nycomed and TEVA. C.F. is a full-time employee of GlaxoSmithKline (GSK), and GSK also funded several aspects of the study as detailed in the Acknowledgements section for Ox-GSK.

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Supplementary information

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  1. Supplementary Text and Figures (4M)

    Supplementary Figure 1, Supplementary Tables 1–6 and Supplementary Note

Additional data