Article | Published:

Genome-wide association analysis identifies six new loci associated with forced vital capacity

Nature Genetics volume 46, pages 669677 (2014) | Download Citation

Abstract

Forced vital capacity (FVC), a spirometric measure of pulmonary function, reflects lung volume and is used to diagnose and monitor lung diseases. We performed genome-wide association study meta-analysis of FVC in 52,253 individuals from 26 studies and followed up the top associations in 32,917 additional individuals of European ancestry. We found six new regions associated at genome-wide significance (P < 5 × 10−8) with FVC in or near EFEMP1, BMP6, MIR129-2HSD17B12, PRDM11, WWOX and KCNJ2. Two loci previously associated with spirometric measures (GSTCD and PTCH1) were related to FVC. Newly implicated regions were followed up in samples from African-American, Korean, Chinese and Hispanic individuals. We detected transcripts for all six newly implicated genes in human lung tissue. The new loci may inform mechanisms involved in lung development and the pathogenesis of restrictive lung disease.

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References

  1. 1.

    et al. Evidence for major genes influencing pulmonary function in the NHLBI family heart study. Genet. Epidemiol. 19, 81–94 (2000).

  2. 2.

    et al. Marginal decline in forced vital capacity is associated with a poor outcome in idiopathic pulmonary fibrosis. Eur. Respir. J. 35, 830–836 (2010).

  3. 3.

    et al. An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management. Am. J. Respir. Crit. Care Med. 183, 788–824 (2011).

  4. 4.

    , , & Pulmonary function: relation to aging, cigarette habit, and mortality. Ann. Intern. Med. 82, 739–745 (1975).

  5. 5.

    & Forced vital capacity, airway obstruction and survival in a general population sample from the USA. Thorax 66, 49–54 (2011).

  6. 6.

    , , , & Forced vital capacity paired with Framingham Risk Score for prediction of all-cause mortality. Eur. Respir. J. 36, 1002–1006 (2010).

  7. 7.

    , , , & Spirometric findings and mortality in never-smokers. J. Clin. Epidemiol. 43, 867–873 (1990).

  8. 8.

    , & Vital capacity as a predictor of cardiovascular disease: the Framingham study. Am. Heart J. 105, 311–315 (1983).

  9. 9.

    et al. Familial aggregation and heritability of adult lung function: results from the Busselton Health Study. Eur. Respir. J. 17, 696–702 (2001).

  10. 10.

    et al. Relationship between parental lung function and their children's lung function early in life. Eur. Respir. J. 38, 664–671 (2011).

  11. 11.

    et al. A genome-wide association study of pulmonary function measures in the Framingham Heart Study. PLoS Genet. 5, e1000429 (2009).

  12. 12.

    et al. Genome-wide association study identifies five loci associated with lung function. Nat. Genet. 42, 36–44 (2010).

  13. 13.

    et al. Meta-analyses of genome-wide association studies identify multiple loci associated with pulmonary function. Nat. Genet. 42, 45–52 (2010).

  14. 14.

    et al. Genome-wide association and large-scale follow up identifies 16 new loci influencing lung function. Nat. Genet. 43, 1082–1090 (2011).

  15. 15.

    et al. The Korean Twin Registry—methods, current stage, and interim results. Twin Res. 5, 394–400 (2002).

  16. 16.

    et al. Healthy Twin: a twin-family study of Korea—protocols and current status. Twin Res. Hum. Genet. 9, 844–848 (2006).

  17. 17.

    et al. The Healthy Twin Study, Korea updates: resources for omics and genome epidemiology studies. Twin Res. Hum. Genet. 16, 241–245 (2013).

  18. 18.

    et al. A large-scale genome-wide association study of Asian populations uncovers genetic factors influencing eight quantitative traits. Nat. Genet. 41, 527–534 (2009).

  19. 19.

    & Genomic control for association studies. Biometrics 55, 997–1004 (1999).

  20. 20.

    1000 Genomes Project Consortium. A map of human genome variation from population-scale sequencing. Nature 467, 1061–1073 (2010).

  21. 21.

    A simple correction for multiple testing for single-nucleotide polymorphisms in linkage disequilibrium with each other. Am. J. Hum. Genet. 74, 765–769 (2004).

  22. 22.

    & Adjusting multiple testing in multilocus analyses using the eigenvalues of a correlation matrix. Heredity (Edinb.) 95, 221–227 (2005).

  23. 23.

    et al. Candidate gene association resource (CARe): design, methods, and proof of concept. Circ Cardiovasc Genet 3, 267–275 (2010).

  24. 24.

    et al. Generalization and dilution of association results from European GWAS in populations of non-European ancestry: the PAGE study. PLoS Biol. 11, e1001661 (2013).

  25. 25.

    , , , & i-GSEA4GWAS: a web server for identification of pathways/gene sets associated with traits by applying an improved gene set enrichment analysis to genome-wide association study. Nucleic Acids Res. 38, W90–W95 (2010).

  26. 26.

    et al. A genome-wide association study of global gene expression. Nat. Genet. 39, 1202–1207 (2007).

  27. 27.

    et al. Abundant quantitative trait loci exist for DNA methylation and gene expression in human brain. PLoS Genet. 6, e1000952 (2010).

  28. 28.

    et al. Common regulatory variation impacts gene expression in a cell type–dependent manner. Science 325, 1246–1250 (2009).

  29. 29.

    Genotype-Tissue Expression Consortium. The Genotype-Tissue Expression (GTEx) project. Nat. Genet. 45, 580–585 (2013).

  30. 30.

    et al. Annotation of functional variation in personal genomes using RegulomeDB. Genome Res. 22, 1790–1797 (2012).

  31. 31.

    et al. Heritability of longitudinal change in lung function. The Framingham study. Am. J. Respir. Crit. Care Med. 164, 1655–1659 (2001).

  32. 32.

    et al. Estimation of effect size distribution from genome-wide association studies and implications for future discoveries. Nat. Genet. 42, 570–575 (2010).

  33. 33.

    et al. Missing heritability and strategies for finding the underlying causes of complex disease. Nat. Rev. Genet. 11, 446–450 (2010).

  34. 34.

    et al. Genome-wide joint meta-analysis of SNP and SNP-by-smoking interaction identifies novel loci for pulmonary function. PLoS Genet. 8, e1003098 (2012).

  35. 35.

    et al. Conditional and joint multiple-SNP analysis of GWAS summary statistics identifies additional variants influencing complex traits. Nat. Genet. 44, 369–375 (2012).

  36. 36.

    et al. Hundreds of variants clustered in genomic loci and biological pathways affect human height. Nature 467, 832–838 (2010).

  37. 37.

    et al. Activation of the canonical Bone Morphogenetic Protein (BMP) pathway during lung morphogenesis and adult lung tissue repair. PLoS ONE 7, e41460 (2012).

  38. 38.

    et al. Activation of bone morphogenetic protein/Smad signaling in bronchial epithelial cells during airway inflammation. Am. J. Respir. Cell Mol. Biol. 27, 160–169 (2002).

  39. 39.

    et al. Targeted disruption of fibulin-4 abolishes elastogenesis and causes perinatal lethality in mice. Mol. Cell. Biol. 26, 1700–1709 (2006).

  40. 40.

    et al. Transforming growth factor β1 and recruitment of macrophages and mast cells in airways in chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 158, 1951–1957 (1998).

  41. 41.

    et al. Increased expression of transforming growth factor-β1 in small airway epithelium from tobacco smokers and patients with chronic obstructive pulmonary disease (COPD). Am. J. Respir. Crit. Care Med. 163, 1476–1483 (2001).

  42. 42.

    et al. Bmi1 regulates cell fate via tumor suppressor WWOX repression in small-cell lung cancer cells. Cancer Sci. 102, 983–990 (2011).

  43. 43.

    et al. Towards a knowledge-based Human Protein Atlas. Nat. Biotechnol. 28, 1248–1250 (2010).

  44. 44.

    Lung function and airway diseases. Nat. Genet. 42, 14–16 (2010).

  45. 45.

    et al. Thirty new loci for age at menarche identified by a meta-analysis of genome-wide association studies. Nat. Genet. 42, 1077–1085 (2010).

  46. 46.

    et al. Genome-wide association scan meta-analysis identifies three loci influencing adiposity and fat distribution. PLoS Genet. 5, e1000508 (2009).

  47. 47.

    , , , & MaCH: using sequence and genotype data to estimate haplotypes and unobserved genotypes. Genet. Epidemiol. 34, 816–834 (2010).

  48. 48.

    , , , & A new multipoint method for genome-wide association studies by imputation of genotypes. Nat. Genet. 39, 906–913 (2007).

  49. 49.

    & A unified approach to genotype imputation and haplotype-phase inference for large data sets of trios and unrelated individuals. Am. J. Hum. Genet. 84, 210–223 (2009).

  50. 50.

    & High-resolution detection of identity by descent in unrelated individuals. Am. J. Hum. Genet. 86, 526–539 (2010).

  51. 51.

    & Imputation-based analysis of association studies: candidate regions and quantitative traits. PLoS Genet. 3, e114 (2007).

  52. 52.

    , & METAL: fast and efficient meta-analysis of genomewide association scans. Bioinformatics 26, 2190–2191 (2010).

  53. 53.

    R Development Core Team. R: A Language and Environement for Statistical Computing (R Foundation for Statistical Computing, Vienna, 2009).

  54. 54.

    et al. Genome-wide association study of coronary heart disease and its risk factors in 8,090 African Americans: the NHLBI CARe Project. PLoS Genet. 7, e1001300 (2011).

  55. 55.

    A simple correction for multiple comparisons in interval mapping genome scans. Heredity (Edinb.) 87, 52–58 (2001).

  56. 56.

    et al. The Rotterdam Study: 2012 objectives and design update. Eur. J. Epidemiol. 26, 657–686 (2011).

  57. 57.

    et al. Systematic identification of trans eQTLs as putative drivers of known disease associations. Nat. Genet. 45, 1238–1243 (2013).

  58. 58.

    et al. HTR4 gene structure and altered expression in the developing lung. Respir. Res. 14, 77 (2013).

  59. 59.

    et al. Expression analysis of asthma candidate genes during human and murine lung development. Respir. Res. 12, 86 (2011).

  60. 60.

    et al. Transcriptomic analysis of human lung development. Am. J. Respir. Crit. Care Med. 181, 54–63 (2010).

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Acknowledgements

For all studies, information on funding and acknowledgments can be found in the Supplementary Note.

Author information

Author notes

    • Daan W Loth
    • , María Soler Artigas
    • , Sina A Gharib
    • , Louise V Wain
    • , Nora Franceschini
    • , Beate Koch
    • , Tess D Pottinger
    • , Albert Vernon Smith
    •  & Qing Duan

    These authors contributed equally to this work.

    • Akshay Sood
    • , Caroline Hayward
    • , Josée Dupuis
    • , Ian P Hall
    • , Guy G Brusselle
    • , Martin D Tobin
    •  & Stephanie J London

    These authors jointly directed this work.

Affiliations

  1. Department of Epidemiology, Erasmus MC, Rotterdam, the Netherlands.

    • Daan W Loth
    • , Lies Lahousse
    • , Albert Hofman
    • , André G Uitterlinden
    • , Bruno H Stricker
    •  & Guy G Brusselle
  2. Netherlands Health Care Inspectorate, The Hague, the Netherlands.

    • Daan W Loth
    •  & Bruno H Stricker
  3. Genetic Epidemiology Group, Department of Health Sciences, University of Leicester, Leicester, UK.

    • María Soler Artigas
    • , Louise V Wain
    •  & Martin D Tobin
  4. National Institute for Health Research (NIHR) Leicester Respiratory Biomedical Research Unit, Glenfield Hospital, Leicester, UK.

    • María Soler Artigas
    • , Louise V Wain
    •  & Martin D Tobin
  5. Computational Medicine Core, 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
    •  & Bruce M Psaty
  7. Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.

    • Nora Franceschini
    • , Laura R Loehr
    •  & Kari E North
  8. Carolina Center for Genome Sciences, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.

    • Nora Franceschini
    •  & Laura R Loehr
  9. Department of Internal Medicine B–Pneumology, Cardiology, Intensive Care and Infectious Diseases, University Hospital Greifswald, Greifswald, Germany.

    • Beate Koch
    •  & Sven Gläser
  10. Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, New York, USA.

    • Tess D Pottinger
    • , David J Lederer
    • , Kristin M Burkart
    •  & R Graham Barr
  11. Iceland Heart Association, Kopavogur, Iceland.

    • Albert Vernon Smith
    • , Gudny Eiriksdottir
    • , Thor Aspelund
    •  & Vilmundur Gudnason
  12. University of Iceland, Reykjavik, Iceland.

    • Albert Vernon Smith
    • , Thor Aspelund
    •  & Vilmundur Gudnason
  13. Department of Genetics, University of North Carolina, Chapel Hill, North Carolina, USA.

    • Qing Duan
    •  & Leslie A Lange
  14. Hunter Medical Research Institute, University of Newcastle, Newcastle, New South Wales, Australia.

    • Chris Oldmeadow
    • , Elizabeth G Holliday
    • , Rodney J Scott
    •  & John R Attia
  15. Faculty of Health, University of Newcastle, Newcastle, New South Wales, Australia.

    • Chris Oldmeadow
    • , Elizabeth G Holliday
    • , Rodney J Scott
    •  & John R Attia
  16. Institute of Health and Environment, Seoul National University, Seoul, South Korea.

    • Mi Kyeong Lee
    •  & Joohon Sung
  17. Division of Population Health Sciences and Education, St George's, University of London, London, UK.

    • David P Strachan
    •  & Alicja R Rudnicka
  18. Department of Pulmonary Physiology and Sleep Medicine/West Australian Sleep Disorders Research Institute, Nedlands, Western Australia, Australia.

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

    • Alan L James
  20. Busselton Population Medical Research Institute, Busselton, Western Australia, Australia.

    • Alan L James
  21. Medical Research Council (MRC) Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine (IGMM), University of Edinburgh, Edinburgh, UK.

    • Jennifer E Huffman
    • , Veronique Vitart
    • , Holly Trochet
    • , Alan F Wright
    • , Nicholas D Hastie
    • , Susan Campbell
    • , Pau Navarro
    •  & Caroline Hayward
  22. Respiratory Epidemiology and Public Health Group, National Heart and Lung Institute, Imperial College London, London, UK.

    • Adaikalavan Ramasamy
    •  & Deborah L Jarvis
  23. Department of Epidemiology and Biostatistics, MRC Health Protection Agency (HPA) Centre for Environment and Health, School of Public Health, Imperial College London, London, UK.

    • Adaikalavan Ramasamy
    • , Alexessander Couto Alves
    •  & Marjo-Riitta Jarvelin
  24. MRC Epidemiology Unit, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK.

    • Nicholas J Wareham
    • , Robert A Scott
    •  & Jing Hua Zhao
  25. Hjelt Institute, Department of Public Health, University of Helsinki, Helsinki, Finland.

    • Jaakko Kaprio
  26. National Institute for Health and Welfare (THL), Helsinki, Finland.

    • Jaakko Kaprio
    •  & Markku Heliövaara
  27. Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.

    • Jaakko Kaprio
    • , Kirsi H Pietiläinen
    • , Ida Surakka
    •  & Samuli Ripatti
  28. Division of Biostatistics and Epidemiology, Department of Public Health Sciences, University of Virginia, Charlottesville, Virginia, USA.

    • Xin-Qun Wang
    •  & Ani Manichaikul
  29. Department of Clinical Physiology, University of Tampere and Tampere University Hospital, Tampere, Finland.

    • Mika Kähönen
  30. Institute of Epidemiology I, Helmholtz Zentrum München–German Research Center for Environmental Health, Neuherberg, Germany.

    • Claudia Flexeder
    • , Holger Schulz
    • , Joachim Heinrich
    •  & Stefan Karrasch
  31. Institute of Genetic Epidemiology, Helmholtz Zentrum München–German Research Center for Environmental Health, Neuherberg, Germany.

    • Eva Albrecht
    •  & Christian Gieger
  32. Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK.

    • Lorna M Lopez
    • , Gail Davies
    • , John M Starr
    •  & Ian J Deary
  33. Department of Psychology, University of Edinburgh, Edinburgh, UK.

    • Lorna M Lopez
    • , Gail Davies
    •  & Ian J Deary
  34. Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.

    • Kim de Jong
    • , Judith M Vonk
    •  & H Marike Boezen
  35. Groningen Research Institute for Asthma and COPD (GRIAC), University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.

    • Kim de Jong
    • , Judith M Vonk
    • , Dirkje S Postma
    •  & H Marike Boezen
  36. Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota, USA.

    • Bharat Thyagarajan
  37. Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.

    • Stefan Enroth
    • , Åsa Johansson
    •  & Ulf Gyllensten
  38. Science for Life Laboratory, Uppsala University, Uppsala, Sweden.

    • Stefan Enroth
    • , Tove Fall
    • , Åsa Johansson
    • , Erik Ingelsson
    •  & Ulf Gyllensten
  39. Centre for Clinical Research, Haukeland University Hospital, Bergen, Norway.

    • Ernst Omenaas
  40. Department of Clinical Sciences, University of Bergen, Bergen, Norway.

    • Ernst Omenaas
  41. Centre for Population Health Sciences, Medical School, University of Edinburgh, Edinburgh, UK.

    • Peter K Joshi
    • , Sarah H Wild
    • , Igor Rudan
    • , Harry Campbell
    •  & James F Wilson
  42. Molecular Epidemiology, Department of Medical Sciences, Uppsala University, Uppsala, Sweden.

    • Tove Fall
    •  & Erik Ingelsson
  43. Department of Twins Research and Genetic Epidemiology, King's College London, London, UK.

    • Ana Viñuela
    • , Pirro G Hysi
    • , Christopher J Hammond
    •  & Timothy D Spector
  44. Laboratory of Epidemiology, Demography and Biometry, National Institute on Aging, US National Institutes of Health, Bethesda, Maryland, USA.

    • Lenore J Launer
    • , Tamara B Harris
    •  & Melissa Garcia
  45. Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, Texas, USA.

    • Myriam Fornage
    •  & Xiangjun Gu
  46. Human Genetics Center, University of Texas Health Science Center at Houston, Houston, Texas, USA.

    • Myriam Fornage
    •  & Xiangjun Gu
  47. Cardiovascular Health Research Unit, University of Washington, Seattle, Washington, USA.

    • Guo Li
    • , Bruce M Psaty
    •  & Susan R Heckbert
  48. Precision Medicine, Pfizer Global Research and Development, Cambridge, Massachusetts, USA.

    • Jemma B Wilk
  49. Division of Nutritional Sciences, Cornell University, Ithaca, New York, USA.

    • Wenbo Tang
    •  & Patricia A Cassano
  50. Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia, USA.

    • Ani Manichaikul
    •  & Stephen S Rich
  51. Department of Respiratory Medicine, Ghent University Hospital, Ghent, Belgium.

    • Lies Lahousse
    • , Ken R Bracke
    • , Fien M Verhamme
    •  & Guy G Brusselle
  52. PathWest Laboratory Medicine Washington, Nedlands, Western Australia, Australia.

    • Jennie Hui
    •  & John Beilby
  53. Department of Statistics, University of Auckland, Auckland, New Zealand.

    • Thomas Lumley
  54. Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.

    • Rajesh Kumar
    •  & Lewis J Smith
  55. Centre Hospitalier Universitaire de Grenoble, Grenoble, France.

    • Isabelle Pin
  56. INSERM U823, Institut Albert Bonniot, Grenoble, France.

    • Isabelle Pin
  57. Université Joseph Fourier, Grenoble, France.

    • Isabelle Pin
  58. Obesity Research Unit, Research Programs Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland.

    • Kirsi H Pietiläinen
  59. Division of Internal Medicine, Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland.

    • Kirsi H Pietiläinen
  60. Public Health Genomics Unit, Department of Chronic Disease Prevention, National Institute for Health and Welfare (THL), Helsinki, Finland.

    • Ida Surakka
    •  & Samuli Ripatti
  61. Department of Epidemiology and Prevention, Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.

    • Yongmei Liu
  62. Comprehensive Pneumology Center Munich (CPC-M), member of the German Center for Lung Research, Munich, Germany.

    • Joachim Heinrich
  63. Medical Genetics Section, Centre for Genomics and Experimental Medicine, MRC IGMM, University of Edinburgh, Edinburgh, UK.

    • Gail Davies
    •  & David J Porteous
  64. MRC Institute of Genetics and Molecular Medicine, Edinburgh, UK.

    • Gail Davies
  65. Department of Statistical Genomics, Washington University, St. Louis, Missouri, USA.

    • Mary Wojczynski
  66. National Institute for Health and Welfare, Oulu, Finland.

    • Anneli Pouta
  67. Department of Clinical Sciences/Obstetrics and Gynecology, University Hospital of Oulu, University of Oulu, Oulu, Finland.

    • Anneli Pouta
  68. Uppsala Clinical Research Center, Uppsala University, Uppsala, Sweden.

    • Åsa Johansson
  69. Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.

    • Erik Ingelsson
    •  & Andrew P Morris
  70. Department of Internal Medicine, Erasmus MC, Rotterdam, the Netherlands.

    • Fernando Rivadeneira
    • , André G Uitterlinden
    • , Joyce B J van Meurs
    • , Bruno H Stricker
    •  & Marjolein J Peters
  71. Netherlands Genomics Initiative (NGI)-sponsored Netherlands Consortium for Healthy Aging (NCHA), Rotterdam, the Netherlands.

    • Fernando Rivadeneira
    • , Albert Hofman
    • , André G Uitterlinden
    • , Joyce B J van Meurs
    • , Bruno H Stricker
    •  & Marjolein J Peters
  72. Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.

    • Henry Völzke
  73. School of Public Health, University of Texas Health Science Center at Houston, Houston, Texas, USA.

    • Alanna C Morrison
  74. Biomedical Research Institute, Harbor–University of California, Los Angeles (UCLA) Medical Center, Torrance, California, USA.

    • Jerome I Rotter
  75. Department of Pediatrics, Harbor-UCLA Medical Center, Torrance, California, USA.

    • Jerome I Rotter
  76. Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, USA.

    • Wei Gao
    •  & Josée Dupuis
  77. Department of Pulmonology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.

    • Dirkje S Postma
  78. Tougaloo College, Jackson, Mississippi, USA.

    • Wendy B White
  79. Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.

    • David Couper
  80. Department of Epidemiology, University of Washington, Seattle, Washington, USA.

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

    • Bruce M Psaty
    •  & Susan R Heckbert
  82. Department of Biostatistical Sciences, Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.

    • Kurt Lohman
  83. Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, California, USA.

    • Esteban G Burchard
  84. Department of Medicine, University of California, San Francisco, San Francisco, California, USA.

    • Esteban G Burchard
  85. Epidemiology Branch, National Institute of Environmental Health Sciences, US National Institutes of Health, US Department of Health and Human Services, Research Triangle Park, North Carolina, USA.

    • Bonnie R Joubert
    • , Dana B Hancock
    •  & Stephanie J London
  86. School of Social and Community Medicine, University of Bristol, Bristol, UK.

    • Wendy L McArdle
  87. Department of Respiratory Medicine, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia.

    • A Bill Musk
  88. Department of Medicine, Johns Hopkins University, Baltimore, Maryland, USA.

    • Nadia Hansel
  89. Department of Public Health and Primary Care, Trinity College Dublin, Dublin, Ireland.

    • Lina Zgaga
  90. Adrija Stampar School of Public Health, Medical School, University of Zagreb, Zagreb, Croatia.

    • Lina Zgaga
  91. Department of Pulmonary and Critical Care Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.

    • Yeon-Mok Oh
  92. Clinical Research Center for Chronic Obstructive Airway Diseases, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.

    • Yeon-Mok Oh
  93. Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.

    • Susan Redline
  94. MRC-PHE Centre for Environment and Health, Imperial College London, London, UK.

    • Deborah L Jarvis
  95. Gerontology Research Centre, Department of Health Sciences, University of Jyväskylä, Jyväskylä, Finland.

    • Taina Rantanen
    •  & Anne Viljanen
  96. Pulmonary Center, Boston University School of Medicine, Boston, Massachusetts, USA.

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

    • George T O'Connor
    •  & Josée Dupuis
  98. Genetic Epidemiology Group, Wellcome Trust Sanger Institute, Hinxton, UK.

    • Samuli Ripatti
  99. Institute and Outpatient Clinic for Occupational, Social and Environmental Medicine, Ludwig Maximilians Universität, Munich, Germany.

    • Stefan Karrasch
  100. Institute of General Practice, University Hospital Klinikum Rechts der Isar, Technische Universität München, Munich, Germany.

    • Stefan Karrasch
  101. Research Unit of Molecular Epidemiology, Helmholtz Zentrum München–German Research Center for Environmental Health, Neuherberg, Germany.

    • Harald Grallert
  102. Research Computing Division, Research Triangle Institute International, Research Triangle Park, North Carolina, USA.

    • Nathan C Gaddis
  103. Alzheimer Scotland Dementia Research Centre, University of Edinburgh, Edinburgh, UK.

    • John M Starr
  104. Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.

    • Cisca Wijmenga
  105. Department of Human Genetics, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

    • Ryan L Minster
  106. Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, New York, USA.

    • David J Lederer
    •  & R Graham Barr
  107. Department of Environmental Health, National Institute for Health and Welfare (THL), Kuopio, Finland.

    • Juha Pekkanen
  108. Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland.

    • Juha Pekkanen
  109. Sticht Center on Aging, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.

    • Stephen B Kritchevsky
  110. Behavioral Health Epidemiology Program, Research Triangle Institute International, Research Triangle Park, North Carolina, USA.

    • Dana B Hancock
  111. Florida International University, Miami, Florida, USA.

    • O Dale Williams
  112. Department of Public Health, Medical School, University of Split, Split, Croatia.

    • Ozren Polasek
    •  & Ivana Kolcic
  113. Department of Medical Biology, Medical School, University of Split, Split, Croatia.

    • Tatijana Zemunik
  114. Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Mississippi Medical Center, Jackson, Mississippi, USA.

    • Marcy F Petrini
  115. Comprehensive Pneumology Center (CPC), Helmholtz Zentrum München (HMGU), Munich, Germany.

    • Matthias Wjst
  116. Department of Internal Medicine, Kangwon National University Hospital, School of Medicine, Kangwon National University, Chuncheon, South Korea.

    • Woo Jin Kim
  117. Environmental Health Center, Kangwon National University Hospital, School of Medicine, Kangwon National University, Chuncheon, South Korea.

    • Woo Jin Kim
  118. A collaboration between the University Medical Schools and National Health Service (NHS) in Aberdeen, Dundee, Edinburgh and Glasgow, UK.

    • Generation Scotland
  119. Medical Research Institute, University of Dundee, Dundee, UK.

    • Blair H Smith
  120. Division of Therapeutics and Molecular Medicine, University of Nottingham, Nottingham, UK.

    • Ian Sayers
    •  & Ian P Hall
  121. Institute of Epidemiology II, Helmholtz Zentrum München–German Research Center for Environmental Health, Neuherberg, Germany.

    • Regina Hampel
  122. Department of Epidemiology, Center for Aging and Population Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

    • Anne Newman
  123. Institute of Health Sciences, University of Oulu, Oulu, Finland.

    • Marjo-Riitta Jarvelin
  124. Biocenter Oulu, University of Oulu, Oulu, Finland.

    • Marjo-Riitta Jarvelin
  125. Unit of Primary Care, Oulu University Hospital, Oulu, Finland.

    • Marjo-Riitta Jarvelin
  126. Department of Children and Young People and Families, National Institute for Health and Welfare, Oulu, Finland.

    • Marjo-Riitta Jarvelin
  127. Department of Medical Sciences, Uppsala University, Uppsala, Sweden.

    • Lars Lind
  128. Department for Genetics and Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany.

    • Alexander Teumer
  129. Institute of Environmental Medicine, Karolinska Institutet and Sachs' Children's Hospital, Stockholm, Sweden.

    • Erik Melén
  130. Complex Disease and Genetic Epidemiology Branch, Department of Epidemiology, Seoul National University School of Public Health, Seoul, South Korea.

    • Joohon Sung
  131. Department of Pulmonology, Leiden University Medical Center, Leiden, the Netherlands.

    • Pieter S Hiemstra
  132. Department of Public Health, Division of Biostatistics and Epidemiology, Weill Cornell Medical College, New York, New York, USA.

    • Patricia A Cassano
  133. University of New Mexico Health Sciences Center School of Medicine, Albuquerque, New Mexico, USA.

    • Akshay Sood
  134. Department of Respiratory Medicine, Erasmus MC, Rotterdam, the Netherlands.

    • Guy G Brusselle

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Contributions

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., D.C., D.B.H., B.R.J., A.C.M., K.E.N. B58C T1DGC: D.P.S. B58C WTCCC: D.P.S. CARDIA: A.S., L.J.S. CHS: S.A.G., S.R.H., B.M.P. CROATIA-Korcula: O.P., A.F.W. CROATIA-Vis: I.R. ECRHS: D.J., E.O., I.P., M. Wjst EPIC: R.A.S., N.J.W., J.H.Z. FHS: J.B.W., G.T.O., J.D. FTC: J.K., K.H.P., T.R., A. Viljanen Health ABC: P.A.C., T.B.H., S.B.K., Y.L. Health 2000: M.H., M.K. HCS: J.R.A., R.J.S. KORA S3: C.G., J. Heinrich MESA-Lung: R.G.B. NFBC1966: M.-R.J., A.P. NSPHS: U.G. ORCADES: H.C., J.F.W., S.H.W. RS I, II and III: A.H., B.H. Stricker, G.G.B. SHIP: S.G., B.K., H.V. Twins UK-I: C.J.H., T.D.S. Stage 2 follow-up studies. BHS 1 and 2: A.L.J., A.B.M., J.B. CROATIA-Split: N.D.H., C.H. Generation Scotland: D.J.P., B.H. Smith. KORA F4: H.S. LBC1936: I.J.D., J.M.S. LifeLines: H.M.B., D.S.P., J.M.V., C.W. LLFS: A.N., B.T., M. Wojczynski, R.L.M. PIVUS: E.I., L. Lind Twins UK-II and III: C.J.H., T.D.S. Multi-ancestry follow-up studies. CARe: R.G.B., K.M.B., D.J.L., R.K., L.J.S., J.B.W., N.H., M.F.P., K.M.B., S. Redline, E.G.B., G.T.O., L.R.L., W.B.W. KARE3 and Healthy Twin Study: J.S., W.J.K., Y.-M.O. Gene expression analyses. RT-PCR: K.R.B., G.G.B. eQTL analysis: J.B.J.v.M., A.G.U. Fetal lung expression analysis: I.P.H., I. Sayers, E.M.

Phenotype collection and data management. Stage 1 GWAS. Ages: T.A. ARIC: D.C., N.F., A.C.M., K.E.N. B58C T1DGC: A.R.R., D.P.S. B58C WTCCC: A.R.R., D.P.S. CARDIA: L.J.S., O.D.W. CHS: S.A.G., S.R.H., B.M.P., T.L. CROATIA-Korcula: O.P., L.Z. CROATIA-Vis: S.C., I.K. ECRHS: D.L.J., E.O., I.P., M. Wjst EPIC: J.H.Z. FHS: J.B.W., G.T.O., J.D. FTC: J.K., K.H.P., T.R., A. Viljanen Health ABC: P.A.C., W.T. Health 2000: M.H., M.K. HCS: J.R.A. KORA S3: J. Heinrich MESA-Lung: R.G.B. NFBC1966: M.-R.J., J.P., A.P. NSPHS: Å.J., S.E., U.G. ORCADES: S.H.W., J.F.W. RS I, II and III: G.G.B., L. Lahousse, D.W.L., B.H. Stricker SHIP: S.G., B.K., H.V. Twins UK-I: P.G.H., A. Viñuela. Stage 2 follow-up studies. BHS 1 and 2: A.L.J., A.B.M., J.B. CROATIA-Split: C.H., T.Z. Generation Scotland: D.J.P., B.H. Smith. KORA F4: R.H., S.K., H.S. LBC1936: I.J.D., J.M.S. LifeLines: D.S.P., J.M.V. LLFS: A.N., B.T., R.L.M. PIVUS: E.I., L. Lind Twins UK-II and III: P.G.H., A. Viñuela Multi-ancestry follow-up studies. CARe: R.G.B., T.D.P., K.M.B., D.J.L., R.K., L.J.S., J.B.W., N.H., M.F.P., K.M.B., S. Ripatti, E.G.B., G.T.O., L.R.L., W.B.W. KARE3 and Healthy Twin Study: J.S., W.J.K., Y.-M.O. Gene expression analyses. RT-PCR: K.R.B., G.G.B., F.M.V., P.S.H. eQTL analysis: J.B.J.v.M., M.J.P. Fetal lung expression analysis: I.P.H., I. Sayers, E.M.

Genotyping. Stage 1 GWAS. B58C T1DGC: W.L.M. B58C WTCCC: W.L.M. CARDIA: M.F., X.G. CHS: J.I.R., B.M.P. CROATIA-Korcula: J.E.H. CROATIA-Vis: S.C. ECRHS: M. Wjst EPIC: J.H.Z. FTC: J.K. Health ABC: Y.L., K.L. Health 2000: S. Ripatti, I. Surakka. HCS: R.J.S. KORA S3: H.G. MESA-Lung: S.S.R. NFBC1966: M.-R.J. NSPHS: Å.J., S.E., U.G. Orcades: H.C., J.F.W. RS I, II and III: F.R., A.G.U. SHIP: S.G., B.K., A.T., H.V. Twins UK-I: C.J.H., T.D.S. Stage 2 follow-up studies. BHS 1 and 2: J. Hui, J.B. CROATIA-Split: C.H., P.N., T.Z. Generation Scotland: D.J.P., B.H. Smith, H.T. LBC1936: G.D. LifeLines: C.W. LLFS: A.N., B.T. PIVUS: E.I., A.P.M. Twins UK-II and III: C.J.H., T.D.S.

Data analysis. Stage 1 GWAS. Ages: A.V.S. ARIC: N.F., D.B.H. B58C T1DGC: A.R.R., D.P.S. B58C WTCCC: A.R.R., D.P.S. CARDIA: X.G. CHS: S.A.G., G.L., S.R.H., T.L. CROATIA-Korcula: J.E.H. CROATIA-Vis: V.V. ECRHS: D.L.J., A.R. EPIC: J.H.Z. FHS: J.B.W., J.D., W.G. Health ABC: P.A.C., Y.L., K.L., W.T. Health 2000: M.K., S. Ripatti, I. Surakka. HCS: C.O., E.G.H. KORA S3: E.A. MESA-Lung: A.M., S.S.R. NFBC1966: A.C.A. NSPHS: S.E. ORCADES: P.K.J. RS I, II and III: L. Lahousse, D.W.L. SHIP: A.T. Twins UK-I: P.G.H. Stage 2 follow-up studies. KORA F4: C.F., R.H. LBC1936: L.M.L. LifeLines: K.d.J., H.M.B. LLFS: M. Wojczynski, B.T. PIVUS: T.F. Twins UK-II and III: P.G.H. Multi-ancestry follow-up studies. N.C.G. CARe: T.D.P., Q.D., L.A.L., X.-Q.W. KARE3 and Healthy Twin Study: M.K.L. Gene expression analyses. RT-PCR: K.R.B., F.M.V. eQTL analysis: M.J.P. Fetal lung expression analysis: I.P.H., I. Sayers, E.M.

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

Writing group: CHARGE Consortium: S.J.L., D.W.L., S.A.G., N.F., J.D., G.G.B., A.S. SpiroMeta Consortium: I.P.H., M.S.A., M.D.T., L.V.W., C.H.

Competing interests

J.B.W. is employed by Pfizer, Inc. None of the other authors have declared a possible conflict of interest.

Corresponding authors

Correspondence to Martin D Tobin or Stephanie J London.

Integrated supplementary information

Supplementary information

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    Supplementary Text and Figures

    Supplementary Figures 1–8, Supplementary Tables 1–12 and Supplementary Note

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    Supplementary Data Set 1

    SNPs, chromosome numbers, HapMap allele frequency for the reference allele and P value for the association with forced vital capacity in stage 1.

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https://doi.org/10.1038/ng.3011

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