Letter | Published:

Genetic loci associated with chronic obstructive pulmonary disease overlap with loci for lung function and pulmonary fibrosis

Nature Genetics volume 49, pages 426432 (2017) | Download Citation

Abstract

Chronic obstructive pulmonary disease (COPD) is a leading cause of mortality worldwide1. We performed a genetic association study in 15,256 cases and 47,936 controls, with replication of select top results (P < 5 × 10−6) in 9,498 cases and 9,748 controls. In the combined meta-analysis, we identified 22 loci associated at genome-wide significance, including 13 new associations with COPD. Nine of these 13 loci have been associated with lung function in general population samples2,3,4,5,6,7, while 4 (EEFSEC, DSP, MTCL1, and SFTPD) are new. We noted two loci shared with pulmonary fibrosis8,9 (FAM13A and DSP) but that had opposite risk alleles for COPD. None of our loci overlapped with genome-wide associations for asthma, although one locus has been implicated in joint susceptibility to asthma and obesity10. We also identified genetic correlation between COPD and asthma. Our findings highlight new loci associated with COPD, demonstrate the importance of specific loci associated with lung function to COPD, and identify potential regions of genetic overlap between COPD and other respiratory diseases.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

    et al. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. Am. J. Respir. Crit. Care Med. 187, 347–365 (2013).

  2. 2.

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

  3. 3.

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

  4. 4.

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

  5. 5.

    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).

  6. 6.

    et al. Sixteen new lung function signals identified through 1000 Genomes Project reference panel imputation. Nat. Commun. 6, 8658 (2015).

  7. 7.

    et al. Novel insights into the genetics of smoking behaviour, lung function, and chronic obstructive pulmonary disease (UK BiLEVE): a genetic association study in UK Biobank. Lancet Respir. Med. 3, 769–781 (2015).

  8. 8.

    et al. Genome-wide association study identifies multiple susceptibility loci for pulmonary fibrosis. Nat. Genet. 45, 613–620 (2013).

  9. 9.

    et al. Genome-wide imputation study identifies novel HLA locus for pulmonary fibrosis and potential role for auto-immunity in fibrotic idiopathic interstitial pneumonia. BMC Genet. 17, 74 (2016).

  10. 10.

    et al. A common 16p11.2 inversion underlies the joint susceptibility to asthma and obesity. Am. J. Hum. Genet. 94, 361–372 (2014).

  11. 11.

    & The electrophoretic α-1-globulin pattern of serum in α-1-antitrypsin deficiency. Scand. J. Clin. Lab. Invest. 15, 132–140 (1963).

  12. 12.

    et al. Genome-wide linkage analysis of severe, early-onset chronic obstructive pulmonary disease: airflow obstruction and chronic bronchitis phenotypes. Hum. Mol. Genet. 11, 623–632 (2002).

  13. 13.

    et al. Risk loci for chronic obstructive pulmonary disease: a genome-wide association study and meta-analysis. Lancet Respir. Med. 2, 214–225 (2014).

  14. 14.

    et al. Opportunities and challenges in the genetics of COPD 2010: an International COPD Genetics Conference report. COPD 8, 121–135 (2011).

  15. 15.

    & Global burden of COPD: risk factors, prevalence, and future trends. Lancet 370, 765–773 (2007).

  16. 16.

    et al. A genome-wide association study in chronic obstructive pulmonary disease (COPD): identification of two major susceptibility loci. PLoS Genet. 5, e1000421 (2009).

  17. 17.

    et al. Variants in FAM13A are associated with chronic obstructive pulmonary disease. Nat. Genet. 42, 200–202 (2010).

  18. 18.

    et al. A genome-wide association study of COPD identifies a susceptibility locus on chromosome 19q13. Hum. Mol. Genet. 21, 947–957 (2012).

  19. 19.

    et al. Exome array analysis identifies a common variant in IL27 associated with chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 194, 48–57 (2016).

  20. 20.

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

  21. 21.

    et al. Genome-wide association studies identify CHRNA5/3 and HTR4 in the development of airflow obstruction. Am. J. Respir. Crit. Care Med. 186, 622–632 (2012).

  22. 22.

    et al. Lung eQTLs to help reveal the molecular underpinnings of asthma. PLoS Genet. 8, e1003029 (2012).

  23. 23.

    et al. Bayesian test for colocalisation between pairs of genetic association studies using summary statistics. PLoS Genet. 10, e1004383 (2014).

  24. 24.

    , , , & Desmoplakin is essential in epidermal sheet formation. Nat. Cell Biol. 3, 1076–1085 (2001).

  25. 25.

    et al. The novel PAR-1-binding protein MTCL1 has crucial roles in organizing microtubules in polarizing epithelial cells. J. Cell Sci. 126, 4671–4683 (2013).

  26. 26.

    et al. MTCL1 crosslinks and stabilizes non-centrosomal microtubules on the Golgi membrane. Nat. Commun. 5, 5266 (2014).

  27. 27.

    et al. Tissue-based map of the human proteome. Science 347, 1260419 (2015).

  28. 28.

    & HaploReg: a resource for exploring chromatin states, conservation, and regulatory motif alterations within sets of genetically linked variants. Nucleic Acids Res. 40, D930–D934 (2012).

  29. 29.

    & HaploReg v4: systematic mining of putative causal variants, cell types, regulators and target genes for human complex traits and disease. Nucleic Acids Res. 44, D877–D881 (2016).

  30. 30.

    et al. The mitochondrial proteins NLRX1 and TUFM form a complex that regulates type I interferon and autophagy. Immunity 36, 933–946 (2012).

  31. 31.

    , & The NLR protein, NLRX1, and its partner, TUFM, reduce type I interferon, and enhance autophagy. Autophagy 9, 432–433 2013).

  32. 32.

    et al. Suppression of NLRX1 in chronic obstructive pulmonary disease. J. Clin. Invest. 125, 2458–2462 (2015).

  33. 33.

    et al. Increased metalloproteinase activity, oxidant production, and emphysema in surfactant protein D gene-inactivated mice. Proc. Natl. Acad. Sci. USA 97, 5972–5977 (2000).

  34. 34.

    et al. Serum surfactant protein D is steroid sensitive and associated with exacerbations of COPD. Eur. Respir. J. 34, 95–102 (2009).

  35. 35.

    et al. Polymorphisms in surfactant protein-D are associated with chronic obstructive pulmonary disease. Am. J. Respir. Cell Mol. Biol. 44, 316–322 (2011).

  36. 36.

    et al. Desmoplakin variants are associated with idiopathic pulmonary fibrosis. Am. J. Respir. Crit. Care Med. 193, 1151–1160 (2016).

  37. 37.

    et al. Detection and interpretation of shared genetic influences on 42 human traits. Nat. Genet. 48, 709–717 (2016).

  38. 38.

    et al. Lung volumes and emphysema in smokers with interstitial lung abnormalities. N. Engl. J. Med. 364, 897–906 (2011).

  39. 39.

    , & The pathogenesis of COPD and IPF: distinct horns of the same devil? Respir. Res. 13, 3 (2012).

  40. 40.

    et al. Telomerase mutations in smokers with severe emphysema. J. Clin. Invest. 125, 563–570 (2015).

  41. 41.

    et al. The proportional Venn diagram of obstructive lung disease: two approximations from the United States and the United Kingdom. Chest 124, 474–481 (2003).

  42. 42.

    et al. The NHGRI GWAS Catalog, a curated resource of SNP–trait associations. Nucleic Acids Res. 42, D1001–D1006 (2014).

  43. 43.

    et al. A large-scale, consortium-based genomewide association study of asthma. N. Engl. J. Med. 363, 1211–1221 (2010).

  44. 44.

    et al. Sequence variants at CHRNB3CHRNA6 and CYP2A6 affect smoking behavior. Nat. Genet. 42, 448–453 (2010).

  45. 45.

    Tobacco and Genetics Consortium. Genome-wide meta-analyses identify multiple loci associated with smoking behavior. Nat. Genet. 42, 441–447 (2010).

  46. 46.

    et al. Partitioning heritability by functional annotation using genome-wide association summary statistics. Nat. Genet. 47, 1228–1235 (2015).

  47. 47.

    et al. An atlas of genetic correlations across human diseases and traits. Nat. Genet. 47, 1236–1241 (2015).

  48. 48.

    et al. Loss-of-function mutations in the RNA biogenesis factor NAF1 predispose to pulmonary fibrosis–emphysema. Sci. Transl. Med. 8, 351ra107 (2016).

  49. 49.

    et al. Leveraging multi-ethnic evidence for mapping complex traits in minority populations: an empirical Bayes approach. Am. J. Hum. Genet. 96, 740–752 (2015).

  50. 50.

    et al. Large-scale association analysis identifies new risk loci for coronary artery disease. Nat. Genet. 45, 25–33 (2013).

  51. 51.

    et al. Defining the role of common variation in the genomic and biological architecture of adult human height. Nat. Genet. 46, 1173–1186 (2014).

  52. 52.

    et al. Genetic studies of body mass index yield new insights for obesity biology. Nature 518, 197–206 (2015).

  53. 53.

    et al. Whole-genome sequencing identifies EN1 as a determinant of bone density and fracture. Nature 526, 112–117 (2015).

  54. 54.

    et al. The association of genome-wide significant spirometric loci with chronic obstructive pulmonary disease susceptibility. Am. J. Respir. Cell Mol. Biol. 45, 1147–1153 (2011).

  55. 55.

    et al. Quality control and conduct of genome-wide association meta-analyses. Nat. Protoc. 9, 1192–1212 (2014).

  56. 56.

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

  57. 57.

    , , & GCTA: a tool for genome-wide complex trait analysis. Am. J. Hum. Genet. 88, 76–82 (2011).

  58. 58.

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

  59. 59.

    et al. Refining susceptibility loci of chronic obstructive pulmonary disease with lung eqtls. PLoS One 8, e70220 (2013).

  60. 60.

    et al. Molecular signature of smoking in human lung tissues. Cancer Res. 72, 3753–3763 (2012).

  61. 61.

    et al. Genetic regulation of gene expression in the lung identifies CST3 and CD22 as potential causal genes for airflow obstruction. Thorax 69, 997–1004 (2014).

  62. 62.

    , , & Ultrafast and memory-efficient alignment of short DNA sequences to the human genome. Genome Biol. 10, R25 (2009).

  63. 63.

    et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am. J. Hum. Genet. 81, 559–575 (2007).

  64. 64.

    et al. Second-generation PLINK: rising to the challenge of larger and richer datasets. Gigascience 4, 7 (2015).

  65. 65.

    R Core Team. R: A Language and Environment for Statistical Computing (R Foundation for Statistical Computing, 2016).

  66. 66.

    et al. The clinical and genetic features of COPD–asthma overlap syndrome. Eur. Respir. J. 44, 341–350 (2014).

  67. 67.

    Bayes factors for genome-wide association studies: comparison with P-values. Genet. Epidemiol. 33, 79–86 (2009).

  68. 68.

    Transethnic meta-analysis of genomewide association studies. Genet. Epidemiol. 35, 809–822 (2011).

  69. 69.

    & Leveraging functional-annotation data in trans-ethnic fine-mapping studies. Am. J. Hum. Genet. 97, 260–271 (2015).

  70. 70.

    , , , & Integrative tissue-specific functional annotations in the human genome provide novel insights on many complex traits and improve signal prioritization in genome wide association studies. PLoS Genet. 12, e1005947 (2016).

  71. 71.

    et al. Disentangling the effects of colocalizing genomic annotations to functionally prioritize non-coding variants within complex-trait loci. Am. J. Hum. Genet. 97, 139–152 (2015).

  72. 72.

    , & SNPsea: an algorithm to identify cell types, tissues and pathways affected by risk loci. Bioinformatics 30, 2496–2497 (2014).

  73. 73.

    et al. Selecting causal genes from genome-wide association studies via functionally coherent subnetworks. Nat. Methods 12, 154–159 (2015).

  74. 74.

    International HapMap Consortium. The International HapMap Project. Nature 426, 789–796 (2003).

  75. 75.

    et al. A genome-wide association study of emphysema and airway quantitative imaging phenotypes. Am. J. Respir. Crit. Care Med. 192, 559–569 (2015).

  76. 76.

    , , , & 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).

  77. 77.

    & KEGG: Kyoto encyclopedia of genes and genomes. Nucleic Acids Res. 28, 27–30 (2000).

  78. 78.

    Gene Ontology Consortium. Gene ontology: tool for the unification of biology. Nat. Genet. 25, 25–29 (2000).

  79. 79.

    Gene Ontology Consortium. Gene Ontology Consortium: going forward. Nucleic Acids Res. 43, D1049–D1056 (2015).

Download references

Acknowledgements

Please refer to the Supplementary Note for full acknowledgments.

Author information

Author notes

    • H Marike Boezen
    •  & Michael H Cho

    These authors jointly supervised this work.

Affiliations

  1. Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.

    • Brian D Hobbs
    • , Peter J Castaldi
    • , Robert P Chase
    • , Augusto A Litonjua
    • , Dandi Qiao
    • , Megan Hardin
    • , Edwin K Silverman
    •  & Michael H Cho
  2. Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.

    • Brian D Hobbs
    • , Augusto A Litonjua
    • , Megan Hardin
    • , Edwin K Silverman
    •  & Michael H Cho
  3. University of Groningen, University Medical Center Groningen, Department of Epidemiology, Groningen, the Netherlands.

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

    • Kim de Jong
    • , Judith M Vonk
    • , Dirkje S Postma
    •  & H Marike Boezen
  5. Institut Universitaire de Cardiologie et de Pneumologie de Québec, Québec, Québec, Canada.

    • Maxime Lamontagne
    •  & Yohan Bossé
  6. Department of Molecular Medicine, Laval University, Québec, Québec, Canada.

    • Yohan Bossé
  7. Genetic Epidemiology Group, Department of Health Sciences, University of Leicester, Leicester, UK.

    • Nick Shrine
    • , María Soler Artigas
    • , Louise V Wain
    • , Victoria E Jackson
    •  & Martin D Tobin
  8. Division of Respiratory Medicine, Queen's Medical Centre, University of Nottingham, Nottingham, UK.

    • Ian P Hall
  9. 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.

    • Annah B Wyss
    •  & Stephanie J London
  10. Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina, USA.

    • Kari E North
    •  & Nora Franceschini
  11. Population Health Research Institute, St George's, University of London, London, UK.

    • David P Strachan
  12. Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland, USA.

    • Terri H Beaty
  13. Department of Epidemiology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.

    • John E Hokanson
  14. Department of Medicine, Division of Pulmonary and Critical Care Medicine, National Jewish Health, Denver, Colorado, USA.

    • James D Crapo
  15. Division of General Internal Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.

    • Peter J Castaldi
  16. Cardiovascular Health Research Unit, University of Washington, Seattle, Washington, USA.

    • Traci M Bartz
    • , Susan R Heckbert
    •  & Bruce M Psaty
  17. Department of Medicine, University of Washington, Seattle, Washington, USA.

    • Traci M Bartz
    •  & Bruce M Psaty
  18. Department of Biostatistics, University of Washington, Seattle, Washington, USA.

    • Traci M Bartz
  19. Department of Epidemiology, University of Washington, Seattle, Washington, USA.

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

    • Susan R Heckbert
    •  & Bruce M Psaty
  21. Department of Health Services, University of Washington, Seattle, Washington, USA.

    • Bruce M Psaty
  22. Computational Medicine Core, Center for Lung Biology, UW Medicine Sleep Center, Department of Medicine, University of Washington, Seattle, Washington, USA.

    • Sina A Gharib
  23. Department of Pulmonology, University Medical Center Utrecht, University of Utrecht, Utrecht, the Netherlands.

    • Pieter Zanen
    •  & Jan W Lammers
  24. University of Groningen, University Medical Center Groningen, Center for Medical Imaging, Groningen, the Netherlands.

    • Matthijs Oudkerk
  25. University of Groningen, University Medical Center Groningen, Department of Pulmonology, Groningen, the Netherlands.

    • H J Groen
    •  & Dirkje S Postma
  26. GSK R&D, King of Prussia, Pennsylvania, USA.

    • Nicholas Locantore
    •  & Ruth Tal-Singer
  27. Pulmonary, Critical Care, Sleep and Allergy Division, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska, USA.

    • Stephen I Rennard
  28. Clinical Discovery Unit, AstraZeneca, Cambridge, UK.

    • Stephen I Rennard
    •  & Megan Hardin
  29. School of Biological Sciences, University of Manchester, Manchester, UK.

    • Jørgen Vestbo
  30. Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, GRIAC Research Institute, Groningen, the Netherlands.

    • Wim Timens
  31. University of British Columbia Center for Heart Lung Innovation and Institute for Heart and Lung Health, St Paul's Hospital, Vancouver, British Columbia, Canada.

    • Peter D Paré
  32. Department of Neurology, Boston University School of Medicine, Boston, Massachusetts, USA.

    • Jeanne C Latourelle
  33. Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, USA.

    • Josée Dupuis
  34. National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, Massachusetts, USA.

    • Josée Dupuis
    • , George T O'Connor
    •  & Jemma B Wilk
  35. Pulmonary Center, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, USA.

    • George T O'Connor
  36. Department of Internal Medicine and Environmental Health Center, School of Medicine, Kangwon National University, Chuncheon, Republic of Korea.

    • Woo Jin Kim
    •  & Mi Kyeong Lee
  37. Department of Pulmonary and Critical Care Medicine, and Clinical Research Center for Chronic Obstructive Airway Diseases, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.

    • Yeon-Mok Oh
  38. Department of Public Health, Erasmus Medical Center Rotterdam, Rotterdam, the Netherlands.

    • Harry J de Koning
  39. Lovelace Respiratory Research Institute, Albuquerque, New Mexico, USA.

    • Shuguang Leng
    • , Steven A Belinsky
    •  & Yohannes Tesfaigzi
  40. Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia, USA.

    • Ani Manichaikul
    •  & Stephen S Rich
  41. Department of Public Health Sciences, University of Virginia, Charlottesville, Virginia, USA.

    • Ani Manichaikul
    • , Xin-Qun Wang
    •  & Stephen S Rich
  42. Department of Medicine, College of Physicians and Surgeons and Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, New York, USA.

    • R Graham Barr
  43. VA Boston Healthcare System and Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, USA.

    • David Sparrow
  44. Department of Clinical Science, University of Bergen, Bergen, Norway.

    • Per Bakke
    •  & Amund Gulsvik
  45. Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands.

    • Lies Lahousse
    • , Guy G Brusselle
    • , Bruno H Stricker
    •  & André G Uitterlinden
  46. Department of Respiratory Medicine, Ghent University Hospital, Ghent, Belgium.

    • Lies Lahousse
    •  & Guy G Brusselle
  47. Department of Respiratory Medicine, Erasmus Medical Center, Rotterdam, the Netherlands.

    • Guy G Brusselle
  48. Netherlands Health Care Inspectorate, The Hague, the Netherlands.

    • Bruno H Stricker
  49. Department of Internal Medicine, Erasmus Medical Center, Rotterdam, the Netherlands.

    • Bruno H Stricker
    •  & André G Uitterlinden
  50. Netherlands Genomics Initiative (NGI)-sponsored Netherlands Consortium for Healthy Aging (NCHA), Leiden, the Netherlands.

    • Bruno H Stricker
    •  & André G Uitterlinden
  51. Center for Genomics and Personalized Medicine Research, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA.

    • Elizabeth J Ampleford
    • , Eugene R Bleecker
    •  & Deborah A Meyers
  52. Cardiovascular Research Institute and Department of Medicine, Division of Pulmonary, Critical Care, Sleep, and Allergy, University of California at San Francisco, San Francisco, California, USA.

    • Prescott G Woodruff
  53. University College London, London, UK.

    • David A Lomas
  54. Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea.

    • Jae-Joon Yim
  55. Seoul National University College of Medicine, SMG-SNU Boramae Medical Center, Seoul, Republic of Korea.

    • Deog Kyeom Kim
  56. 2nd Department of Respiratory Medicine, Institute of Tuberculosis and Lung Diseases, Warsaw, Poland.

    • Iwona Hawrylkiewicz
    •  & Pawel Sliwinski
  57. Center for Genes, Environment and Health, National Jewish Health, Denver, Colorado, USA.

    • Tasha E Fingerlin
    •  & David A Schwartz
  58. Department of Biostatistics and Informatics, University of Colorado Denver, Aurora, Colorado, USA.

    • Tasha E Fingerlin
  59. Department of Medicine, School of Medicine, University of Colorado Denver, Aurora, Colorado, USA.

    • David A Schwartz
  60. Department of Immunology, School of Medicine, University of Colorado Denver, Aurora, Colorado, USA.

    • David A Schwartz
  61. University of Edinburgh, Edinburgh, UK.

    • William MacNee
  62. National Institute for Health Research (NIHR) Leicester Respiratory Biomedical Research Unit, Glenfield Hospital, Leicester, UK.

    • Martin D Tobin

Consortia

  1. COPDGene Investigators

    A list of members and affiliations appears in the Supplementary Note.

  2. ECLIPSE Investigators

    A list of members and affiliations appears in the Supplementary Note.

  3. LifeLines Investigators

    A list of members and affiliations appears in the Supplementary Note.

  4. SPIROMICS Research Group

    A list of members and affiliations appears in the Supplementary Note.

  5. International COPD Genetics Network Investigators

    A list of members and affiliations appears in the Supplementary Note.

  6. UK BiLEVE Investigators

    A list of members and affiliations appears in the Supplementary Note.

  7. International COPD Genetics Consortium

    A list of members and affiliations appears in the Supplementary Note.

Authors

  1. Search for Brian D Hobbs in:

  2. Search for Kim de Jong in:

  3. Search for Maxime Lamontagne in:

  4. Search for Yohan Bossé in:

  5. Search for Nick Shrine in:

  6. Search for María Soler Artigas in:

  7. Search for Louise V Wain in:

  8. Search for Ian P Hall in:

  9. Search for Victoria E Jackson in:

  10. Search for Annah B Wyss in:

  11. Search for Stephanie J London in:

  12. Search for Kari E North in:

  13. Search for Nora Franceschini in:

  14. Search for David P Strachan in:

  15. Search for Terri H Beaty in:

  16. Search for John E Hokanson in:

  17. Search for James D Crapo in:

  18. Search for Peter J Castaldi in:

  19. Search for Robert P Chase in:

  20. Search for Traci M Bartz in:

  21. Search for Susan R Heckbert in:

  22. Search for Bruce M Psaty in:

  23. Search for Sina A Gharib in:

  24. Search for Pieter Zanen in:

  25. Search for Jan W Lammers in:

  26. Search for Matthijs Oudkerk in:

  27. Search for H J Groen in:

  28. Search for Nicholas Locantore in:

  29. Search for Ruth Tal-Singer in:

  30. Search for Stephen I Rennard in:

  31. Search for Jørgen Vestbo in:

  32. Search for Wim Timens in:

  33. Search for Peter D Paré in:

  34. Search for Jeanne C Latourelle in:

  35. Search for Josée Dupuis in:

  36. Search for George T O'Connor in:

  37. Search for Jemma B Wilk in:

  38. Search for Woo Jin Kim in:

  39. Search for Mi Kyeong Lee in:

  40. Search for Yeon-Mok Oh in:

  41. Search for Judith M Vonk in:

  42. Search for Harry J de Koning in:

  43. Search for Shuguang Leng in:

  44. Search for Steven A Belinsky in:

  45. Search for Yohannes Tesfaigzi in:

  46. Search for Ani Manichaikul in:

  47. Search for Xin-Qun Wang in:

  48. Search for Stephen S Rich in:

  49. Search for R Graham Barr in:

  50. Search for David Sparrow in:

  51. Search for Augusto A Litonjua in:

  52. Search for Per Bakke in:

  53. Search for Amund Gulsvik in:

  54. Search for Lies Lahousse in:

  55. Search for Guy G Brusselle in:

  56. Search for Bruno H Stricker in:

  57. Search for André G Uitterlinden in:

  58. Search for Elizabeth J Ampleford in:

  59. Search for Eugene R Bleecker in:

  60. Search for Prescott G Woodruff in:

  61. Search for Deborah A Meyers in:

  62. Search for Dandi Qiao in:

  63. Search for David A Lomas in:

  64. Search for Jae-Joon Yim in:

  65. Search for Deog Kyeom Kim in:

  66. Search for Iwona Hawrylkiewicz in:

  67. Search for Pawel Sliwinski in:

  68. Search for Megan Hardin in:

  69. Search for Tasha E Fingerlin in:

  70. Search for David A Schwartz in:

  71. Search for Dirkje S Postma in:

  72. Search for William MacNee in:

  73. Search for Martin D Tobin in:

  74. Search for Edwin K Silverman in:

  75. Search for H Marike Boezen in:

  76. Search for Michael H Cho in:

Contributions

B.D.H. and M.H.C. contributed to the study concept and design, data analysis, statistical support, and manuscript writing. K.d.J., A.B.W., S.J.L., and D.P.S. contributed to the study concept and design and to data analysis. N.S. and M.S.A. contributed to the data analysis and statistical support. T.H.B. and J.E.H. contributed to the study concept and design and to statistical support. L.L. contributed to the data collection, data analysis, and statistical support. K.E.N. contributed to data collection and data analysis. J.D.C., B.M.P., N.L., R.T.-S., G.T.O., Y.T., R.G.B., S.I.R., P.B., A.G., P.G.W., D.A.M., D.A.S., and E.K.S. contributed to the study concept and design and to data collection. D.Q., T.A.F., M.L., Y.B., N.S., N.F., P.J.C., R.P.C., T.M.B., S.A.G., J.C.L., J.D., J.B.W., M.K.L., S.L., A.M., X.-Q.W., and E.J.A. contributed to the data analysis. L.V.W., I.P.H., P.D.P., D.S.P., W.M., M.D.T., and H.M.B. contributed to the study concept and design. S.R.H., M.O., J.V., P.A.D., W.J.K., Y.-M.O., S.S.R., D.S., A.A.L., G.G.B., B.H.S., A.G.U., E.R.B., D.A.L., J.-J.Y., D.K.K., I.H., P.S., and M.H. contributed to the data collection. All authors, including those whose initials are not listed above, contributed to the critical review and editing of the manuscript and approved the final version of the manuscript.

Competing interests

I.P.H. has received grant support from Pfizer. P.J.C. has received research funding from GlaxoSmithKline. B.P. serves on the data and safety monitoring board (DSMB) of a clinical trial funded by the manufacturer and on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. N.L. and R.T.-S. are shareholders and employees of GlaxoSmithKline. S.I.R. is a current employee and shareholder at AstraZeneca. He has served as a consultant, participated on advisory boards, and received honoraria for speaking or grant support from the American Board of Internal Medicine, Advantage Healthcare, Almirall, the American Thoracic Society, AstraZeneca, Baxter, Boehringer Ingelheim, Chiesi, ClearView Healthcare, the Cleveland Clinic, Complete Medical Group, CSL, Dailchi Sankyo, Decision Resources, Forest, Gerson Lehman, Grifols, GroupH, Guidepoint Global, Haymarket, Huron Consulting, Inthought, Johnson & Johnson, Methodist Health System–Dallas, NCI Consulting, Novartis, Pearl, Penn Technology, Pfizer, PlanningShop, PSL FirstWord, Qwessential, Takeda, Theron, and WebMD. W.T. reports fees to the Department, all outside the submitted work, from Pfizer, GSK, Chiesi, Roche Diagnostics/Ventana, Biotest, Merck Sharp Dohme, Novartis, Lilly Oncology, Boehringer Ingelheim, and grants from Dutch Asthma Fund. J.C.L. is currently an employee of GNS Healthcare. J.B.W. was employed by Pfizer during the time this research was performed. P.B. has received consulting and lecture fees from AstraZeneca, Boehringer Ingelheim, Chiesi, Novartis, and Teva. L.L. has performed consultancy for Boehringer Ingelheim and has received an AstraZeneca Scientific Award and travel support from Novartis, the European Respiratory Society, and the Belgian Respiratory Society. P.G.W. has consulted for Amgen, Sanofi, Novartis, Genentech/Roche, Boehringer Ingelheim, and Neostem and has had research grants from Pfizer and Genentech. D.L. received grant support, honoraria, and consultancy fees from GlaxoSmithKline for work on the ICGN and ECLIPSE studies and was a member of and chaired the GSK Respiratory Therapy Area Board (2009–2015). M.H. is a current employee of AstraZeneca. D.A.S. is serving on the scientific advisory boards of Apellis Pharmaceuticals and Pliant Therapeutics, and is the founder and owner of Eleven P15. The University of Groningen has received money for D.S.P. with regard to a grant for research from AstraZeneca, Chiesi, Genentec, GlaxoSmithKline, and Roche. Fees for consultancies were given to the University of Groningen by AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Takeda, and TEVA. E.K.S. has received honoraria and consulting fees from Merck, grant support and consulting fees from GlaxoSmithKline, and honoraria and travel support from Novartis. M.H.C. has received grant support from GlaxoSmithKline.

Corresponding author

Correspondence to Michael H Cho.

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1–6, Supplementary Tables 1, 2, 4–7, 9–13 and 15–20, and Supplementary Note

Excel files

  1. 1.

    Supplementary Table 3

    Full results table for all 79 variants submitted for testing in UK BiLEVE stage 2 analysis.

  2. 2.

    Supplementary Table 8

    Full results (P < 0.05 in meta-analysis) for lung expression quantitative trait locus (eQTL) analysis.

  3. 3.

    Supplementary Table 14

    Lookup of NHGRI-EBI GWAS Catalog asthma-associated trait genome-wide significant GWAS loci in our COPD association stage 1 meta-analysis results.

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/ng.3752

Further reading