Article | Published:

Genome-wide association analyses for lung function and chronic obstructive pulmonary disease identify new loci and potential druggable targets

Nature Genetics volume 49, pages 416425 (2017) | Download Citation

Abstract

Chronic obstructive pulmonary disease (COPD) is characterized by reduced lung function and is the third leading cause of death globally. Through genome-wide association discovery in 48,943 individuals, selected from extremes of the lung function distribution in UK Biobank, and follow-up in 95,375 individuals, we increased the yield of independent signals for lung function from 54 to 97. A genetic risk score was associated with COPD susceptibility (odds ratio per 1 s.d. of the risk score (6 alleles) (95% confidence interval) = 1.24 (1.20–1.27), P = 5.05 × 10−49), and we observed a 3.7-fold difference in COPD risk between individuals in the highest and lowest genetic risk score deciles in UK Biobank. The 97 signals show enrichment in genes for development, elastic fibers and epigenetic regulation pathways. We highlight targets for drugs and compounds in development for COPD and asthma (genes in the inositol phosphate metabolism pathway and CHRM3) and describe targets for potential drug repositioning from other clinical indications.

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Acknowledgements

This work was funded by a Medical Research Council (MRC) strategic award to M.D.T., I.P.H., D.S. and L.V.W. (MC_PC_12010). This research has been conducted using the UK Biobank Resource under application 648. This article presents independent research funded partially by the National Institute for Health Research (NIHR). The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the UK Department of Health. This research used the ALICE and SPECTRE High-Performance Computing Facilities at the University of Leicester. Additional acknowledgments and funding details can be found in the Supplementary Note.

Author information

Affiliations

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

    • Louise V Wain
    • , Nick Shrine
    • , María Soler Artigas
    • , A Mesut Erzurumluoglu
    • , Boris Noyvert
    • , Catherine John
    • , Tineka Blake
    • , Victoria E Jackson
    • , Richard J Allen
    •  & Martin D Tobin
  2. National Institute for Health Research, Leicester Respiratory Biomedical Research Unit, Glenfield Hospital, Leicester, UK.

    • Louise V Wain
    • , Chris Brightling
    •  & Martin D Tobin
  3. Wellcome Trust Sanger Institute, Hinxton, UK.

    • Lara Bossini-Castillo
    •  & Gosia Trynka
  4. University of British Columbia Centre for Heart Lung Innovation, St Paul's Hospital, Vancouver, British Columbia, Canada.

    • Ma'en Obeidat
    • , Peter D Paré
    •  & Don D Sin
  5. Division of Respiratory Medicine, University of Nottingham, Nottingham, UK.

    • Amanda P Henry
    • , Michael A Portelli
    • , Robert J Hall
    • , Charlotte K Billington
    • , Tracy L Rimington
    • , Ian Sayers
    •  & Ian P Hall
  6. Department of Clinical Pharmacology and Therapeutics, University of Malta, Msida, Malta.

    • Anthony G Fenech
  7. Department of Human Genetics, Wellcome Trust Sanger Institute, Hinxton, UK.

    • Bram P Prins
    •  & Eleftheria Zeggini
  8. Medical Genetics Section, Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.

    • Archie Campbell
    • , David J Porteous
    •  & Sarah E Harris
  9. Generation Scotland, Centre for Genomic and Experimental Medicine, University of Edinburgh, Edinburgh, UK.

    • Archie Campbell
    •  & David J Porteous
  10. Department of Epidemiology and Biostatistics, MRC–PHE Centre for Environment and Health, School of Public Health, Imperial College London, London, UK.

    • Marjo-Riitta Jarvelin
    •  & Matthias Wielscher
  11. Faculty of Medicine, Center for Life Course Health Research, University of Oulu, Oulu, Finland.

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

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

    • Marjo-Riitta Jarvelin
  14. Busselton Population Medical Research Institute, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia.

    • Alan L James
    •  & Jennie Hui
  15. Department of Pulmonary Physiology and Sleep Medicine, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia.

    • Alan L James
  16. School of Medicine and Pharmacology, University of Western Australia, Crawley, Western Australia, Australia.

    • Alan L James
  17. School of Population Health, University of Western Australia, Crawley, Western Australia, Australia.

    • Jennie Hui
  18. PathWest Laboratory Medicine of Western Australia, Sir Charles Gairdner Hospital, Crawley, Western Australia, Australia.

    • Jennie Hui
  19. School of Pathology and Laboratory Medicine, University of Western Australia, Crawley, Western Australia, Australia.

    • Jennie Hui
  20. MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Institute of Metabolic Science, Cambridge Biomedical Campus, Cambridge, UK.

    • Nicholas J Wareham
    •  & Jing Hua Zhao
  21. Centre for Global Health Research, Usher Institute for Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, UK.

    • James F Wilson
    • , Peter K Joshi
    • , Igor Rudan
    •  & Ozren Polasek
  22. Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.

    • James F Wilson
    • , Jonathan Marten
    • , Shona M Kerr
    • , Veronique Vitart
    •  & Caroline Hayward
  23. Department of Internal Medicine B–Cardiology, Intensive Care, Pulmonary Medicine and Infectious Diseases, University Medicine Greifswald, Greifswald, Germany.

    • Beate Stubbe
  24. Research Unit of Molecular Epidemiology, Institute of Epidemiology II, Helmholtz Zentrum München–German Research Center for Environmental Health, Neuherberg, Germany.

    • Rajesh Rawal
    •  & Christian Gieger
  25. Institute of Epidemiology I, Helmholtz Zentrum München–German Research Center for Environmental Health, Neuherberg, Germany.

    • Holger Schulz
    •  & Stefan Karrasch
  26. Comprehensive Pneumology Center Munich (CPC-M), Member of the German Center for Lung Research, Neuherberg, Germany.

    • Holger Schulz
  27. Swiss Tropical and Public Health Institute, Basel, Switzerland.

    • Medea Imboden
    •  & Nicole M Probst-Hensch
  28. University of Basel, Basel, Switzerland.

    • Medea Imboden
    •  & Nicole M Probst-Hensch
  29. Institute and Outpatient Clinic for Occupational, Social and Environmental Medicine, Ludwig-Maximilians-Universität, Munich, Germany.

    • Stefan Karrasch
  30. Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK.

    • Ian J Deary
    •  & Sarah E Harris
  31. Department of Psychology, University of Edinburgh, Edinburgh, UK.

    • Ian J Deary
  32. Department of Immunology, Genetics and Pathology, Uppsala Universitet, Science for Life Laboratory, Uppsala, Sweden.

    • Stefan Enroth
    •  & Ulf Gyllensten
  33. University of Split School of Medicine, Split, Croatia.

    • Ozren Polasek
  34. Department of Clinical Physiology, University of Tampere and Tampere University Hospital, Tampere, Finland.

    • Mika Kähönen
  35. Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.

    • Ida Surakka
  36. National Institute for Health and Welfare (THL), Helsinki, Finland.

    • Ida Surakka
  37. Department of Clinical Chemistry, Fimlab Laboratories and School of Medicine University of Tampere, Tampere, Finland.

    • Terho Lehtimäki
  38. Department of Clinical Chemistry, University of Tampere School of Medicine, Tampere, Finland.

    • Terho Lehtimäki
  39. Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland.

    • Olli T Raitakari
  40. Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland.

    • Olli T Raitakari
  41. University of Queensland Diamantina Institute, Translational Research Institute, University of Queensland, Brisbane, Queensland, Australia.

    • David M Evans
  42. MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.

    • David M Evans
  43. School of Social and Community Medicine, University of Bristol, Bristol, UK.

    • A John Henderson
  44. School of Women's and Infants' Health, University of Western Australia, Perth, Western Australia, Australia.

    • Craig E Pennell
    •  & Carol A Wang
  45. Child Health Research Centre, Faculty of Medicine, University of Queensland, Brisbane, Queensland, Australia.

    • Peter D Sly
  46. Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.

    • Emily S Wan
    • , Robert Busch
    • , Brian D Hobbs
    • , Augusto A Litonjua
    • , Michael H Cho
    •  & Edwin K Silverman
  47. Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.

    • Emily S Wan
    • , Robert Busch
    • , Brian D Hobbs
    • , Augusto A Litonjua
    • , Michael H Cho
    •  & Edwin K Silverman
  48. VA Boston Healthcare System, Boston, Massachusetts, USA.

    • David W Sparrow
  49. Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, USA.

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

    • Amund Gulsvik
    •  & Per S Bakke
  51. National Jewish Health, Denver, Colorado, USA.

    • James D Crapo
  52. Division of Pulmonary, Critical Care and Sleep Medicine, National Jewish Health, Denver, Colorado, USA.

    • James D Crapo
  53. Department of Epidemiology, Johns Hopkins University School of Public Health, Baltimore, Maryland, USA.

    • Terri H Beaty
  54. Pulmonary and Critical Care Medicine, School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA.

    • Nadia N Hansel
  55. Division of Allergy and Clinical Immunology, School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA.

    • Rasika A Mathias
  56. Department of Biostatistics, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, USA.

    • Ingo Ruczinski
  57. Division of Biomedical Informatics and Personalized Medicine, Department of Medicine, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, Colorado, USA.

    • Kathleen C Barnes
  58. Department of Molecular Medicine, Laval University, Quebec City, Quebec, Canada.

    • Yohan Bossé
  59. Institut Universitaire de Cardiologie et de Pneumologie de Québec, Laval University, Quebec City, Quebec, Canada.

    • Yohan Bossé
    •  & Philippe Joubert
  60. Department of Molecular Biology, Medical Biochemistry and Pathology, Laval University, Quebec City, Quebec, Canada.

    • Philippe Joubert
  61. University of Groningen, University Medical Center Groningen, Department of Pulmonology, GRIAC Research Institute, Groningen, the Netherlands.

    • Maarten van den Berge
  62. University of Groningen, University Medical Center Groningen, Department of Pathology and Medical Biology, GRIAC Research Institute, Groningen, the Netherlands.

    • Corry-Anke Brandsma
  63. Respiratory Division, Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada.

    • Peter D Paré
    •  & Don D Sin
  64. Merck Research Laboratories, Genetics and Pharmacogenomics, Boston, Massachusetts, USA.

    • David C Nickle
  65. Icahn Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

    • Ke Hao
  66. Regeneron Genetics Center, Regeneron Pharmaceuticals, Tarrytown, New York, USA.

    • Omri Gottesman
    • , Frederick E Dewey
    •  & Shannon E Bruse
  67. Geisinger Health System, Danville, Pennsylvania, USA.

    • David J Carey
    •  & H Lester Kirchner
  68. deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.

    • Stefan Jonsson
    • , Gudmar Thorleifsson
    • , Ingileif Jonsdottir
    •  & Kari Stefansson
  69. Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland.

    • Ingileif Jonsdottir
    • , Thorarinn Gislason
    •  & Kari Stefansson
  70. Department of Respiratory Medicine and Sleep, Landspitali University Hospital Reykjavik, Reykjavik, Iceland.

    • Thorarinn Gislason
  71. Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

    • Claudia Schurmann
    • , Girish Nadkarni
    • , Erwin P Bottinger
    •  & Ruth J F Loos
  72. Genetics of Obesity and Related Metabolic Traits Program, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

    • Claudia Schurmann
    •  & Ruth J F Loos
  73. Mindich Child Health Development Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

    • Ruth J F Loos
  74. Clinical Trial Service Unit and Epidemiological Studies Unit (CTSU), Nuffield Department of Population Health, University of Oxford, Oxford, UK.

    • Robin G Walters
    • , Zhengming Chen
    • , Iona Y Millwood
    • , Julien Vaucher
    •  & Om P Kurmi
  75. Medical Research Council Population Health Research Unit at the University of Oxford, Oxford, UK.

    • Iona Y Millwood
  76. Chinese Academy of Medical Sciences, Beijing, China.

    • Liming Li
  77. Department of Epidemiology and Biostatistics, Peking University Health Science Centre, Peking University, Beijing, China.

    • Liming Li
  78. UK Small Area Health Statistics Unit, MRC–PHE Centre for Environment and Health, School of Public Health, Imperial College London, London, UK.

    • Anna L Hansell
  79. Imperial College Healthcare NHS Trust, St Mary's Hospital, Paddington, London, UK.

    • Anna L Hansell
  80. Department of Infection, Inflammation and Immunity, Institute for Lung Health, University of Leicester, Leicester, UK.

    • Chris Brightling
  81. Department of Biostatistics, University of Liverpool, Liverpool, UK.

    • Andrew P Morris
  82. Population Health Research Institute, St George's, University of London, London, UK.

    • David P Strachan

Consortia

  1. Understanding Society Scientific Group

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

  2. Geisinger-Regeneron DiscovEHR Collaboration

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

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  97. Search for Chris Brightling in:

  98. Search for Eleftheria Zeggini in:

  99. Search for Michael H Cho in:

  100. Search for Edwin K Silverman in:

  101. Search for Ian Sayers in:

  102. Search for Gosia Trynka in:

  103. Search for Andrew P Morris in:

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Contributions

L.V.W., D.J.P., M.-R.J., A.L.J., N.J.W., J.F.W., B.S., H.S., N.M.P.-H., S.K., C.G., I.J.D., I. Rudan, S.M.K., O.P., M.K., C.H., T.L., O.T.R., A.J.H., C.E.P., P.D.S., A.G., P.S.B., J.D.C., T.H.B., N.N.H., R.A.M., I. Ruczinski, K.C.B., Y.B., P.J., P.D.P., D.D.S., K.H., E.P.B., R.J.F.L., R.G.W., Z.C., I.Y.M., L.L., E.Z., I. Sayers, D.P.S., I.P.H., U.G. and M.D.T. contributed to the conception and study design. L.V.W., N.S., M.S., A.M.E., B.N., L.B.-C., M.O., A.P.H., M.A.P., R.J.H., C.K.B., T.L.R., A.G.F., C.J., T.B., V.E.J., R.J.A., B.P.P., A.C., M.W., J.H., J.Z., P.K.J., B.S., R.R., M.I., N.M.P.-H., S.E.H., J.M., S.E., I. Surakka, V.V., C.H., T.L., D.M.E., C.A.W., E.S.W., R.B., B.D.H., A.A.L., D.W.S., M.v.d.B., C.-A.B., D.C.N., O.G., F.E.D., S.E.B., D.J.C., H.L.K., S.J., G. Thorleifsson, I.J., T.G., K.S., C.S., G.N., R.G.W., J.V., O.P.K., M.H.C., E.K.S., G. Trynka, J.H.Z. and D.P.S. contributed to data analysis. L.V.W., N.S., M.S., A.M.E., B.N., M.O., A.P.H., M.A.P., R.J.H., C.K.B., T.L.R., A.G.F., C.J., V.E.J., A.C., M.-R.J., B.S., R.R., H.S., M.I., N.M.P.-H., S.K., C.G., C.H., A.G., C.S., G.N., R.J.F.L., A.L.H., C.B., I. Sayers, A.P.M., D.P.S., I.P.H. and M.D.T. contributed to data interpretation.

Competing interests

F.E.D. and S.E.B. are employed by Regeneron Pharmaceuticals. D.C.N. is employed by Merck. In the past three years, E.K.S. received honoraria and consulting fees from Merck, grant support and consulting fees from GlaxoSmithKline, and honoraria and travel support from Novartis. S.J., G. Thorleifsson, I.J. and K.S. are employed by deCODE Genetics/Amgen. M.H.C. receives grant funding from GlaxoSmithKline.

Corresponding authors

Correspondence to Louise V Wain or Ian P Hall or Martin D Tobin.

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DOI

https://doi.org/10.1038/ng.3787

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