Article | Published:

New genetic signals for lung function highlight pathways and chronic obstructive pulmonary disease associations across multiple ancestries

Nature Geneticsvolume 51pages481493 (2019) | Download Citation

Abstract

Reduced lung function predicts mortality and is key to the diagnosis of chronic obstructive pulmonary disease (COPD). In a genome-wide association study in 400,102 individuals of European ancestry, we define 279 lung function signals, 139 of which are new. In combination, these variants strongly predict COPD in independent populations. Furthermore, the combined effect of these variants showed generalizability across smokers and never smokers, and across ancestral groups. We highlight biological pathways, known and potential drug targets for COPD and, in phenome-wide association studies, autoimmune-related and other pleiotropic effects of lung function–associated variants. This new genetic evidence has potential to improve future preventive and therapeutic strategies for COPD.

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Data availability

SpiroMeta GWAS summary statistics and UK Biobank GWAS summary statistics are available online via LD-Hub (http://ldsc.broadinstitute.org/ldhub/). Single-variant PheWAS results are available by request to the corresponding authors. The newly derived spirometry variables are available from UK Biobank (http://www.ukbiobank.ac.uk/).

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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Acknowledgements

This research has been conducted using the UK Biobank Resource under applications 648, 4892 and 26041. L. Wain holds a GSK/British Lung Foundation Chair in Respiratory Research. M. Tobin is supported by a Wellcome Trust Investigator Award (WT202849/Z/16/Z). M. Tobin and L. Wain have been supported by the Medical Research Council (MRC) (MR/N011317/1). The research was partially supported by the National Institute for Health Research (NIHR) Leicester Biomedical Research Centre; the views expressed are those of the author(s) and not necessarily those of the National Health Service (NHS), the NIHR or the Department of Health. I.H. was partially supported by the NIHR Nottingham Biomedical Research Centre; the views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. This research used the ALICE and SPECTRE High Performance Computing Facilities at the University of Leicester. Additional acknowledgments and funding details for other co-authors and contributing studies (including the SpiroMeta consortium) are in the Supplementary Note.

Author information

Author notes

  1. These authors contributed equally: N. Shrine, A. L. Guyatt, A. M. Erzurumluoglu, I. P. Hall, M. D. Tobin, L. V. Wain.

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

Affiliations

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

    • Nick Shrine
    • , Anna L. Guyatt
    • , A. Mesut Erzurumluoglu
    • , Victoria E. Jackson
    • , Carl A. Melbourne
    • , Chiara Batini
    • , Katherine A. Fawcett
    • , Nicola F. Reeve
    • , Richard J. Allen
    • , Frank Dudbridge
    • , Richard Packer
    • , Megan L. Paynton
    • , Martin D. Tobin
    •  & Louise V. Wain
  2. Population Health and Immunity Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia

    • Victoria E. Jackson
  3. Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia

    • Victoria E. Jackson
  4. Channing Division of Network Medicine, Brigham and Women’s Hospital, Boston, MA, USA

    • Brian D. Hobbs
    • , Phuwanat Sakornsakolpat
    • , Dawn L. DeMeo
    • , Margaret M. Parker
    • , Dmitry Prokopenko
    • , Dandi Qiao
    • , Edwin K. Silverman
    •  & Michael H. Cho
  5. Division of Pulmonary and Critical Care Medicine, Brigham and Women’s Hospital, Boston, MA, USA

    • Brian D. Hobbs
    • , Dawn L. DeMeo
    • , Edwin K. Silverman
    •  & Michael H. Cho
  6. Target Sciences, GlaxoSmithKline, Collegeville, PA, USA

    • Kijoung Song
    • , Joshua D. Hoffman
    •  & Laura M. Yerges-Armstrong
  7. Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand

    • Phuwanat Sakornsakolpat
  8. Division of Genetics, Genomics and Precision Medicine, Department of Medicine, University of Arizona, Tucson, AZ, USA

    • Xingnan Li
    • , Eugene R. Bleecker
    •  & Deborah A. Meyers
  9. Nuffield Department of Population Health, University of Oxford, Oxford, UK

    • Ruth Boxall
    • , Zhengming Chen
    • , Kuang Lin
    •  & Robin G. Walters
  10. Medical Research Council Population Health Research Unit, University of Oxford, Oxford, UK

    • Ruth Boxall
  11. The University of British Columbia Centre for Heart Lung Innovation, St Paul’s Hospital, Vancouver, British Columbia, Canada

    • Ma’en Obeidat
    • , Xuan Li
    •  & Don D Sin
  12. Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK

    • Jing Hua Zhao
  13. Department of Epidemiology and Biostatistics, MRC-PHE Centre for Environment & Health, School of Public Health, Imperial College London, London, UK

    • Matthias Wielscher
    •  & Marjo-Riitta Jarvelin
  14. Interfaculty Institute for Genetics and Functional Genomics, Department of Functional Genomics, University Medicine Greifswald, Greifswald, Germany

    • Stefan Weiss
    •  & Georg Homuth
  15. Centre for Global Health Research, Usher Institute for Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, UK

    • Katherine A. Kentistou
    • , Peter K. Joshi
    • , Paul R. H. J. Timmers
    • , Ozren Polašek
    • , Igor Rudan
    •  & James F. Wilson
  16. Centre for Cardiovascular Sciences, Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, UK

    • Katherine A. Kentistou
  17. Department of Biostatistics, University of Liverpool, Liverpool, UK

    • James P. Cook
    •  & Andrew P. Morris
  18. MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK

    • Benjamin B. Sun
    • , John Danesh
    •  & Adam S. Butterworth
  19. Flatiron Institute, Simons Foundation, New York, NY, USA

    • Jian Zhou
  20. Busselton Population Medical Research Institute, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia

    • Jennie Hui
    •  & Alan L James
  21. School of Population Health, The University of Western Australia, Crawley, Western Australia, Australia

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

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

    • Jennie Hui
  24. Institute of Epidemiology, Helmholtz Zentrum Muenchen—German Research Center for Environmental Health, Neuherberg, Germany

    • Stefan Karrasch
    •  & Holger Schulz
  25. Institute and Outpatient Clinic for Occupational, Social and Environmental Medicine, Ludwig-Maximilians-Universität, Munich, Germany

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

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

    • Sarah E Harris
    • , David J. Porteous
    •  & Ian J. Deary
  30. Centre for Genomic and Experimental Medicine, Institute of Genetics & Molecular Medicine, University of Edinburgh, Edinburgh, UK

    • Sarah E Harris
    •  & David J. Porteous
  31. Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK

    • Jonathan Marten
    • , Shona M. Kerr
    • , Veronique Vitart
    • , James F. Wilson
    •  & Caroline Hayward
  32. Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala Universitet, Uppsala, Sweden

    • Stefan Enroth
    •  & Ulf Gyllensten
  33. Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland

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

    • Ida Surakka
  35. Department of Clinical Chemistry, Fimlab Laboratories, and Finnish Cardiovascular Research Center - Tampere, Faculty of Medicine and Life Sciences, University of Tampere, Tampere, Finland

    • Terho Lehtimäki
  36. Department of Clinical Science, University of Bergen, Bergen, Norway

    • Per S. Bakke
    •  & Amund Gulsvik
  37. Department of Epidemiology, Johns Hopkins University School of Public Health, Baltimore, MD, USA

    • Terri H. Beaty
  38. Department of Molecular Medicine, Laval University, Québec, Canada

    • Yohan Bossé
  39. Institut Universitaire de Cardiologie et de Pneumologie de Québec, Laval University, Québec, Canada

    • Yohan Bossé
    •  & Philippe Joubert
  40. University of Groningen, University Medical Center Groningen, Department of Pathology and Medical Biology, GRIAC Research Institute, University of Groningen, Groningen, The Netherlands

    • Corry-Anke Brandsma
  41. National Jewish Health, Denver, CO, USA

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

    • James D. Crapo
  43. British Heart Foundation Cambridge Centre of Excellence, Division of Cardiovascular Medicine, Addenbrooke’s Hospital, Cambridge, UK

    • John Danesh
  44. Department of Human Genetics, Wellcome Trust Sanger Institute, Cambridge, UK

    • John Danesh
  45. NIHR Blood and Transplant Research Unit in Donor Health and Genomics, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK

    • John Danesh
    •  & Adam S. Butterworth
  46. Department of Internal Medicine B - Cardiology, Intensive Care, Pulmonary Medicine and Infectious Diseases, University Medicine Greifswald, Greifswald, Germany

    • Ralf Ewert
    •  & Beate Stubbe
  47. Research Unit of Molecular Epidemiology, Institute of Epidemiology, Helmholtz Zentrum Muenchen – German Research Center for Environmental Health, Neuherberg, Germany

    • Christian Gieger
    •  & Rajesh Rawal
  48. Centre for Environmental Health & Sustainability, University of Leicester, Leicester, UK

    • Anna L. Hansell
  49. 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
  50. Imperial College Healthcare NHS Trust, St Mary’s Hospital, London, UK

    • Anna L. Hansell
  51. Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    • Ke Hao
  52. Department of Epidemiology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA

    • John E. Hokanson
  53. Department of Molecular Biology, Medical Biochemistry, and Pathology, Laval University, Québec, Canada

    • Philippe Joubert
  54. MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Cambridge, UK

    • Claudia Langenberg
    • , Jian’an Luan
    •  & Nick Wareham
  55. Department of Epidemiology & Biostatistics, Peking University Health Science Center, Beijing, China

    • Liming Li
  56. Department of Medical Sciences, Cardiovascular Epidemiology, Uppsala University, Uppsala, Sweden

    • Lars Lind
  57. GSK R&D, Collegeville, PA, USA

    • Nicholas Locantore
    •  & Ruth Tal-Singer
  58. Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK

    • Anubha Mahajan
    •  & Andrew P. Morris
  59. MRL, Merck & Co., Inc, Kenilworth, NJ, USA

    • Joseph C. Maranville
    • , David C. Nickle
    •  & Heiko Runz
  60. The Institute of Medical Sciences, Aberdeen Biomedical Imaging Centre, University of Aberdeen, Aberdeen, UK

    • Alison Murray
  61. Gossamer Bio, San Diego, CA, USA

    • David C. Nickle
  62. Institute of Epidemiology and Social Medicine, University of Münster, Münster, Germany

    • Rajesh Rawal
  63. Division of Respiratory Medicine and NIHR-Nottingham Biomedical Research Centre, University of Nottingham, Nottingham, UK

    • Ian Sayers
    •  & Ian P. Hall
  64. Respiratory Division, Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada

    • Don D Sin
  65. Division of Population Health and Genomics, Ninewells Hospital and Medical School, University of Dundee, Dundee, UK

    • Blair H Smith
  66. Psychiatric Genetics Unit, Group of Psychiatry, Mental Health and Addiction, Vall d’Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain

    • María Soler Artigas
  67. Department of Psychiatry, Hospital Universitari Vall d’Hebron, Barcelona, Spain

    • María Soler Artigas
  68. Biomedical Network Research Centre on Mental Health (CIBERSAM), Instituto de Salud Carlos III, Barcelona, Spain

    • María Soler Artigas
  69. VA Boston Healthcare System, Boston, MA, USA

    • David Sparrow
  70. Department of Medicine, Boston University School of Medicine, Boston, MA, USA

    • David Sparrow
  71. University of Groningen, University Medical Center Groningen, Department of Pulmonology, GRIAC Research Institute, University of Groningen, Groningen, The Netherlands

    • Maarten Van den Berge
  72. Target Sciences - R&D, GSK Medicines Research Centre, Stevenage, UK

    • John C. Whittaker
    •  & Robert A. Scott
  73. UCSF Pulmonary, Critical Care, Allergy and Sleep Medicine, University of California, San Francisco, CA, USA

    • Prescott G. Woodruff
  74. Department of Computer Science, Princeton University, Princeton, NJ, USA

    • Olga G. Troyanskaya
  75. Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ, USA

    • Olga G. Troyanskaya
  76. Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland

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

    • Olli T. Raitakari
  78. Department of Clinical Physiology, Tampere University Hospital, and Finnish Cardiovascular Research Center - Tampere, Faculty of Medicine and Life Sciences, University of Tampere, Tampere, Finland

    • Mika Kähönen
  79. University of Split School of Medicine, Split, Croatia

    • Ozren Polašek
  80. Department of Psychology, University of Edinburgh, Edinburgh, UK

    • Ian J. Deary
  81. Department of Pulmonary Physiology and Sleep Medicine, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia

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

    • Alan L James
  83. Wellcome Sanger Institute, Hinxton, UK

    • Eleftheria Zeggini
  84. Institute of Translational Genomics, Helmholtz Zentrum Muenchen – German Research Center for Environmental Health, Neuherberg, Germany

    • Eleftheria Zeggini
  85. Center for Life Course Health Research, Faculty of Medicine, University of Oulu, Oulu, Finland

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

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

    • Marjo-Riitta Jarvelin
  88. Department of Life Sciences, College of Health and Life Sciences, Brunel University London, Uxbridge, UK

    • Marjo-Riitta Jarvelin
  89. Population Health Research Institute, St George’s, University of London, London, UK

    • David P. Strachan
  90. National Institute for Health Research, Leicester Respiratory Biomedical Research Centre, Glenfield Hospital, Leicester, UK

    • Martin D. Tobin
    •  & Louise V. Wain

Authors

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Consortia

  1. Understanding Society Scientific Group

    Contributions

    All authors critically reviewed the manuscript before submission. K.S., U.S.S.G., S.K., S.M.K., T.L., P.S.B., T.H.B., E.R.B., Y.B., Z.C., J.D.C., J.D., D.L.D., C.G., A.G., K.H., J.D.H., J.E.H., P.J., C.L., L.Li, N.L., J.C.M., H.R., I.Sayers, D.D.S., R.T-S., J.C.W., P.G.W., L.M.Y., O.T.R., M.K., O.P., U.G., I.R., I.J.D., N.M.P., H.S., A.L.J., J.F.W., E.Z., M.J., N.W., A.S.B., R.A.S., D.A.M., M.H.C., D.P.S., I.P.H., M.D.T. and L.V.W. contributed to the conception and design of the study. N.S., A.L.G., A.M.E., V.E.J., B.D.H., C.A.M., C.Batini, K.A.F., K.S., P.S., Xingnan Li, R.B., N.F.R., M.O., J.Zhao, M.W., S.W., K.A.K., J.P.C., B.B.S., J.Zhou, J.H., M.I., S.E.H., J.M., S.E., I.Surakka, V.V., T.L., R.J.A., F.D., J.D.H., P.K.J., Xuan Li, A.Mahajan, J.C.M., D.C.N., M.M.P., D.P., D.Q., R.R., H.R., D.S., P.R.H.J.T., M.V., L.M.Y., O.G.T., N.M.P., N.W., E.K.S., C.H., A.P.M., A.S.B., R.A.S., M.H.C., D.P.S., M.D.T. and L.V.W. undertook data analysis. N.S., A.L.G., A.M.E., V.E.J., C.A.M., C.Batini, K.A.F., K.S., P.S., Xingnan Li, N.F.R., M.O., M.W., K.A.K., B.B.S., S.K., M.I., R.J.A., C.Brandsma, J.D., F.D., R.E., C.G., A.G., A.L.H., J.D.H., G.H., P.K.J., C.L., Xuan Li, K.L., L.Lind, J.L., J.C.M., A.Murray, R.P., M.M.P., M.L.P., D.J.P., D.P., D.Q., R.R., H.R., I.Sayers, B.H.S., M.S., L.M.Y., O.G.T., N.M.P., H.S., J.F.W., B.S., M.J., N.W., C.H., A.P.M., A.S.B., R.A.S., R.G.W., M.H.C., D.P.S., I.P.H., M.D.T. and L.V.W. contributed to data acquisition and/or interpretation. N.S., A.L.G., A.M.E., I.P.H., M.D.T. and L.V.W. drafted the manuscript.

    Competing interests

    The following authors report potential conflicts of interest: K.S. is an employee of GlaxoSmithKline (GSK) and may own company stock. Z.C. reports grants from GSK and Merck. J.D. reports personal fees and nonfinancial support from Merck Sharp & Dohme (MSD) and Novartis, and grants from British Heart Foundation, European Research Council, MSD, NIHR, NHS Blood and Transplant, Novartis, Pfizer, UK MRC, Wellcome Trust and AstraZeneca. J.D.H. is an employee of GlaxoSmithKline and may own company stock. N.L. is an employee and shareholder of GSK. J.C.M. was a Merck employee during this study, and is now a Celgene employee. D.C.N. has been a Merck & Co. employee during this study and is now an employee at Biogen Inc. H.R. has been a Merck & Co. employee during this study and is now an employee at Biogen Inc. I.S. has received support from GSK and Boehringer Ingelheim. R.T.-S. is an employee and shareholder of GlaxoSmithKline. M.v.d.B. reports grants paid to the University from Astra Zeneca, TEVA, GSK and Chiesi outside the submitted work. J.C.W. is an employee of GSK and may own company stock. L.M.Y.-A. is an employee of GSK and may own company stock. For H.S., Helmholtz Center Munich is funded by the German Federal Ministry of Education and Research (BMBF) and by the State of Bavaria, Competence Network Asthma and COPD (ASCONET), network COSYCONET (subproject 2, BMBF FKZ 01GI0882), funded by the BMBF. In the past three years, E.K.S. received honoraria from Novartis for Continuing Medical Education Seminars and grant and travel support from GlaxoSmithKline. A.S.B. reports grants from Merck, Pfizer, Novartis, Biogen and AstraZeneca and personal fees from Novartis. R.A.S. is an employee and shareholder in GSK. R.G.W. reports that the China Kadoorie Biobank study has received grant support from GSK. M.H.C. has received grant support from GSK. I.P.H. has funded research collaborations with GSK, Boehringer Ingelheim and Orion. M.D.T. receives funding from GSK for a collaborative research project outside of the submitted work. L.V.W. receives funding from GSK for a collaborative research project outside of the submitted work.

    Corresponding authors

    Correspondence to Martin D. Tobin or Louise V. Wain.

    Supplementary information

    1. Supplementary Text and Figures

      Supplementary Note and Supplementary Figures 1–10 and Supplementary Tables 1–3, 14–16, 19–22, 24 and 27

    2. Reporting Summary

    3. Supplementary Tables

      Supplementary Tables 4–13, 17, 18, 23, 25, 26, 28 and 29

    4. Supplementary Data 1

      Region plots for 139 novel signals of association with lung function

    5. Supplementary Data 2

      Region plots for 140 previous signals of association with lung function

    About this article

    Publication history

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    DOI

    https://doi.org/10.1038/s41588-018-0321-7