Article

Multiancestry association study identifies new asthma risk loci that colocalize with immune-cell enhancer marks

  • Nature Geneticsvolume 50pages4253 (2018)
  • doi:10.1038/s41588-017-0014-7
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Abstract

We examined common variation in asthma risk by conducting a meta-analysis of worldwide asthma genome-wide association studies (23,948 asthma cases, 118,538 controls) of individuals from ethnically diverse populations. We identified five new asthma loci, found two new associations at two known asthma loci, established asthma associations at two loci previously implicated in the comorbidity of asthma plus hay fever, and confirmed nine known loci. Investigation of pleiotropy showed large overlaps in genetic variants with autoimmune and inflammatory diseases. The enrichment in enhancer marks at asthma risk loci, especially in immune cells, suggested a major role of these loci in the regulation of immunologically related mechanisms.

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Acknowledgements

We thank all participants who provided data for each study and also thank our valued colleagues who contributed to data collection and phenotypic characterization of clinical samples, genotyping, and analysis of individual datasets. Detailed acknowledgments and funding for individual studies can be found in the Supplementary Note.

Author information

Author notes

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

  2. Florence Demenais, Patricia Margaritte-Jeannin, Kathleen C. Barnes, William O. C. Cookson, Miriam F. Moffatt, Carole Ober and Dan Nicolae contributed equally to this work.

Affiliations

  1. Genetic Variation and Human Diseases Unit (UMR-946), Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, France

    • Florence Demenais
    • , Patricia Margaritte-Jeannin
    • , Emmanuelle Bouzigon
    • , Myriam Brossard
    • , Sébastien Letort
    • , Hamida Mohamdi
    •  & Amaury Vaysse
  2. Institut Universitaire d’Hématologie, Université Paris Diderot, Université Sorbonne Paris Cité, Paris, France

    • Florence Demenais
    • , Patricia Margaritte-Jeannin
    • , Emmanuelle Bouzigon
    • , Myriam Brossard
    • , Sébastien Letort
    • , Hamida Mohamdi
    •  & Amaury Vaysse
  3. Division of Biomedical Informatics and Personalized Medicine, Colorado Center for Personalized Medicine, University of Colorado, Denver, CO, USA

    • Kathleen C. Barnes
  4. Section of Genomic Medicine, National Heart and Lung Institute, London, UK

    • William O. C. Cookson
    •  & Miriam F. Moffatt
  5. Cologne Center for Genomics and Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany

    • Janine Altmüller
  6. School of Women’s and Infants’ Health, University of Western Australia, Perth, Western Australia, Australia

    • Wei Ang
    •  & Craig E. Pennell
  7. Departments of Medicine and Epidemiology, Columbia University, New York, NY, USA

    • R. Graham Barr
    •  & Kathleen M. Donohue
  8. Division of Genetic Epidemiology, Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA

    • Terri H. Beaty
  9. Department of Pediatrics and Child Health, University of Manitoba, Winnipeg, Manitoba, Canada

    • Allan B. Becker
  10. Department of the Diagnostic Genomics Laboratory, PathWest Laboratory Medicine, Queen Elizabeth II Medical Centre, Nedlands, Western Australia, Australia

    • John Beilby
    •  & Jennie Hui
  11. Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark

    • Hans Bisgaard
    • , Klaus Bønnelykke
    • , Eskil Kreiner
    •  & Johannes Waage
  12. Department of Medicine, Landspitali, National University Hospital of Iceland, Reykjavik, Iceland

    • Unnur Steina Bjornsdottir
  13. Center for Genomics, Wake Forest University School of Medicine, Winston-Salem, NC, USA

    • Eugene Bleecker
    •  & Deborah Meyers
  14. Department of Biological Psychology, Amsterdam Public Health Research Institute, Vrjie Universiteit, Amsterdam, The Netherlands

    • Dorret I. Boomsma
    • , Jouke Hottenga
    • , Hamdi Mbarek
    •  & Gonneke Willemsen
  15. University of Leicester, Institute for Lung Health, Glenfield Hospital, Leicester, UK

    • Christopher E. Brightling
  16. Department of Respiratory Medicine, Ghent University Hospital, Ghent, Belgium

    • Guy G. Brusselle
  17. Department of Epidemiology, Erasmus MC–University Medical Center Rotterdam, Rotterdam, The Netherlands

    • Guy G. Brusselle
    • , Albert Hofman
    • , Lies Lahousse
    • , Daan W. Loth
    •  & Bruno H. Stricker
  18. Department of Respiratory Medicine, Erasmus MC–University Medical Center Rotterdam, Rotterdam, The Netherlands

    • Guy G. Brusselle
  19. Department of Bioengineering & Therapeutic Sciences and Medicine, University of California, San Francisco, San Francisco, CA, USA

    • Esteban Burchard
  20. Division of Pulmonary, Allergy and Critical Care, College of Physicians and Surgeons, Columbia University, New York, NY, USA

    • Kristin M. Burkart
  21. National Heart and Lung Institute, Imperial College London, London, UK

    • Andrew Bush
    • , Kian Fan Chung
    •  & Deborah Jarvis
  22. Royal Brompton Harefield National Health Service (NHS) Foundation Trust, London, UK

    • Andrew Bush
  23. Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada

    • Moira Chan-Yeung
    • , Denise Daley
    •  & Julie E. Park
  24. Biomedical Research Unit, Royal Brompton & Harefield National Health Service (NHS) Trust, London, UK

    • Kian Fan Chung
  25. Department of Epidemiology and Biostatistics, Imperial College London, London, UK

    • Alexessander Couto Alves
    •  & Adaikalavan Ramasamy
  26. Division of Infection, Immunity and Respiratory Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK

    • John A. Curtin
    •  & Angela Simpson
  27. Department of Paediatrics, Imperial College London, London, UK

    • Adnan Custovic
  28. Centre for Heart and Lung Innovation, University of British Columbia, Vancouver, BC, Canada

    • Denise Daley
  29. Department of Pediatrics, Division of Respiratory Medicine, Erasmus MC–University Medical Center Rotterdam, Rotterdam, The Netherlands

    • Johan C. de Jongste
  30. Hospital Infantil de Mexico Federico Gomez, Mexico City, Mexico

    • Blanca E. Del-Rio-Navarro
  31. Department of Pediatrics, Division of Respiratory Medicine, and Department of Pediatrics, Division of Neonatology, Erasmus MC–University Medical Center Rotterdam, Rotterdam, The Netherlands

    • Liesbeth Duijts
  32. Department of Medicine, University of California, San Francisco, San Francisco, CA, USA

    • Celeste Eng
    •  & Dara G. Torgerson
  33. Department of General Practice and Primary Health Care, University of Helsinki and Helsinki University Hospital, Helsinki, Finland

    • Johan G. Eriksson
  34. Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK

    • Martin Farrall
  35. Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK

    • Martin Farrall
  36. Institute of Biochemistry and Genetics, Ufa Scientific Center of the Russian Academy of Sciences, Ufa, Russian Federation

    • Yuliya Fedorova
    • , Alexandra S. Karunas
    •  & Elza Khusnutdinova
  37. Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark

    • Bjarke Feenstra
    • , Frank Geller
    •  & Mads Melbye
  38. Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia

    • Manuel A. Ferreira
  39. Population Genetics Laboratory, Research Institute of Medical Genetics, Tomsk NRMC, Tomsk, Russian Federation

    • Maxim B. Freidin
    •  & Valery P. Puzyrev
  40. Divisions of Genetics and Endocrinology, Children’s Hospital, Boston, MA, USA

    • Zofia Gajdos
    •  & Sailaja Vedantam
  41. Broad Institute, Cambridge, MA, USA

    • Zofia Gajdos
    • , Joel N. Hirschhorn
    • , Cameron D. Palmer
    •  & Sailaja Vedantam
  42. Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

    • Jim Gauderman
    • , Frank Gilliland
    •  & Muhammad T. Salam
  43. Division of Environmental Epidemiology, Institute for Risk Assessment Sciences, Utrecht University, Utrecht, The Netherlands

    • Ulrike Gehring
    • , Dick Heederik
    •  & Inge M. Wouters
  44. Institute of Epidemiology and Medical Biometry, Ulm University, Ulm, Germany

    • Jon Genuneit
  45. Department of Medicine, University of Washington, Seattle, WA, USA

    • Sina A. Gharib
    •  & Guo Li
  46. Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK

    • Raquel Granell
    •  & John Henderson
  47. MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK

    • Raquel Granell
    •  & John Henderson
  48. Asthma and Airway Disease Research Center and BIO5 Institute, University of Arizona, Tucson, AZ, USA

    • Penelope E. Graves
    •  & Fernando J. Martinez
  49. deCODE genetics, Amgen Inc., Reykjavik, Iceland

    • Daniel F. Gudbjartsson
    • , Ingileif Jonsdottir
    • , Kari Stefansson
    • , Gudmar Thorleifsson
    •  & Unnur Thorsteinsdottir
  50. School of Engineering and Natural Sciences, University of Iceland, Reykjavik, Iceland

    • Daniel F. Gudbjartsson
  51. Skin and Allergy Hospital, University of Helsinki, Helsinki, Finland

    • Tari Haahtela
  52. Department of Epidemiology, University of Washington, Seattle, WA, USA

    • Susan R. Heckbert
  53. Institute and Outpatient Clinic for Occupational, Social and Environmental Medicine, University Hospital in Munich, Munich, Germany

    • Joachim Heinrich
  54. Institute of Epidemiology I, Helmholtz Zentrum München, German Research Centre for Environmental Health, Neuherberg, Germany

    • Joachim Heinrich
    • , Marie Standl
    •  & Carla M. T. Tiesler
  55. National Institute for Health and Welfare (THL), Helsinki, Finland

    • Markku Heliövaara
    • , Pekka Jousilahti
    • , Mikko Kuokkanen
    •  & Veikko Salomaa
  56. Department of Biostatistics, Epidemiology and Informatics, University of Pennsylvania, Philadelphia, PA, USA

    • Blanca E. Himes
  57. Health Center, Department of Internal Medicine, Keio University, Tokyo, Japan

    • Hiroshi Hirose
  58. Division of Endocrinology and Center for Basic and Translational Obesity Research, Boston Children’s Hospital, Boston, MA, USA

    • Joel N. Hirschhorn
    •  & Cameron D. Palmer
  59. Departments of Pediatrics and Genetics, Harvard Medical School, Boston, MA, USA

    • Joel N. Hirschhorn
  60. Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA

    • Albert Hofman
    •  & Liming Liang
  61. Cell Biology Telethon Kids Institute, University of Western Australia, Subiaco, Western Australia, Australia

    • Patrick Holt
  62. Ontario Institute for Cancer Research, Toronto, Ontario, Canada

    • Thomas J. Hudson
  63. AbbVie Inc., Redwood City, CA, USA

    • Thomas J. Hudson
  64. Busselton Population Medical Research Institute, Perth, Western Australia, Australia

    • Jennie Hui
  65. School of Population and Global Health, University of Western Australia, Nedlands, Western Australia, Australia

    • Jennie Hui
  66. Department of Epidemiology and Public Health, Swiss Tropical and Public Health Institute, Basel, Switzerland

    • Medea Imboden
    • , Ashish Kumar
    •  & Nicole Probst-Hensch
  67. University of Basel, Basel, Switzerland

    • Medea Imboden
    • , Ashish Kumar
    •  & Nicole Probst-Hensch
  68. Department of Biology, Medical Genetics and Ecology, Kursk State Medical University, Kursk, Russian Federation

    • Vladimir Ivanov
    • , Alexey Polonikov
    •  & Maria Solodilova
  69. The Generation R Study Group, Department of Pediatrics and Department of Epidemiology, Erasmus MC–University Medical Center Rotterdam, Rotterdam, The Netherlands

    • Vincent W. V. Jaddoe
  70. Department of Pulmonary Physiology and Sleep Medicine, Busselton Population Medical Research Institute, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia

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

    • Alan James
  72. Department of Medical Sciences: Respiratory, Allergy & Sleep Research, Uppsala University, Uppsala, Sweden

    • Christer Janson
  73. Department of Epidemiology and Biostatistics, MRC–PHE Centre for Environment & Health, School of Public Health, Imperial College London, London, UK

    • Marjo-Riitta Jarvelin
  74. Center for Life Course Health Research, Faculty of Medicine, University of Oulu, Oulu, Finland

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

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

    • Marjo-Riitta Jarvelin
  77. MRC–PHE Centre for Environment and Health, Imperial College London, London, UK

    • Deborah Jarvis
  78. School of Science and Health, Western Sydney University, Sydney, New South Wales, Australia

    • Graham Jones
  79. Faculty of Medicine, University of Iceland, Reykjavik, Iceland

    • Ingileif Jonsdottir
    • , Kari Stefansson
    •  & Unnur Thorsteinsdottir
  80. Department of Pediatric Pneumology and Allergy, University Children’s Hospital Regensburg (KUNO), Regensburg, Germany

    • Michael Kabesch
    •  & Sven Michel
  81. Department of Clinical Physiology, University of Tampere and Tampere University Hospital, Tampere, Finland

    • Mika Kähönen
  82. Department of Anesthesiology, Perioperative and Pain Medicine, Division of Critical Care Medicine, Boston Children’s Hospital, Boston, MA, USA

    • David B. Kantor
  83. Department of Anaesthesia, Harvard Medical School, Boston, MA, USA

    • David B. Kantor
  84. Department of Genetics and Fundamental Medicine, Bashkir State University, Ufa, Russian Federation

    • Alexandra S. Karunas
    •  & Elza Khusnutdinova
  85. University of Groningen, University Medical Center Groningen, Department of Pediatric Pulmonology and Pediatric Allergology, Beatrix Children’s Hospital, Groningen, The Netherlands

    • Gerard H. Koppelman
  86. Groningen Research Institute for Asthma and COPD (GRIAC), Groningen, The Netherlands

    • Gerard H. Koppelman
    • , Maartje A. E. Nieuwenhuis
    • , Dirkje S. Postma
    •  & Judith M. Vonk
  87. Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada

    • Anita L. Kozyrskyj
  88. RIKEN Center for Integrative Medical Sciences, Yokohama, Japan

    • Michiaki Kubo
    • , Atsushi Takahashi
    •  & Tatsuhiko Tsunoda
  89. Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL, USA

    • Rajesh Kumar
  90. Divison of Allergy and Clinical Immunology, Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, IL, USA

    • Rajesh Kumar
  91. Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden

    • Ashish Kumar
    • , Erik Melén
    • , Göran Pershagen
    •  & Magnus Wickman
  92. Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland

    • Mikko Kuokkanen
    • , Aarno Palotie
    •  & Elisabeth Widén
  93. Pharmaceutical Care Unit, Faculty of Pharmaceutical Sciences, Ghent University, Ghent, Belgium

    • Lies Lahousse
  94. Department of Pulmonary Medicine, University of Turku and Turku University Hospital, Turku, Finland

    • Tarja Laitinen
  95. Département des Sciences Fondamentales, Université du Québec à Chicoutimi, Chicoutimi, Quebec, Canada

    • Catherine Laprise
  96. Centre de Santé et de Services Sociaux du Saguenay-Lac-Saint-Jean, Saguenay, QC, Canada

    • Catherine Laprise
  97. McGill University and Genome Quebec Innovation Centre, Montréal, QC, Canada

    • Mark Lathrop
  98. Pediatric Pneumology and Immunology, Charité Universitätsmedizin, Berlin, Germany

    • Susanne Lau
  99. Max-Delbrück-Centrum (MDC) for Molecular Medicine, Berlin, Germany

    • Young-Ae Lee
    •  & Ingo Marenholz
  100. Pediatric Allergology, Experimental and Clinical Research Center, Charité Universitätsmedizin, Berlin, Germany

    • Young-Ae Lee
    •  & Ingo Marenholz
  101. Department of Clinical Chemistry, Fimlab Laboratories, Faculty of Medicine and Life Sciences, University of Tampere, Tampere, Finland

    • Terho Lehtimäki
  102. Department of Public Health Sciences, Henry Ford Health System, Detroit, MI, USA

    • Albert M. Levin
  103. Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA

    • Liming Liang
  104. Division of General Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    • Laura R. Loehr
  105. National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, NC, USA

    • Stephanie J. London
  106. Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA

    • Ani Manichaikul
    •  & Stephen S. Rich
  107. Melbourne School of Population and Global Health, University of Melbourne, Melbourne, Victoria, Australia

    • Melanie C. Matheson
  108. Division of Allergy & Clinical Immunology, Department of Medicine, Johns Hopkins University, Baltimore, MD, USA

    • Rasika A. Mathias
  109. Department of Allergy and Clinical Immunology, National Research Institute for Child Health and Development, Tokyo, Japan

    • Kenji Matsumoto
  110. Bristol Bioresource Laboratories, School of Social and Community Medicine, University of Bristol, Bristol, UK

    • Wendy L. McArdle
  111. Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark

    • Mads Melbye
  112. Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA

    • Mads Melbye
  113. Centre for Occupational and Environmental Medicine, Stockholm County Council, Stockholm, Sweden

    • Erik Melén
    •  & Göran Pershagen
  114. Sachs Children’s Hospital, Stockholm, Sweden

    • Erik Melén
  115. Department of Respiratory Medicine, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia

    • Arthur W. Musk
  116. Schools of Population Health and of Medicine and Pharmacology, University of Western Australia, Perth, Western Australia, Australia

    • Arthur W. Musk
  117. Center for Applied Genomics and Precision Medicine, Duke University School of Medicine, Durham, NC, USA

    • Rachel A. Myers
  118. University Medical Center Groningen, Department of Pulmonology, University of Groningen, Groningen, The Netherlands

    • Maartje A. E. Nieuwenhuis
    •  & Dirkje S. Postma
  119. Department of Medical Genetics, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan

    • Emiko Noguchi
  120. Pulmonary Center, Department of Medicine, Boston University School of Medicine, Boston, MA, USA

    • George T. O’Connor
  121. The National Heart, Lung, and Blood Institute’s Framingham Heart Study, Framingham, MA, USA

    • George T. O’Connor
  122. Department of Faculty Pediatrics, Siberian State Medical University, Tomsk, Russian Federation

    • Ludmila M. Ogorodova
  123. Analytic and Translational Genetics Unit, Departments of Medicine, of Neurology and of Psychiatry, Massachusetts General Hospital, Boston, MA, USA

    • Aarno Palotie
  124. The Stanley Center for Psychiatric Research and Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA

    • Aarno Palotie
  125. Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA

    • Benjamin A. Raby
    •  & Scott T. Weiss
  126. Department of Clinical Physiology and Nuclear Medicine, University of Turku and Turku University Hospital, Turku, Finland

    • Olli T. Raitakari
  127. Department of Medical and Molecular Genetics, King’s College London, London, UK

    • Adaikalavan Ramasamy
  128. Respiratory Medicine, Murdoch Children’s Research Institute, Melbourne, Victoria, Australia

    • Colin F. Robertson
  129. Hubert Department of Global Health, Mory University, Atlanta, GA, USA

    • Isabelle Romieu
  130. Center for Population Health Research, National Institute of Public Health, Cuernavaca, Mexico

    • Isabelle Romieu
  131. Department of Psychiatry, Kern Medical, Bakersfield, CA, USA

    • Muhammad T. Salam
  132. Department of Public Health, Section for Environment, Occupation & Health, Aarhus University, Aarhus, Denmark

    • Vivi Schlünssen
    •  & Torben Sigsgaard
  133. MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Institute of Metabolic Science, Cambridge Biomedical Campus, Cambridge, UK

    • Robert Scott
    • , Nick J. Wareham
    •  & Jing Hua Zhao
  134. Department of Faculty Therapy, Siberian State Medical University, Tomsk, Russian Federation

    • Polina A. Selivanova
  135. University Hospital of South Manchester, National Health Service (NHS) Foundation Trust, Manchester, UK

    • Angela Simpson
  136. Institut National de la Santé et de la Recherche Médicale (INSERM) U1209, Institute for Advanced Biosciences, Team of Environmental Epidemiology Applied to Reproduction and Respiratory Health, Grenoble, France

    • Valérie Siroux
  137. Université de Grenoble Alpes/CNRS UMR5309, Institute for Advanced Biosciences, Team of Environmental Epidemiology Applied to Reproduction and Respiratory Health, Grenoble, France

    • Valérie Siroux
  138. Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA

    • Lewis J. Smith
  139. Population Health Research Institute, St George’s University of London, London, UK

    • David P. Strachan
  140. Netherlands Healthcare Inspectorate, The Hague, The Netherlands

    • Bruno H. Stricker
  141. Department of Internal Medicine, Erasmus MC–University Medical Center Rotterdam, Rotterdam, The Netherlands

    • Bruno H. Stricker
    •  & André G. Uitterlinden
  142. Institute for Respiratory Health and Harry Perkins Institute of Medical Research, University of Western Australia and The Lung Health Clinic, Nedlands, Western Australia, Australia

    • Philip J. Thompson
  143. Division of Metabolic Diseases and Nutritional Medicine, Dr. von Hauner Children’s Hospital, Ludwig-Maximilians-University of Munich, Munich, Germany

    • Carla M. T. Tiesler
  144. Department of Medical Science Mathematics, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan

    • Tatsuhiko Tsunoda
  145. The Generation R Study Group, Department of Pediatrics, Division of Respiratory Medicine and Department of Epidemiology, Erasmus MC–University Medical Center Rotterdam, Rotterdam, The Netherlands

    • Ralf J. P. van der Valk
  146. Department of Pediatrics, Marien-Hospital Wesel, Wesel, Germany

    • Andrea von Berg
  147. Dr. Von Hauner Children’s Hospital, Ludwig Maximilians University Munich, Munich, Germany

    • Erika von Mutius
  148. German Center for Lung Research, Munich, Germany

    • Erika von Mutius
  149. University of Groningen, University Medical Center Groningen, Department of Epidemiology, Groningen, The Netherlands

    • Judith M. Vonk
  150. Undergraduate Training and Education Center (UTEC), Jackson Heart Study, Tougaloo College, Jackson, MI, USA

    • Wendy B. White
  151. Centre for Clinical Research Sörmland, Uppsala University, Eskilstuna, Sweden

    • Magnus Wickman
  152. Center for Health Policy and Health Services Research, Henry Ford Health System, Detroit, MI, USA

    • L. Keoki Williams
  153. Department of Internal Medicine, Henry Ford Health System, Detroit, MI, USA

    • L. Keoki Williams
  154. School of Nursing, University of Michigan, Ann Arbor, MI, USA

    • James J. Yang
  155. Department of Human Genetics, University of Chicago, Chicago, IL, USA

    • Carole Ober
  156. Departments of Statistics, Human Genetics and Medicine, Section of Genetic Medicine, University of Chicago, Chicago, IL, USA

    • Dan L. Nicolae

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Consortia

  1. Australian Asthma Genetics Consortium (AAGC) collaborators

    Contributions

    TAGC study management: F.D., K.C.B., W.O.C.C., M.F.M., C.O., and D.L.N.

    F.D. and D.L.N. designed the study and wrote the manuscript. F.D., D.L.N., and P.M.-J. designed and conducted the statistical analysis. K.C.B., W.O.C.C., M.F.M., and C.O. designed the study and wrote the manuscript. M.B., A.V., S. Letort, and H.M. carried out the quality control of the data and performed statistical analysis.

    AAGC (Australia): study principal investigators (PIs), M.A.F., M.C.M., C.F.R., and P.J.T.; data collection or analysis, M.A.F., M.C.M., C.F.R., G.J., and P.J.T.

    ALLERGEN Canadian Asthma Primary Prevention Study (CAPPS) and Study of Asthma, Genes and the Environment (SAGE): study PIs, A.B.B., M.C.-Y., D.D., and A.L.K.; data collection or analysis, D.D. and J.E.P.; study phenotyping, A.B.B. and M.C.-Y.

    Saguenay‐Lac‐Saint‐Jean (SLSJ) Study: study PIs, C.L. and T.J.H.; study design and management, C.L.

    Analysis in Population-based Cohorts of Asthma Traits (APCAT) Consortium: study PIs, J.N.H., M.-R.J., and V. Salomaa. Framingham Heart Study (FHS): study PI, G.T.O.; data collection or analysis, S.V. and Z.G. The European Prospective Investigation of Cancer (EPIC)-Norfolk: study PI, N.J.W.; data collection or analysis, J.H.Z. and R.S. Northern Finland Birth Cohort of 1966 (NFBC1966): study PI, M.-R.J.; data collection or analysis, A.C.A. and A.R. FINRISK: study PI, V. Salomaa; data collection or analysis, M. Kuokkanen and T. Laitinen. Health 2000 (H2000) Survey: study PIs, M.H. and P.J.; data collection or analysis, M. Kuokkanen and T.H. Helsinki Birth Cohort Study (HBCS): study PI, J.G.E.; data collection or analysis, E.W. and A. Palotie. Young Finns Study (YFS): study PI, O.T.R.; data collection or analysis, T. Lehtimäki and M. Kähönen.

    African Ancestry Studies from the Candidate Gene Association Resource (CARe) Consortium: study PIs, J.N.H. and S.S.R.; data collection or analysis, C.D.P., D.B.K., L.J.S., R.K., K.M.B., and W.B.W.

    Multi‐Ethnic Study of Atherosclerosis (MESA): study PIs, R.G.B. and S.S.R.; data collection or analysis, K.M.D. and A.M.

    Atherosclerosis Risk in Communities Study (ARIC): study PI, S.J.L.; data collection or analysis, S.J.L. and L.R.L.

    Cardiovascular Health Study (CHS): study PIs, S.A.G. and S.R.H.; data collection or analysis, G.L., S.A.G., and S.R.H.

    deCode genetics: study PIs, K.S., I.J., D.F.G., U.T., and G.T.; data collection or analysis, I.J., D.F.G., and G.T.; study phenotyping, U.S.B.

    Early Genetics and Lifecourse Epidemiology (EAGLE) Consortium: PI, H.B. Cophenhagen Prospective Study on Asthma in Childhood (COPSAC): study PIs, H.B. and K.B.; data analysis, E. Kreiner and J.W.; study phenotyping, K.B. Danish National Birth Cohort (DNBC): study PI, M.M.; data collection or analysis, B.F. and F. Geller. GENERATION R: study PI, J.C.d.J.; data collection or analysis, R.J.P.v.d.V., L.D., and V.W.V.J. GINIplus/LISAplus: study PI, J. Heinrich; genotyping, data collection or analysis, M. Standl and C.M.T.T.; study phenotyping, J. Heinrich. Manchester Asthma and Allergy Study (MAAS): study PIs, A.S. and A.C.; data collection or analysis, J.A.C. Western Australian Pregnancy Cohort Study (RAINE): study PI, P.H.; data collection or analysis, W.A. and C.E.P.

    British 1958 Birth Cohort (B58C) Study: PI and statistical analysis, D.P.S.

    EVE Consortium: study PIs, C.O., D.L.N., K.C.B., E. Bleecker, E. Burchard, J. Gauderman, F. Gilliland, S.J.L., F.J.M., D.M., I.R., S.T.W., L.K.W., and B.A.R.; data collection or analysis, D.L.N., J. Gauderman, S.J.L., D.M., D.G.T., B.A.R., B.E.H., P.E.G., M.T.S., C.E., B.E.D.-R.-N., J.J.Y., A.M.L., R.A. Myers, R.A. Mathias, and T.H.B.

    Japanese Adult Asthma Research Consortium (JAARC): study PI, T.T.; data collection or analysis, T.T., A.T., and M. Kubo.

    Japan Pediatric Asthma Consortium (JPAC): study PI, E.N.; data collection or analysis, H.H. and K.M.

    GABRIEL Consortium: study PIs, W.O.C.C. and E.V.M.; genotyping, M.L.; data analysis, E.B., F.D., M.F., and D.P.S. Epidemiological study on the Genetics and Environment of Asthma (EGEA): study PIs, V. Siroux and F.D.; genotyping, data collection or analysis, M.L. and E. Bouzigon. Avon Longitudinal Study of Parents and Children (ALSPAC): study PI, J. Henderson; genotyping, data collection or analysis, W.L.M. and R.G.; study phenotyping, J. Henderson. European Community Respiratory Health Survey (ECRHS): study PI, D.J.; data collection or analysis, C.J. and J. Heinrich. Children, Allergy, Milieu, Stockholm, Epidemiology (BAMSE) study: study PIs, E.M., M.W., and G.P. Busselton Health Study: study PIs, A.W.M., A.J., and J.B.; genotyping, data collection or analysis, A.W.M., A.J., J. Hui, and J.B. GABRIEL Advanced Surveys: study PI, E.V.M.; data collection or analysis, M. Kabesch and J. Genuneit. Kursk State Medical University (KSMU) Study: study PI, A. Polonikov; data collection or analysis, M. Solodilova and V.I.; Medical Research Council-funded Collection of Nuclear Families with Asthma (MRCA-UKC): study PIs, W.O.C.C. and M.M.; data collection or analysis, L. Liang. Multicentre Asthma Genetics in Childhood Study (MAGICS): study PI, M. Kabesch; data collection or analysis, A.V.B. and S.M. German Multicentre Allergy Study (MAS): study PI, Y.-A.L.; data collection or analysis, S. Lau and I.M. Prevention and Incidence of Asthma and Mite Allergy (PIAMA) cohort : study PIs, G.H.K. and D.S.P.; data collection or analysis, G.H.K., D.S.P., and U.G. Swiss Cohort Study on Air Pollution and Lung and Heart Diseases in Adults (SAPALDIA): study PI, N.P.-H.; data collection or analysis, M.I. and A.K. Tomsk Study: study PIs, L.M.O. and V.P.P.; data collection or analysis, M.B.F. and P.A.S. UFA Study: study PI, E. Khusnutdinova; data collection or analysis, A.S.K. and Y.F. Industrial Cohorts Research Group (INDUSTRIAL): study PIs, D.H. and T.S.; data collection or analysis, I.M.W. and V. Schlünssen. Severe Asthma Cohorts (SEVERE): study PIs, A.B., K.F.C., and C.E.B.

    Netherlands Twin Register (NTR) Study: study PI, D.I.B.; genotyping, data collection or analysis, J.J.H., H.M., and G.W.

    Rotterdam Study: study PIs, A.H., B.H.S., and G.G.B.; genotyping, data collection or analysis, G.G.B., B.H.S., D.W.L., L. Lahousse, and A.G.U.

    Dutch Asthma Genetics Consortium (DAGC): study PIs, G.H.K. and D.S.P.; genotyping, data collection or analysis, G.H.K., D.S.P., J.A., M.A.E.N., and J.M.V.

    All authors provided critical review of the manuscript.

    Competing interests

    The authors affiliated with deCODE (D.F.G., I.J., K.S., U.T., and G.T.) are employees of deCODE genetics/Amgen. All other coauthors have no conflicts of interest to declare.

    Corresponding authors

    Correspondence to Florence Demenais or Dan L. Nicolae.

    Supplementary information

    1. Supplementary Text and Figures

      Supplementary Figures 1–7, Supplementary Tables 3, 5–7, 9, 10, 12–17, 20 and 21, and Supplementary Note.

    2. Life Sciences Reporting Summary

    3. Supplementary Table 1

      Description of TAGC studies included in the meta-analysis.

    4. Supplementary Table 2

      Information on genotyping methods, imputation, and statistical analysis by study. Details and references for each study are in the Supplementary Note.

    5. Supplementary Table 4

      Genome-wide significant SNPs (Prandom ≤ 5 × 10−8) in the European-ancestry meta-analysis.

    6. Supplementary Table 8

      Genome-wide significant SNPs (Prandom ≤ 5 × 10−8) in the multi-ancestry meta-analysis.

    7. Supplementary Table 11

      Association of 17q12-21 SNPs with asthma in multi-ancestry and pediatric meta-analyses.

    8. Supplementary Table 18

      Overlap between TAGC asthma-association signals (Prandom <10−3) and GWAS signals with diseases/traits in the GWAS catalog.

    9. Supplementary Table 19

      Enrichment of asthma risk loci in promoter and enhancer marks by cell type. The results presented in this table are for 16 out of the 18 asthma loci shown in Table 1. The 6p21.33 and 6p21.32 loci spanning the HLA complex were excluded because of high variability and LD in the region. Enhancer and promoter marks were defined using the ChromHMM 15-state model applied to 127 ROADMAP/ENCODE reference epigenomes (PMID 25693563).