Letter | Published:

Genome-wide association and HLA fine-mapping studies identify risk loci and genetic pathways underlying allergic rhinitis

Nature Geneticsvolume 50pages10721080 (2018) | Download Citation


Allergic rhinitis is the most common clinical presentation of allergy, affecting 400 million people worldwide, with increasing incidence in westernized countries1,2. To elucidate the genetic architecture and understand the underlying disease mechanisms, we carried out a meta-analysis of allergic rhinitis in 59,762 cases and 152,358 controls of European ancestry and identified a total of 41 risk loci for allergic rhinitis, including 20 loci not previously associated with allergic rhinitis, which were confirmed in a replication phase of 60,720 cases and 618,527 controls. Functional annotation implicated genes involved in various immune pathways, and fine mapping of the HLA region suggested amino acid variants important for antigen binding. We further performed genome-wide association study (GWAS) analyses of allergic sensitization against inhalant allergens and nonallergic rhinitis, which suggested shared genetic mechanisms across rhinitis-related traits. Future studies of the identified loci and genes might identify novel targets for treatment and prevention of allergic rhinitis.

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Detailed acknowledgements and funding details for each contributing study are provided in the Supplementary Note.

Author information

Author notes

  1. These authors contributed equally: Johannes Waage, Marie Standl.

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


  1. COPSAC, Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark

    • Johannes Waage
    • , Leon E. Jessen
    • , Jonathan Thorsen
    • , Tarunveer S. Ahluwalia
    • , Hans Bisgaard
    •  & Klaus Bønnelykke
  2. Institute of Epidemiology, Helmholtz Zentrum München–German Research Center for Environmental Health, Neuherberg, Germany

    • Marie Standl
    • , Christian Gieger
    • , Joachim Heinrich
    •  & Elisabeth Thiering
  3. Division of Infection, Immunity and Respiratory Medicine, University of Manchester, Manchester Academic Health Science Centre, Manchester University NHS Foundation Trust, Manchester, UK

    • John A. Curtin
    •  & Angela Simpson
  4. 23andMe, Inc., Mountain View, CA, USA

    • Chao Tian
    • , Joyce Y. Tung
    •  & David A. Hinds
  5. Department of Human Genetics, University of Chicago, Chicago, IL, USA

    • Nathan Schoettler
    • , Rachel Myers
    • , Dan L. Nicolae
    •  & Carole Ober
  6. Research Unit, Hospital Universitario N.S. de Candelaria, Universidad de La Laguna, Tenerife, Spain

    • Carlos Flores
    • , Amalia Barreto-Luis
    • , Natalia Hernandez-Pacheco
    •  & Maria Pino-Yanes
  7. CIBER de Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III, Madrid, Spain

    • Carlos Flores
    •  & Maria Pino-Yanes
  8. Department of Biological Psychology, Netherlands Twin Register, VU University, Amsterdam, The Netherlands

    • Abdel Abdellaoui
    • , Catharina E. M. van Beijsterveldt
    • , Dorret I. Boomsma
    •  & Gonneke Willemsen
  9. Department of Psychiatry, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

    • Abdel Abdellaoui
  10. Department of Epidemiology and Biostatistics, MRC–PHE Centre for Environment & Health, School of Public Health, Imperial College London, London, UK

    • Alexessander C. Alves
    •  & Marjo-Riitta Jarvelin
  11. Population Health and Occupational Disease, National Heart and Lung Institute, Imperial College London, London, UK

    • Andre F. S. Amaral
    •  & Deborah L. Jarvis
  12. ISGlobal, Barcelona, Spain

    • Josep M. Antó
    •  & Jordi Sunyer
  13. IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain

    • Josep M. Antó
  14. Universitat Pompeu Fabra (UPF), Barcelona, Spain

    • Josep M. Antó
  15. CIBER Epidemiología y Salud Pública (CIBERESP), Barcelona, Spain

    • Josep M. Antó
  16. Clinic and Polyclinic of Dermatology, University Medicine Greifswald, Greifswald, Germany

    • Andreas Arnold
  17. Department of Dermatology, Venereology and Allergology, University-Hospital Schleswig-Hostein, Campus Kiel, Kiel, Germany

    • Hansjörg Baurecht
    •  & Stephan Weidinger
  18. Divisions of Pharmacogenomics and Genetics, Genomics and Precision Medicine, Department of Medicine, University of Arizona College of Medicine, Tucson, AZ, USA

    • Eugene R. Bleecker
    •  & Deborah A. Meyers
  19. Barcelona Supercomputing Center (BSC), Joint BSC–CRG–IRB Research Program in Computational Biology, Barcelona, Spain

    • Sílvia Bonàs-Guarch
    • , Josep M. Mercader
    •  & David Torrents
  20. APH Amsterdam Public Health, Amsterdam, The Netherlands

    • Dorret I. Boomsma
  21. Department of Biotechnology and Biomedicine, Technical University of Denmark, Kongens Lyngby, Denmark

    • Susanne Brix
  22. Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    • Supinda Bunyavanich
  23. Department of Medicine, University of California San Francisco, San Francisco, CA, USA

    • Esteban G. Burchard
  24. Department of Bioengineering & Therapeutic Sciences, University of California San Francisco, San Francisco, CA, USA

    • Esteban G. Burchard
  25. Department of Preventive Medicine, University of Southern California, Keck School of Medicine, Los Angeles, CA, USA

    • Zhanghua Chen
    • , W. James Gauderman
    •  & Frank Gilliland
  26. University of Basel, Basel, Switzerland

    • Ivan Curjuric
    • , Medea Imboden
    • , Ashish Kumar
    •  & Nicole M. Probst-Hensch
  27. Swiss Tropical and Public Health Institute, Basel, Switzerland

    • Ivan Curjuric
    • , Medea Imboden
    • , Ashish Kumar
    •  & Nicole M. Probst-Hensch
  28. Department of Paediatrics, Imperial College London, London, UK

    • Adnan Custovic
  29. The Generation R Study Group, Erasmus Medical Center, Rotterdam, The Netherlands

    • Herman T. den Dekker
    • , Liesbeth Duijts
    •  & Vincent W. V. Jaddoe
  30. Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands

    • Herman T. den Dekker
    •  & Vincent W. V. Jaddoe
  31. Department of Pediatrics, Division of Respiratory Medicine, Erasmus Medical Center, Rotterdam, The Netherlands

    • Herman T. den Dekker
    •  & Liesbeth Duijts
  32. Allergy and Lung Health Unit, Melbourne School of Population and Global Health, University of Melbourne, Melbourne, Victoria, Australia

    • Shyamali C. Dharmage
  33. Laboratory of Animal Genomics, Unit of Medical Genomics, GIGA Institute, University of Liège, Liège, Belgium

    • Julia Dmitrieva
    •  & Michel Georges
  34. Department of Pediatrics, Division of Neonatology, Erasmus Medical Center, Rotterdam, The Netherlands

    • Liesbeth Duijts
  35. LMU Munich, Dr von Hauner Children’s Hospital, Munich, and German Center for Lung Research (DZL), Munich, Germany

    • Markus J. Ege
  36. Research Unit of Molecular Epidemiology, Helmholtz Zentrum München–German Research Center for Environmental Health, Neuherberg, Germany

    • Christian Gieger
  37. MRC Integrative Epidemiology Unit, Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK

    • Raquel Granell
    • , John Henderson
    •  & Lavinia Paternoster
  38. Center for Health Policy and Health Services Research, Henry Ford Health System, Detroit, MI, USA

    • Hongsheng Gui
    •  & L. Keoki Williams
  39. Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, Department of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

    • Torben Hansen
  40. Institute and Outpatient Clinic for Occupational, Social and Environmental Medicine, University of Munich Medical Center, Ludwig-Maximilians-Universität München, Munich, Germany

    • Joachim Heinrich
  41. Genomics and Health Group, Department of Biochemistry, Microbiology, Cell Biology and Genetics, Universidad de La Laguna, La Laguna, Tenerife, Spain

    • Natalia Hernandez-Pacheco
    • , Fabian Lorenzo-Diaz
    •  & Maria Pino-Yanes
  42. Telethon Kids Institute (TKI), Perth, Western Australia, Australia

    • Patrick Holt
  43. Department of Pediatrics, Erasmus Medical Center, Rotterdam, The Netherlands

    • Vincent W. V. Jaddoe
  44. Center for Life Course Health Research, Faculty of Medicine, University of Oulu, Oulu, Finland

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

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

    • Marjo-Riitta Jarvelin
  47. Department of Bio and Health Informatics, Technical University of Denmark, Kongens Lyngby, Denmark

    • Kamilla K. Jensen
  48. deCODE genetics/Amgen Inc, Reykjavik, Iceland

    • Ingileif Jónsdóttir
    • , Kari Stefansson
    •  & Gardar Sveinbjornsson
  49. Faculty of Medicine, University of Iceland, Reykjavik, Iceland

    • Ingileif Jónsdóttir
    •  & Kari Stefansson
  50. Department of Pediatric Pneumology and Allergy, University Children’s Hospital Regensburg (KUNO), Regensburg, Germany

    • Michael Kabesch
  51. Department of Public Health, University of Helsinki, Helsinki, Finland

    • Jaakko Kaprio
  52. Institute for Molecular Medicine Finland FIMM, University of Helsinki, Helsinki, Finland

    • Jaakko Kaprio
    •  & Teemu Palviainen
  53. National Institute for Health and Welfare, Helsinki, Finland

    • Jaakko Kaprio
  54. Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden

    • Ashish Kumar
    • , Erik Melén
    •  & Göran Pershagen
  55. Max-Delbrück-Center (MDC) for Molecular Medicine, Berlin, Germany

    • Young-Ae Lee
    •  & Franz Rüschendorf
  56. Clinic for Pediatric Allergy, Experimental and Clinical Research Center, Charité Universitätsmedizin Berlin, Berlin, Germany

    • Young-Ae Lee
  57. Department of Public Health Sciences, Henry Ford Health System, Detroit, MI, USA

    • Albert M. Levin
  58. Divisions of Genetics, Genomics and Precision Medicine, Department of Medicine, University of Arizona College of Medicine, Tucson, AZ, USA

    • Xingnan Li
  59. Sachs’ Children’s Hospital, Stockholm, Sweden

    • Erik Melén
  60. Programs in Metabolism and Medical & Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA

    • Josep M. Mercader
  61. Diabetes Unit and Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA

    • Josep M. Mercader
  62. Institute of Clinical Research, University of Southern Denmark, Department of Obstetrics & Gynecology, Odense University Hospital, Odense, Denmark

    • Ellen A. Nohr
  63. School of Medicine and Public Health, Faculty of Medicine and Health, University of Newcastle, Callaghan, New South Wales, Australia

    • Craig E. Pennell
    •  & Carol A. Wang
  64. Centre for Occupational and Environmental Medicine, Stockholm County Council, Stockholm, Sweden

    • Göran Pershagen
  65. Ludwig-Maximilians-University of Munich, Dr. von Hauner Children’s Hospital, Division of Metabolic Diseases and Nutritional Medicine, Munich, Germany

    • Elisabeth Thiering
  66. Institute for Respiratory Health, Harry Perkins Institute of Medical Research, University of Western Australia, Nedlands, Western Australia, Australia

    • Philip J. Thompson
  67. Ib-Salut, Area de Salut de Menorca, Institut d’Investigacio Sanitaria Illes Balears (IdISBa), Palma de Mallorca, Spain

    • Maties Torrent
  68. Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain

    • David Torrents
  69. Channing Division of Network Medicine, Brigham & Women’s Hospital and Harvard Medical School, Boston, MA, USA

    • Scott Weiss
  70. Department of Internal Medicine, Henry Ford Health System, Detroit, MI, USA

    • L. Keoki Williams
  71. QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia

    • Manuel A. Ferreira
  72. Population Health Research Institute, St George’s, University of London, London, UK

    • David P. Strachan


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  1. The 23andMe Research Team

    1. AAGC collaborators


      Study design and management: K.B., J.W., M.S., and D.P.S. Meta-analyses: M.S. and J.W. Manuscript writing: K.B., J.W., M.S., J.A.C., J.T., L.E.J., and M.A.F. Systems biology analyses: J.W., J.A.C., J.T., L.E.J., J.M.M., S.B.-G., and D.T. Data collection, analysis, and design in the individual contributing studies: K.B., J.W., M.S., J.A.C., C.F., A. Abdellaoui, T.S.A., A.C.A., A.F.S.A., J.M.A., A. Arnold, A.B.-L., H. Baurecht, C.E.M.v.B., E.R.B., D.I.B., S. Bunyavanich, E.B., Z.C., I.C., A.C., H.T.d.D., S.C.D., J.D., L.D., M.J.E., W.J.G., C.G., F.G., R.G., H.G., T.H., J. Heinrich, J. Henderson, N.H.-P., D.A.H., P.H., M.I., V.W.V.J., M.-R.J., D.L.J., I.J., M.K., J.K., A.K., Y.-A.L., A.M.L., X.L., F.L.-D., E.M., D.A.M., R.M., D.L.N., E.A.N., T.P., L.P., C.E.P., G.P., M.P.-Y., N.M.P.-H., F.R., A.S., K.S., J.S., G.S., E.T., P.J.T., C.T., M.T., J.Y.T., C.A.W., S. Weidinger, S. Weiss, G.W., L.K.W., C.O., M.A.F., H. Bisgaard, D.P.S., The 23andMe Research Team and AAGC collaborators. Immunological interpretation: N.S. and S. Brix. Gene-expression analysis: M.G. and J.D. Protein modeling: K.K.J.

      Competing interests

      G.S., I.J., and K.S. are affiliated with deCODE genetics/Amgen and declare competing financial interests as employees. C.T., D.A.H., J.Y.T., and the 23andMe Research Team are employees of and hold stock and/or stock options in 23andMe, Inc. L.P. has received a fee for participating in a scientific-input engagement meeting from Merck Sharp & Dohme Limited, outside of this work.

      Corresponding author

      Correspondence to Klaus Bønnelykke.

      Supplementary information

      1. Supplementary Text and Figures

        Supplementary Figures 1–10 and Supplementary Note

      2. Reporting Summary

      3. Supplementary Tables

        Supplementary Tables 1–25

      About this article

      Publication history