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Meta-analysis of genome-wide association studies identifies ten loci influencing allergic sensitization

Nature Genetics volume 45, pages 902906 (2013) | Download Citation

Abstract

Allergen-specific immunoglobulin E (present in allergic sensitization) has a central role in the pathogenesis of allergic disease. We performed the first large-scale genome-wide association study (GWAS) of allergic sensitization in 5,789 affected individuals and 10,056 controls and followed up the top SNP at each of 26 loci in 6,114 affected individuals and 9,920 controls. We increased the number of susceptibility loci with genome-wide significant association with allergic sensitization from three to ten, including SNPs in or near TLR6, C11orf30, STAT6, SLC25A46, HLA-DQB1, IL1RL1, LPP, MYC, IL2 and HLA-B. All the top SNPs were associated with allergic symptoms in an independent study. Risk-associated variants at these ten loci were estimated to account for at least 25% of allergic sensitization and allergic rhinitis. Understanding the molecular mechanisms underlying these associations may provide new insights into the etiology of allergic disease.

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Acknowledgements

A full list of acknowledgments for each study is given in the Supplementary Note.

Author information

Author notes

    • Klaus Bønnelykke
    • , Melanie C Matheson
    •  & Tune H Pers

    These authors contributed equally to this work.

    • Manuel A Ferreira
    • , Hans Bisgaard
    •  & A John Henderson

    These authors jointly directed this work.

Affiliations

  1. COPSAC (Copenhagen Prospective Studies on Asthma in Childhood), Health Sciences, University of Copenhagen & Copenhagen University Hospital, Gentofte, Denmark.

    • Klaus Bønnelykke
    • , Eskil Kreiner-Møller
    •  & Hans Bisgaard
  2. Centre for Molecular, Environmental, Genetic and Analytic Epidemiology, University of Melbourne, Melbourne, Victoria, Australia.

    • Melanie C Matheson
    •  & Shyamali C Dharmage
  3. Center for Biological Sequence Analysis, Technical University of Denmark, Lyngby, Denmark.

    • Tune H Pers
    •  & Ramneek Gupta
  4. Division of Endocrinology, Children's Hospital, Boston, Massachusetts, USA.

    • Tune H Pers
    •  & Joel N Hirschhorn
  5. Center for Basic and Translational Obesity Research, Children's Hospital, Boston, Massachusetts, USA.

    • Tune H Pers
  6. Broad Institute, Cambridge, Massachusetts, USA.

    • Tune H Pers
    •  & Joel N Hirschhorn
  7. School of Social and Community Medicine, University of Bristol, Bristol, UK.

    • Raquel Granell
    • , Beate St Pourcain
    • , Susan M Ring
    • , Wendy L McArdle
    • , John P Kemp
    • , Nicholas Timpson
    •  & A John Henderson
  8. Division of Population Health Sciences & Education, St. George's, University of London, London, UK.

    • David P Strachan
    •  & Wendy L McArdle
  9. Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK.

    • Alexessander Couto Alves
    • , Lachlan Coin
    •  & Paul Elliot
  10. Research Centre for Prevention and Health, Glostrup Hospital, Glostrup, Denmark.

    • Allan Linneberg
    •  & Lise L Husemoen
  11. Manchester Academic Health Science Centre, University of Manchester, University Hospital of South Manchester National Health Service (NHS) Foundation Trust, Manchester, UK.

    • John A Curtin
    • , Angela Simpson
    •  & Adnan Custovic
  12. School of Women's and Infants' Health, The University of Western Australia, Crawley, Western Australia, Australia.

    • Nicole M Warrington
    •  & Craig E Pennell
  13. Institute of Epidemiology I, Helmholtz Zentrum München–German Research Center for Environmental Health, Neuherberg, Germany.

    • Marie Standl
    • , Carla M T Tiesler
    • , Elisabeth Thiering
    •  & Joachim Heinrich
  14. Department of Epidemiology, Groningen Research Institute for Asthma and COPD (GRIAC), University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

    • Marjan Kerkhof
  15. deCODE Genetics, Reykjavik, Iceland.

    • Ingileif Jonsdottir
    • , Gudmar Thorleifsson
    • , Unnur Thorsteinsdottir
    •  & Kari Stefansson
  16. University of Iceland, Reykjavik, Iceland.

    • Ingileif Jonsdottir
    • , Unnur Thorsteinsdottir
    •  & Kari Stefansson
  17. Department of Pediatrics, General Hospital Dr. Josip Bencevic Slavonski Brod, University of Osijek, Osijek, Croatia.

    • Blazenka K Bukvic
    •  & Mario Blekic
  18. Institute of Health Sciences, University of Oulu, Oulu, Finland.

    • Marika Kaakinen
    •  & Marjo-Riitta Jarvelin
  19. Biocenter Oulu, University of Oulu, Oulu, Finland.

    • Marika Kaakinen
    •  & Marjo-Riitta Jarvelin
  20. Center for Applied Genomics, The Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.

    • Patrick Sleimann
    •  & Hakon Hakonarsson
  21. Division of Human Genetics, The Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.

    • Patrick Sleimann
    •  & Hakon Hakonarsson
  22. Institute of Human Genetics, Helmholtz Zentrum München–German Research Center for Environmental Health, Neuherberg, Germany.

    • Katharina Schramm
  23. Lung Institute of Western Australia, The University of Western Australia, Perth, Western Australia, Australia.

    • Svetlana Baltic
    • , Loren Price
    •  & Philip J Thompson
  24. Centre for Asthma, Allergy and Respiratory Research, The University of Western Australia, Perth, Western Australia, Australia.

    • Svetlana Baltic
    • , Loren Price
    •  & Philip J Thompson
  25. PathWest Laboratory Medicine of Western Australia, Nedlands, Western Australia, Australia.

    • Jennie Hui
  26. School of Population Health, The University of Western Australia, Nedlands, Western Australia, Australia.

    • Jennie Hui
  27. School of Pathology and Laboratory Medicine, The University of Western Australia, Nedlands, Western Australia, Australia.

    • Jennie Hui
  28. Busselton Population Medical Research Foundation, Sir Charles Gairdner Hospital, Perth, Western Australia, Australia.

    • Jennie Hui
    •  & Alan James
  29. School of Medicine, University of Tasmania, Hobart, Tasmania, Australia.

    • Eugene H Walters
  30. Queensland Institute of Medical Research, Brisbane, Queensland, Australia.

    • David L Duffy
    • , Clara S Tang
    • , Grant W Montgomery
    •  & Manuel A Ferreira
  31. School of Science and Health, University of Western Sydney, Penrith, New South Wales, Australia.

    • Graham Jones
  32. Respiratory Medicine, Murdoch Children's Research Institute, Melbourne, Victoria, Australia.

    • Colin F Robertson
  33. Department of Environmental Health, National Institute for Health and Welfare (THL), Kuopio, Finland.

    • Juha Pekkanen
  34. Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland.

    • Juha Pekkanen
  35. Department of Clinical Sciences, Obstetrics and Gynecology, Institute of Clinical Medicine, University of Oulu, Oulu, Finland.

    • Anna-Liisa Hartikainen
  36. Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany.

    • Christian Herder
  37. School of Medicine and Pharmacology, The University of Western Australia, Nedlands, Western Australia, Australia.

    • Alan James
  38. Department of Pulmonary Physiology, West Australian Sleep Disorders Research Institute, Nedlands, Western Australia, Australia.

    • Alan James
  39. Research Unit of Molecular Epidemiology, Helmholtz Zentrum München–German Research Center for Environmental Health, Neuherberg, Germany.

    • Melanie Waldenberger
  40. Department of Epidemiology & Preventive Medicine, Monash University, Melbourne, Victoria, Australia.

    • Michael J Abramson
  41. Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.

    • Benjamin P Fairfax
    •  & Julian C Knight
  42. Telethon Institute for Child Health Research, The University of Western Australia, Perth, Western Australia, Australia.

    • Patrick Holt
  43. Centre for Child Health Research, The University of Western Australia, Perth, Western Australia, Australia.

    • Patrick Holt
  44. Queensland Children's Medical Research Institute, University of Queensland, World Health Organization (WHO) Collaborating Centre for Research on Children's Environmental Health, Brisbane, Queensland, Australia.

    • Peter Sly
  45. Division of Genetics, Children's Hospital, Boston, Massachusetts, USA.

    • Joel N Hirschhorn
  46. Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.

    • Joel N Hirschhorn
  47. Department of Dermatology, Allergology and Venerology, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.

    • Stephan Weidinger
  48. Department of Pulmonology, GRIAC, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

    • Dirkje S Postma
  49. Department of Epidemiology and Biostatistics, School of Public Health, Medical Research Council–Health Protection Agency (MRC-HPA) Centre for Environment and Health, Imperial College London, London, UK.

    • Marjo-Riitta Jarvelin
  50. National Institute of Health and Welfare, Oulu, Finland.

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

    • Marjo-Riitta Jarvelin
  52. Department of Pediatric Pulmonology and Pediatric Allergology, Beatrix Children's Hospital, GRIAC, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

    • Gerard H Koppelman

Consortia

  1. Australian Asthma Genetics Consortium (AAGC)

  2. the EArly Genetics and Lifecourse Epidemiology (EAGLE) Consortium

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Contributions

Study-level data analysis: K.B., T.H.P. (meta-analysis and systems biology analyses), R. Granell (meta-analysis), D.P.S., A.C.A. (systems biology analyses), A.L., J.A.C., N.M.W., M.S., M. Kerkhof, B.K.B., M. Kaakinen, P. Sleimann, G.T., K. Schramm, E.K.-M., A.S., L.C., C.S.T., B.P.F., R. Gupta, M.B., S.W., H.H., D.S.P., A.C., G.H.K. and N.T. Study design: K.B., M.C.M., T.H.P., D.P.S., A.L., B.K.B., E.K.-M., A.S., C.F.R., G.W.M., S.C.D., P.E., M.J.A., J.C.K., R. Gupta, P.J.T., J.N.H., M.B., S.W., H.H., J. Heinrich, D.S.P., A.C., C.E.P., M.-R.J., G.H.K., N.T., M.A.F., H.B. and A.J.H. Writing manuscript: K.B., T.H.P., R. Granell, D.P.S., A.C.A., A.L., J.A.C., G.H.K., N.T., M.A.F., H.B. and A.J.H. Data collection: K.B., M.C.M., D.P.S., A.L., I.J., B.K.B., U.T., A.S., J. Hui, E.H.W., D.L.D., G.J., L.P., C.F.R., J.P., E.T., A.-L.H., S.C.D., L.L.H., C.H., A.J., B.P.F., J.C.K., M.J.A., P.J.T., P.H., P. Sly, M.B., H.H., K. Stefansson, J. Heinrich, D.S.P., A.C., M.-R.J., G.H.K., H.B. and A.J.H. Genotyping: K.B., A.L., J.A.C., I.J., P. Sleimann, U.T., S.B., E.K.-M., A.S., B.S.P., C.M.T.T., S.M.R., W.L.M., G.W.M., L.L.H., J.P.K., M.W., H.H., K. Stefansson, A.C., C.E.P., M.-R.J., G.H.K. and H.B. Revising and reviewing manuscript: K.B., M.C.M., T.H.P., R. Granell, D.P.S., A.C.A., A.L., J.A.C., N.M.W., M.S., M. Kerkhof, I.J., B.K.B., M. Kaakinen, P. Sleimann, G.T., U.T., K. Schramm, S.B., E.K.-M., A.S., B.S.P., L.C., J. Hui, E.H.W., C.M.T.T., D.L.D., G.J., S.M.R., W.L.M., L.P., C.F.R., J.P., C.S.T., E.T., G.W.M., A.-L.H., S.C.D., L.L.H., C.H., J.P.K., P.E., A.J., M.W., M.J.A., B.P.F., J.C.K., R. Gupta, P.J.T., P.H., P. Sly, J.N.H., M.B., S.W., H.H., K. Stefansson, J. Heinrich, D.S.P., A.C., C.E.P., M.-R.J., G.H.K., N.T., M.A.F., H.B. and A.J.H.

Competing interests

I.J., G.T., U.T. and K. Stefansson are employees of deCODE Genetics. The other authors declare no competing financial interests.

Corresponding author

Correspondence to Klaus Bønnelykke.

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https://doi.org/10.1038/ng.2694

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