Abstract

Asthma exacerbations are among the most frequent causes of hospitalization during childhood, but the underlying mechanisms are poorly understood. We performed a genome-wide association study of a specific asthma phenotype characterized by recurrent, severe exacerbations occurring between 2 and 6 years of age in a total of 1,173 cases and 2,522 controls. Cases were identified from national health registries of hospitalization, and DNA was obtained from the Danish Neonatal Screening Biobank. We identified five loci with genome-wide significant association. Four of these, GSDMB, IL33, RAD50 and IL1RL1, were previously reported as asthma susceptibility loci, but the effect sizes for these loci in our cohort were considerably larger than in the previous genome-wide association studies of asthma. We also obtained strong evidence for a new susceptibility gene, CDHR3 (encoding cadherin-related family member 3), which is highly expressed in airway epithelium. These results demonstrate the strength of applying specific phenotyping in the search for asthma susceptibility genes.

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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
    • , Patrick Sleiman
    •  & Kasper Nielsen

    These authors contributed equally to this work.

    • Klaus Bønnelykke
    • , Hakon Hakonarson
    •  & Hans Bisgaard

    These authors jointly directed this work.

Affiliations

  1. Copenhagen Prospective Studies on Asthma in Childhood, Health Sciences, University of Copenhagen & Danish Pediatric Asthma Center, Copenhagen University Hospital, Gentofte, Denmark.

    • Klaus Bønnelykke
    • , Eskil Kreiner-Møller
    • , Anders Husby
    • , Astrid Sevelsted
    • , Li Juel Mortensen
    • , Richard Flaaten
    • , Anne Mølgaard
    •  & Hans Bisgaard
  2. Center for Applied Genomics, Children's Hospital of Philadelphia (CHOP), Philadelphia, Pennsylvania, USA.

    • Patrick Sleiman
    • , Michael E March
    •  & Hakon Hakonarson
  3. Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark, Lyngby, Denmark.

    • Kasper Nielsen
    • , Rachita Yadav
    •  & Ramneek Gupta
  4. Joint Institute for Research in Biomedicine and Barcelona Supercomputing Center (IRB-BSC) Program on Computational Biology, Barcelona Supercomputing Center, Barcelona, Spain.

    • Josep M Mercader
    • , Silvia Bonàs-Guarch
    •  & David Torrents
  5. Centre for Respiratory Medicine and Allergy, Institute of Inflammation and Repair, University of Manchester and University Hospital of South Manchester, Manchester, UK.

    • Danielle Belgrave
    • , Angela Simpson
    •  & Adnan Custovic
  6. Centre for Health Informatics, Institute of Population Health, University of Manchester, Manchester, UK.

    • Danielle Belgrave
  7. Generation R Study Group, Erasmus Medical Center, Rotterdam, The Netherlands.

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

    • Herman T den Dekker
    •  & Liesbeth Duijts
  9. Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.

    • Herman T den Dekker
    • , Vincent W V Jaddoe
    •  & Liesbeth Duijts
  10. Brooke Laboratory, Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, University Hospital Southampton, Southampton, UK.

    • Anders Husby
    • , David E Smart
    •  & Donna E Davies
  11. Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton, UK.

    • Grissel Faura-Tellez
    • , Peter M Lackie
    •  & John W Holloway
  12. Pediatric Pulmonology and Pediatric Allergology, University of Groningen, University Medical Center Groningen, Beatrix Children's Hospital, Groningen Research Institute for Asthma and COPD, Groningen, The Netherlands.

    • Grissel Faura-Tellez
  13. Integrative Epidemiology Unit, School of Social & Community Medicine, University of Bristol, Bristol, UK.

    • Lavinia Paternoster
  14. Center for GeoGenetics, Natural History Museum of Denmark, University of Copenhagen, Copenhagen, Denmark.

    • Philip F Thomsen
  15. Department of Food Science, University of Copenhagen, Copenhagen, Denmark.

    • Morten A Rasmussen
  16. Institute of Preventive Medicine, Copenhagen University Hospital, Copenhagen, Denmark.

    • Claus Holst
  17. Institute of Clinical Research, University of Southern Denmark, Aarhus, Denmark.

    • Ellen A Nohr
  18. Department of Public Health, Section for Epidemiology, Aarhus University, Aarhus, Denmark.

    • Ellen A Nohr
  19. Novo Nordisk Foundation Center for Protein Research, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.

    • Thomas Blicher
  20. Department of Pediatrics, Erasmus Medical Center, Rotterdam, The Netherlands.

    • Vincent W V Jaddoe
  21. Department of Pediatrics, Division of Neonatology, Erasmus Medical Center, Rotterdam, The Netherlands.

    • Liesbeth Duijts
  22. Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain.

    • David Torrents
  23. Danish Centre for Neonatal Screening, Department of Clinical Biochemistry and Immunology, Statens Serum Institut (SSI), Copenhagen, Denmark.

    • Mads V Hollegaard
    •  & David M Hougaard

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Contributions

K.B. was the main author responsible for designing the study, analyzing and interpreting data, writing the manuscript and directing the work. He had full access to the data and final responsibility for the decision to submit the work for publication. H.B. contributed to design of the study, analysis of data and writing of the manuscript. P.S. and H.H. contributed to design of the study and analysis of data in relation to whole-genome genotyping. K.N. performed the GWAS analysis and contributed to regional imputation. E.K.-M., A. Sevelsted, M.A.R., R.Y. and R.G. contributed to data analysis. J.M.M., S.B.-G. and D.T. directed and contributed to regional imputation and data analyses. M.V.H. and D.M.H. were responsible for subject identification, collection of dried blood spots and DNA extraction and amplification. K.B., E.K.-M., L.J.M., R.F. and A.M. contributed to data acquisition. T.B. performed modeling of the CDHR3 protein structure. L.P., C.H. and E.A.N. were responsible for data from the discovery control cohort. H.H. and M.E.M. were responsible for the functional studies of the CDHR3 variant involving flow cytometry. A.H., D.E.S. and D.E.D. were responsible for the experimental studies involving immunofluorescence staining. A. Simpson, A.C. and D.B. were responsible for data from the MAAS cohort. H.T.d.D., L.D. and V.W.V.J. were responsible for data from the Generation R cohort. G.F.-T., P.M.L. and J.W.H. were responsible for the studies of lung tissue. P.F.T. studied the evolutionary aspects of the CDHR3 risk variant (rs6967330). All coauthors provided important intellectual input to the study and approved the final version of the manuscript.

Competing interests

A patent has been filed for CDHR3 as a susceptibility gene for asthma by K.B., H.B. and H.H. on behalf of COPSAC and CHOP. None of the authors report any other conflict of interest relevant to the content of this report.

Corresponding author

Correspondence to Klaus Bønnelykke.

Supplementary information

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    Supplementary Text and Figures

    Supplementary Figures 1–10, Supplementary Tables 1–11 and Supplementary Note