A genome-wide association study identifies CDHR3 as a susceptibility locus for early childhood asthma with severe exacerbations

Klaus Bønnelykke¹, Patrick Sleiman², Kasper Nielsen³, Eskil Kreiner-Møller⁴, Josep M Mercader⁵, Danielle Belgrave⁶, Herman T den Dekker⁷, Anders Husby⁸, Astrid Sevelsted⁴, Grissel Faura-Tellez⁹, Li Juel Mortensen⁴, Lavinia Paternoster¹⁰, Richard Flaaten⁴, Anne Mølgaard⁴, David E Smart¹¹, Philip F Thomsen¹², Morten A Rasmussen¹³, Silvia Bonàs-Guarch⁵, Claus Holst¹⁴, Ellen A Nohr¹⁵, Rachita Yadav¹⁶, Michael E March¹⁷, Thomas Blicher¹⁸, Peter M Lackie¹⁹, Vincent W V Jaddoe²⁰, Angela Simpson²¹, John W Holloway¹⁹, Liesbeth Duijts²², Adnan Custovic²¹, Donna E Davies¹¹, David Torrents²³, Ramneek Gupta¹⁶, Mads V Hollegaard²⁴, David M Hougaard²⁴, Hakon Hakonarson², Hans Bisgaard²⁵

Affiliations

¹ 1] Copenhagen Prospective Studies on Asthma in Childhood, Health Sciences, University of Copenhagen & Danish Pediatric Asthma Center, Copenhagen University Hospital, Gentofte, Denmark. [2] [3].
² 1] Center for Applied Genomics, Children's Hospital of Philadelphia (CHOP), Philadelphia, Pennsylvania, USA. [2].
³ 1] Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark, Lyngby, Denmark. [2].
⁴ Copenhagen Prospective Studies on Asthma in Childhood, Health Sciences, University of Copenhagen & Danish Pediatric Asthma Center, Copenhagen University Hospital, Gentofte, Denmark.
⁵ Joint Institute for Research in Biomedicine and Barcelona Supercomputing Center (IRB-BSC) Program on Computational Biology, Barcelona Supercomputing Center, Barcelona, Spain.
⁶ 1] Centre for Respiratory Medicine and Allergy, Institute of Inflammation and Repair, University of Manchester and University Hospital of South Manchester, Manchester, UK. [2] Centre for Health Informatics, Institute of Population Health, University of Manchester, Manchester, UK.
⁷ 1] Generation R Study Group, Erasmus Medical Center, Rotterdam, The Netherlands. [2] Department of Pediatrics, Division of Respiratory Medicine, Erasmus Medical Center, Rotterdam, The Netherlands. [3] Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.
⁸ 1] Copenhagen Prospective Studies on Asthma in Childhood, Health Sciences, University of Copenhagen & Danish Pediatric Asthma Center, Copenhagen University Hospital, Gentofte, Denmark. [2] Brooke Laboratory, Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, University Hospital Southampton, Southampton, UK.
⁹ 1] Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton, UK. [2] 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.
¹⁰ Integrative Epidemiology Unit, School of Social & Community Medicine, University of Bristol, Bristol, UK.
¹¹ Brooke Laboratory, Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, University Hospital Southampton, Southampton, UK.
¹² Center for GeoGenetics, Natural History Museum of Denmark, University of Copenhagen, Copenhagen, Denmark.
¹³ Department of Food Science, University of Copenhagen, Copenhagen, Denmark.
¹⁴ Institute of Preventive Medicine, Copenhagen University Hospital, Copenhagen, Denmark.
¹⁵ 1] Institute of Clinical Research, University of Southern Denmark, Aarhus, Denmark. [2] Department of Public Health, Section for Epidemiology, Aarhus University, Aarhus, Denmark.
¹⁶ Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark, Lyngby, Denmark.
¹⁷ Center for Applied Genomics, Children's Hospital of Philadelphia (CHOP), Philadelphia, Pennsylvania, USA.
¹⁸ Novo Nordisk Foundation Center for Protein Research, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.
¹⁹ Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton, UK.
²⁰ 1] Generation R Study Group, Erasmus Medical Center, Rotterdam, The Netherlands. [2] Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands. [3] Department of Pediatrics, Erasmus Medical Center, Rotterdam, The Netherlands.
²¹ Centre for Respiratory Medicine and Allergy, Institute of Inflammation and Repair, University of Manchester and University Hospital of South Manchester, Manchester, UK.
²² 1] Department of Pediatrics, Division of Respiratory Medicine, Erasmus Medical Center, Rotterdam, The Netherlands. [2] Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands. [3] Department of Pediatrics, Division of Neonatology, Erasmus Medical Center, Rotterdam, The Netherlands.
²³ 1] Joint Institute for Research in Biomedicine and Barcelona Supercomputing Center (IRB-BSC) Program on Computational Biology, Barcelona Supercomputing Center, Barcelona, Spain. [2] Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain.
²⁴ Danish Centre for Neonatal Screening, Department of Clinical Biochemistry and Immunology, Statens Serum Institut (SSI), Copenhagen, Denmark.
²⁵ 1] Copenhagen Prospective Studies on Asthma in Childhood, Health Sciences, University of Copenhagen & Danish Pediatric Asthma Center, Copenhagen University Hospital, Gentofte, Denmark. [2].

PMID: 24241537
DOI: 10.1038/ng.2830

A genome-wide association study identifies CDHR3 as a susceptibility locus for early childhood asthma with severe exacerbations

Klaus Bønnelykke et al. Nat Genet. 2014 Jan.

. 2014 Jan;46(1):51-5.

doi: 10.1038/ng.2830. Epub 2013 Nov 17.

Authors

Affiliations

¹ 1] Copenhagen Prospective Studies on Asthma in Childhood, Health Sciences, University of Copenhagen & Danish Pediatric Asthma Center, Copenhagen University Hospital, Gentofte, Denmark. [2] [3].
² 1] Center for Applied Genomics, Children's Hospital of Philadelphia (CHOP), Philadelphia, Pennsylvania, USA. [2].
³ 1] Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark, Lyngby, Denmark. [2].
⁴ Copenhagen Prospective Studies on Asthma in Childhood, Health Sciences, University of Copenhagen & Danish Pediatric Asthma Center, Copenhagen University Hospital, Gentofte, Denmark.
⁵ Joint Institute for Research in Biomedicine and Barcelona Supercomputing Center (IRB-BSC) Program on Computational Biology, Barcelona Supercomputing Center, Barcelona, Spain.
⁶ 1] Centre for Respiratory Medicine and Allergy, Institute of Inflammation and Repair, University of Manchester and University Hospital of South Manchester, Manchester, UK. [2] Centre for Health Informatics, Institute of Population Health, University of Manchester, Manchester, UK.
⁷ 1] Generation R Study Group, Erasmus Medical Center, Rotterdam, The Netherlands. [2] Department of Pediatrics, Division of Respiratory Medicine, Erasmus Medical Center, Rotterdam, The Netherlands. [3] Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.
⁸ 1] Copenhagen Prospective Studies on Asthma in Childhood, Health Sciences, University of Copenhagen & Danish Pediatric Asthma Center, Copenhagen University Hospital, Gentofte, Denmark. [2] Brooke Laboratory, Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, University Hospital Southampton, Southampton, UK.
⁹ 1] Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton, UK. [2] 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.
¹⁰ Integrative Epidemiology Unit, School of Social & Community Medicine, University of Bristol, Bristol, UK.
¹¹ Brooke Laboratory, Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, University Hospital Southampton, Southampton, UK.
¹² Center for GeoGenetics, Natural History Museum of Denmark, University of Copenhagen, Copenhagen, Denmark.
¹³ Department of Food Science, University of Copenhagen, Copenhagen, Denmark.
¹⁴ Institute of Preventive Medicine, Copenhagen University Hospital, Copenhagen, Denmark.
¹⁵ 1] Institute of Clinical Research, University of Southern Denmark, Aarhus, Denmark. [2] Department of Public Health, Section for Epidemiology, Aarhus University, Aarhus, Denmark.
¹⁶ Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark, Lyngby, Denmark.
¹⁷ Center for Applied Genomics, Children's Hospital of Philadelphia (CHOP), Philadelphia, Pennsylvania, USA.
¹⁸ Novo Nordisk Foundation Center for Protein Research, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.
¹⁹ Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton, UK.
²⁰ 1] Generation R Study Group, Erasmus Medical Center, Rotterdam, The Netherlands. [2] Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands. [3] Department of Pediatrics, Erasmus Medical Center, Rotterdam, The Netherlands.
²¹ Centre for Respiratory Medicine and Allergy, Institute of Inflammation and Repair, University of Manchester and University Hospital of South Manchester, Manchester, UK.
²² 1] Department of Pediatrics, Division of Respiratory Medicine, Erasmus Medical Center, Rotterdam, The Netherlands. [2] Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands. [3] Department of Pediatrics, Division of Neonatology, Erasmus Medical Center, Rotterdam, The Netherlands.
²³ 1] Joint Institute for Research in Biomedicine and Barcelona Supercomputing Center (IRB-BSC) Program on Computational Biology, Barcelona Supercomputing Center, Barcelona, Spain. [2] Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain.
²⁴ Danish Centre for Neonatal Screening, Department of Clinical Biochemistry and Immunology, Statens Serum Institut (SSI), Copenhagen, Denmark.
²⁵ 1] Copenhagen Prospective Studies on Asthma in Childhood, Health Sciences, University of Copenhagen & Danish Pediatric Asthma Center, Copenhagen University Hospital, Gentofte, Denmark. [2].

PMID: 24241537
DOI: 10.1038/ng.2830

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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References

1. J Allergy Clin Immunol. 2011 May;127(5):1155-64.e2 - PubMed
1. Nucleic Acids Res. 2012 Jan;40(Database issue):D930-4 - PubMed
1. Can J Physiol Pharmacol. 2008 Mar;86(3):105-12 - PubMed
1. Int J Biochem Cell Biol. 2009 Feb;41(2):349-69 - PubMed
1. J Allergy Clin Immunol. 2010 Sep;126(3):626-30 - PubMed

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A genome-wide association study identifies CDHR3 as a susceptibility locus for early childhood asthma with severe exacerbations

Affiliations

A genome-wide association study identifies CDHR3 as a susceptibility locus for early childhood asthma with severe exacerbations

Authors

Affiliations

Abstract

References

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Medical

Molecular Biology Databases

Research Materials

Miscellaneous