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

Klaus Bønnelykke, Patrick Sleiman, Kasper Nielsen, Eskil Kreiner-Møller, Josep M Mercader, Danielle Belgrave, Herman T den Dekker, Anders Husby, Astrid Sevelsted, Grissel Faura-Tellez, Li Juel Mortensen, Lavinia Paternoster, Richard Flaaten, Anne Mølgaard, D E Smart, Philip F Thomsen, Morten A Rasmussen, Silvia Bonàs-Guarch, Claus Holst, Ellen A NohrRachita Yadav, Michael E March, Thomas Blicher, Peter M Lackie, Vincent W V Jaddoe, Angela Simpson, John W Holloway, Liesbeth Duijts, Adnan Custovic, Donna E Davies, David Torrents, Ramneek Gupta, Mads V Hollegaard, David M Hougaard, Hakon Hakonarson, Hans Bisgaard

Research output: Contribution to journalArticle (Academic Journal)

284 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)51–55
Number of pages5
JournalNature Genetics
Volume46
Issue number1
DOIs
Publication statusPublished - Jan 2014

Keywords

  • Asthma
  • Cadherins
  • Case-Control Studies
  • Child
  • Child, Preschool
  • Chromosomes, Human, Pair 17
  • DNA Repair Enzymes
  • DNA-Binding Proteins
  • Denmark
  • Female
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study
  • Humans
  • Interleukins
  • Male
  • Membrane Proteins
  • Models, Molecular
  • Neoplasm Proteins
  • Polymorphism, Single Nucleotide
  • Protein Conformation
  • Receptors, Cell Surface

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    Bønnelykke, K., Sleiman, P., Nielsen, K., Kreiner-Møller, E., Mercader, J. M., Belgrave, D., den Dekker, H. T., Husby, A., Sevelsted, A., Faura-Tellez, G., Mortensen, L. J., Paternoster, L., Flaaten, R., Mølgaard, A., Smart, D. E., Thomsen, P. F., Rasmussen, M. A., Bonàs-Guarch, S., Holst, C., ... Bisgaard, H. (2014). A genome-wide association study identifies CDHR3 as a susceptibility locus for early childhood asthma with severe exacerbations. Nature Genetics, 46(1), 51–55. https://doi.org/10.1038/ng.2830