A genome-wide association study identifies CDHR3 as a susceptibility locus for early childhood asthma with severe exacerbations.
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.
1] Copenhagen Prospective Studies on Asthma in Childhood, Health Sciences, University of Copenhagen & Danish Pediatric Asthma Center, Copenhagen University Hospital, Gentofte, Denmark. [2] [3].
Klaus
K
Bønnelykke
1] Center for Applied Genomics, Children's Hospital of Philadelphia (CHOP), Philadelphia, Pennsylvania, USA. [2].
Patrick
P
Sleiman
1] Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark, Lyngby, Denmark. [2].
Kasper
0000000255107767
K
Nielsen
Copenhagen Prospective Studies on Asthma in Childhood, Health Sciences, University of Copenhagen & Danish Pediatric Asthma Center, Copenhagen University Hospital, Gentofte, Denmark.
Eskil
0000000312042438
E
Kreiner-Møller
Joint Institute for Research in Biomedicine and Barcelona Supercomputing Center (IRB-BSC) Program on Computational Biology, Barcelona Supercomputing Center, Barcelona, Spain.
Josep M
JM
Mercader
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.
Danielle
D
Belgrave
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.
Herman T
HT
den Dekker
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.
Anders
A
Husby
Copenhagen Prospective Studies on Asthma in Childhood, Health Sciences, University of Copenhagen & Danish Pediatric Asthma Center, Copenhagen University Hospital, Gentofte, Denmark.
Astrid
A
Sevelsted
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.
Grissel
G
Faura-Tellez
Copenhagen Prospective Studies on Asthma in Childhood, Health Sciences, University of Copenhagen & Danish Pediatric Asthma Center, Copenhagen University Hospital, Gentofte, Denmark.
Li Juel
LJ
Mortensen
Integrative Epidemiology Unit, School of Social & Community Medicine, University of Bristol, Bristol, UK.
Lavinia
L
Paternoster
Copenhagen Prospective Studies on Asthma in Childhood, Health Sciences, University of Copenhagen & Danish Pediatric Asthma Center, Copenhagen University Hospital, Gentofte, Denmark.
Richard
R
Flaaten
Copenhagen Prospective Studies on Asthma in Childhood, Health Sciences, University of Copenhagen & Danish Pediatric Asthma Center, Copenhagen University Hospital, Gentofte, Denmark.
Anne
A
Mølgaard
Brooke Laboratory, Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, University Hospital Southampton, Southampton, UK.
David E
DE
Smart
Center for GeoGenetics, Natural History Museum of Denmark, University of Copenhagen, Copenhagen, Denmark.
Philip F
PF
Thomsen
Department of Food Science, University of Copenhagen, Copenhagen, Denmark.
Morten A
MA
Rasmussen
Joint Institute for Research in Biomedicine and Barcelona Supercomputing Center (IRB-BSC) Program on Computational Biology, Barcelona Supercomputing Center, Barcelona, Spain.
Silvia
S
Bonàs-Guarch
Institute of Preventive Medicine, Copenhagen University Hospital, Copenhagen, Denmark.
Claus
C
Holst
1] Institute of Clinical Research, University of Southern Denmark, Aarhus, Denmark. [2] Department of Public Health, Section for Epidemiology, Aarhus University, Aarhus, Denmark.
Ellen A
EA
Nohr
Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark, Lyngby, Denmark.
Rachita
R
Yadav
Center for Applied Genomics, Children's Hospital of Philadelphia (CHOP), Philadelphia, Pennsylvania, USA.
Michael E
ME
March
Novo Nordisk Foundation Center for Protein Research, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.
Thomas
T
Blicher
Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton, UK.
Peter M
PM
Lackie
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.
Vincent W V
VW
Jaddoe
Centre for Respiratory Medicine and Allergy, Institute of Inflammation and Repair, University of Manchester and University Hospital of South Manchester, Manchester, UK.
Angela
A
Simpson
Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton, UK.
John W
JW
Holloway
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.
Liesbeth
L
Duijts
Centre for Respiratory Medicine and Allergy, Institute of Inflammation and Repair, University of Manchester and University Hospital of South Manchester, Manchester, UK.
Adnan
A
Custovic
Brooke Laboratory, Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, University Hospital Southampton, Southampton, UK.
Donna E
DE
Davies
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.
David
D
Torrents
Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark, Lyngby, Denmark.
Ramneek
R
Gupta
Danish Centre for Neonatal Screening, Department of Clinical Biochemistry and Immunology, Statens Serum Institut (SSI), Copenhagen, Denmark.
Mads V
MV
Hollegaard
Danish Centre for Neonatal Screening, Department of Clinical Biochemistry and Immunology, Statens Serum Institut (SSI), Copenhagen, Denmark.
David M
DM
Hougaard
1] Center for Applied Genomics, Children's Hospital of Philadelphia (CHOP), Philadelphia, Pennsylvania, USA. [2].
Hakon
H
Hakonarson
1] Copenhagen Prospective Studies on Asthma in Childhood, Health Sciences, University of Copenhagen & Danish Pediatric Asthma Center, Copenhagen University Hospital, Gentofte, Denmark. [2].
Hans
H
Bisgaard
D017766:Acid Anhydride Hydrolases; D001249:Asthma / Q000209:etiology / Q000235:genetics*; D000070585:Cadherin Related Proteins; D015820:Cadherins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D002886:Chromosomes, Human, Pair 17; D045643:DNA Repair Enzymes / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D003718:Denmark; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D000072179:Interleukin-1 Receptor-Like 1 Protein; D000067596:Interleukin-33; D007378:Interleukins / Q000235:genetics; D008297:Male; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D008958:Models, Molecular; D009363:Neoplasm Proteins / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D011487:Protein Conformation; D011956:Receptors, Cell Surface / Q000235:genetics; D000094524:Gasdermins
D017766:Acid Anhydride Hydrolases; D000070585:Cadherin Related Proteins; D015820:Cadherins; D045643:DNA Repair Enzymes; D004268:DNA-Binding Proteins; D000072179:Interleukin-1 Receptor-Like 1 Protein; D000067596:Interleukin-33; D007378:Interleukins; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D011956:Receptors, Cell Surface; C586717:CDHR3 protein, human; C527978:GSDMB protein, human; D000094524:Gasdermins; C079241:IL1RL1 protein, human; C506536:IL33 protein, human; C112158:RAD50 protein, human