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 Nohr; Rachita 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

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, 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 journal › Article (Academic Journal) › peer-review

463 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 language	English
Pages (from-to)	51–55
Number of pages	5
Journal	Nature Genetics
Volume	46
Issue number	1
DOIs	https://doi.org/10.1038/ng.2830
Publication status	Published - 17 Nov 2013

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/ng.2830

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Alam, S. R. (Manager), Eccleston, P. E. (Other), Williams, D. A. G. (Manager) & Atack, S. H. (Other)
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Dr Lavinia Paternoster
- lavinia.paternosterbristol.acuk
- Bristol Medical School (PHS) - Associate Professor in Genetic Epidemiology
- Bristol Population Health Science Institute
- MRC Integrative Epidemiology Unit
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Cite this

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. (2013). 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

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

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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author = "Klaus B{\o}nnelykke and Patrick Sleiman and Kasper Nielsen and Eskil Kreiner-M{\o}ller and Mercader, {Josep M} and Danielle Belgrave and {den Dekker}, {Herman T} and Anders Husby and Astrid Sevelsted and Grissel Faura-Tellez and Mortensen, {Li Juel} and Lavinia Paternoster and Richard Flaaten and Anne M{\o}lgaard and Smart, {D E} and Thomsen, {Philip F} and Rasmussen, {Morten A} and Silvia Bon{\`a}s-Guarch and Claus Holst and Nohr, {Ellen A} and Rachita Yadav and March, {Michael E} and Thomas Blicher and Lackie, {Peter M} and Jaddoe, {Vincent W V} and Angela Simpson and Holloway, {John W} and Liesbeth Duijts and Adnan Custovic and Davies, {Donna E} and David Torrents and Ramneek Gupta and Hollegaard, {Mads V} and Hougaard, {David M} and Hakon Hakonarson and Hans Bisgaard",

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doi = "10.1038/ng.2830",

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Bønnelykke, K, Sleiman, P, Nielsen, K, Kreiner-Møller, E, Mercader, JM, Belgrave, D, den Dekker, HT, Husby, A, Sevelsted, A, Faura-Tellez, G, Mortensen, LJ, Paternoster, L, Flaaten, R, Mølgaard, A, Smart, DE, Thomsen, PF, Rasmussen, MA, Bonàs-Guarch, S, Holst, C, Nohr, EA, Yadav, R, March, ME, Blicher, T, Lackie, PM, Jaddoe, VWV, Simpson, A, Holloway, JW, Duijts, L, Custovic, A, Davies, DE, Torrents, D, Gupta, R, Hollegaard, MV, Hougaard, DM, Hakonarson, H & Bisgaard, H 2013, 'A genome-wide association study identifies CDHR3 as a susceptibility locus for early childhood asthma with severe exacerbations', Nature Genetics, vol. 46, no. 1, pp. 51–55. https://doi.org/10.1038/ng.2830

TY - JOUR

T1 - A genome-wide association study identifies CDHR3 as a susceptibility locus for early childhood asthma with severe exacerbations

AU - Bønnelykke, Klaus

AU - Sleiman, Patrick

AU - Nielsen, Kasper

AU - Kreiner-Møller, Eskil

AU - Mercader, Josep M

AU - Belgrave, Danielle

AU - den Dekker, Herman T

AU - Husby, Anders

AU - Sevelsted, Astrid

AU - Faura-Tellez, Grissel

AU - Mortensen, Li Juel

AU - Paternoster, Lavinia

AU - Flaaten, Richard

AU - Mølgaard, Anne

AU - Smart, D E

AU - Thomsen, Philip F

AU - Rasmussen, Morten A

AU - Bonàs-Guarch, Silvia

AU - Holst, Claus

AU - Nohr, Ellen A

AU - Yadav, Rachita

AU - March, Michael E

AU - Blicher, Thomas

AU - Lackie, Peter M

AU - Jaddoe, Vincent W V

AU - Simpson, Angela

AU - Holloway, John W

AU - Duijts, Liesbeth

AU - Custovic, Adnan

AU - Davies, Donna E

AU - Torrents, David

AU - Gupta, Ramneek

AU - Hollegaard, Mads V

AU - Hougaard, David M

AU - Hakonarson, Hakon

AU - Bisgaard, Hans

PY - 2013/11/17

Y1 - 2013/11/17

N2 - 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.

AB - 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.

KW - Asthma

KW - Cadherins

KW - Case-Control Studies

KW - Child

KW - Child, Preschool

KW - Chromosomes, Human, Pair 17

KW - DNA Repair Enzymes

KW - DNA-Binding Proteins

KW - Denmark

KW - Female

KW - Genetic Predisposition to Disease

KW - Genome-Wide Association Study

KW - Humans

KW - Interleukins

KW - Male

KW - Membrane Proteins

KW - Models, Molecular

KW - Neoplasm Proteins

KW - Polymorphism, Single Nucleotide

KW - Protein Conformation

KW - Receptors, Cell Surface

U2 - 10.1038/ng.2830

DO - 10.1038/ng.2830

M3 - Article (Academic Journal)

C2 - 24241537

SN - 1061-4036

VL - 46

SP - 51

EP - 55

JO - Nature Genetics

JF - Nature Genetics

IS - 1

ER -

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

Abstract

Keywords

UN SDGs

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