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, David E Smart, Philip Francis Thomsen, Morten A Rasmussen, Silvia Bonàs-Guarch, Claus Holst, Ellen A Nohr & 16 others Rachita Yadav, Michael E March, Thomas Holberg 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 Flinker Bisgaard

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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
JournalNature Genetics
Volume46
Issue number1
Pages (from-to)51-5
ISSN1061-4036
DOIs
Publication statusPublished - Jan 2014

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Genome-Wide Association Study
Neonatal Screening
Registries
Epithelium
DNA
Health

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Bønnelykke, K., Sleiman, P., Nielsen, K., Kreiner-Møller, E., Mercader, J. M., Belgrave, D., ... Bisgaard, H. F. (2014). A genome-wide association study identifies CDHR3 as a susceptibility locus for early childhood asthma with severe exacerbations. Nature Genetics, 46(1), 51-5. https://doi.org/10.1038/ng.2830
Bønnelykke, Klaus ; Sleiman, Patrick ; Nielsen, Kasper ; Kreiner-Møller, Eskil ; Mercader, Josep M ; Belgrave, Danielle ; den Dekker, Herman T ; Husby, Anders ; Sevelsted, Astrid ; Faura-Tellez, Grissel ; Mortensen, Li Juel ; Paternoster, Lavinia ; Flaaten, Richard ; Mølgaard, Anne ; Smart, David E ; Thomsen, Philip Francis ; Rasmussen, Morten A ; Bonàs-Guarch, Silvia ; Holst, Claus ; Nohr, Ellen A ; Yadav, Rachita ; March, Michael E ; Blicher, Thomas Holberg ; Lackie, Peter M ; Jaddoe, Vincent W V ; Simpson, Angela ; Holloway, John W ; Duijts, Liesbeth ; Custovic, Adnan ; Davies, Donna E ; Torrents, David ; Gupta, Ramneek ; Hollegaard, Mads V ; Hougaard, David M ; Hakonarson, Hakon ; Bisgaard, Hans Flinker. / A genome-wide association study identifies CDHR3 as a susceptibility locus for early childhood asthma with severe exacerbations. In: Nature Genetics. 2014 ; Vol. 46, No. 1. pp. 51-5.
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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.",
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, {David E} and Thomsen, {Philip Francis} 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 Blicher, {Thomas Holberg} 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 Bisgaard, {Hans Flinker}",
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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, TH, 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, HF 2014, '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. 51-5. https://doi.org/10.1038/ng.2830

A genome-wide association study identifies CDHR3 as a susceptibility locus for early childhood asthma with severe exacerbations. / Bønnelykke, Klaus; Sleiman, Patrick; Nielsen, Kasper; Kreiner-Møller, Eskil; Mercader, Josep M; Belgrave, Danielle; den Dekker, Herman T; Husby, Anders; Sevelsted, Astrid; Faura-Tellez, Grissel; Mortensen, Li Juel; Paternoster, Lavinia; Flaaten, Richard; Mølgaard, Anne; Smart, David E; Thomsen, Philip Francis; Rasmussen, Morten A; Bonàs-Guarch, Silvia; Holst, Claus; Nohr, Ellen A; Yadav, Rachita; March, Michael E; Blicher, Thomas Holberg; Lackie, Peter M; Jaddoe, Vincent W V; Simpson, Angela; Holloway, John W; Duijts, Liesbeth; Custovic, Adnan; Davies, Donna E; Torrents, David; Gupta, Ramneek; Hollegaard, Mads V; Hougaard, David M; Hakonarson, Hakon; Bisgaard, Hans Flinker.

In: Nature Genetics, Vol. 46, No. 1, 01.2014, p. 51-5.

Research output: Contribution to journalJournal articleResearchpeer-review

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, David E

AU - Thomsen, Philip Francis

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 Holberg

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 Flinker

PY - 2014/1

Y1 - 2014/1

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.

U2 - 10.1038/ng.2830

DO - 10.1038/ng.2830

M3 - Journal article

VL - 46

SP - 51

EP - 55

JO - Nature Genetics

JF - Nature Genetics

SN - 1061-4036

IS - 1

ER -