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

被引：443

作者：

Bonnelykke, Klaus ^{[1
,2
]}

Sleiman, Patrick ^{[3
]}

Nielsen, Kasper ^{[4
]}

Kreiner-Moller, Eskil ^{[1
,2
]}

Mercader, Josep M. ^{[5
,6
]}

Belgrave, Danielle ^{[7
,8
,9
]}

den Dekker, Herman T. ^{[10
,11
,12
]}

Husby, Anders ^{[1
,2
,13
]}

Sevelsted, Astrid ^{[1
,2
]}

Faura-Tellez, Grissel ^{[14
,15
]}

Mortensen, Li Juel ^{[1
,2
]}

Paternoster, Lavinia ^{[16
]}

Flaaten, Richard ^{[1
,2
]}

Molgaard, Anne ^{[1
,2
]}

Smart, David E.

Thomsen, Philip F. ^{[17
]}

Rasmussen, Morten A. ^{[18
]}

Bonas-Guarch, Silvia ^{[5
,6
]}

Holst, Claus ^{[19
]}

Nohr, Ellen A. ^{[20
,21
]}

Yadav, Rachita ^{[4
]}

March, Michael E. ^{[3
]}

Blicher, Thomas ^{[22
]}

Lackie, Peter M.

Jaddoe, Vincent W. V. ^{[10
,12
,23
]}

Simpson, Angela ^{[7
,8
]}

Holloway, John W. ^{[14
]}

Duijts, Liesbeth ^{[11
,12
,24
]}

Custovic, Adnan ^{[7
,8
]}

Davies, Donna E. ^{[13
]}

Torrents, David ^{[5
,6
,25
]}

Gupta, Ramneek ^{[4
]}

Hollegaard, Mads V. ^{[26
]}

Hougaard, David M. ^{[26
]}

Hakonarson, Hakon

Bisgaard, Hans

机构：

[1] Univ Copenhagen, Gentofte, Denmark

[2] Copenhagen Univ Hosp, Danish Pediat Asthma Ctr, Gentofte, Denmark

[3] Childrens Hosp Philadelphia, Ctr Appl Gen, Philadelphia, PA 19104 USA

[4] Tech Univ Denmark, Ctr Biol Sequence Anal, Dept Syst Biol, DK-2800 Lyngby, Denmark

[5] Joint Inst Res Biomed, Barcelona, Spain

[6] IRB BSC, Barcelona Supercomputing Ctr, Program Computat Biol, Barcelona, Spain

[7] Univ Manchester, Ctr Resp Med & Allergy, Inst Inflammat & Repair, Manchester, Lancs, England

[8] Univ S Manchester Hosp, Manchester M20 8LR, Lancs, England

[9] Univ Manchester, Ctr Hlth Informat, Inst Populat Hlth, Manchester, Lancs, England

[10] Erasmus MC, Generat R Study Grp, Rotterdam, Netherlands

[11] Erasmus MC, Dept Pediat, Div Resp Med, Rotterdam, Netherlands

[12] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands

[13] Univ Southampton, Southampton Univ Hosp, Fac Med, Brooke Lab Clin & Expt Sci, Southampton, Hants, England

[14] Univ Southampton, Southampton Gen Hosp, Fac Med, Southampton, Hants, England

[15] Univ Groningen, Univ Med Ctr Groningen, Beatrix Childrens Hosp, Groningen Res Inst Asthma & COPD, Groningen, Netherlands

[16] Univ Bristol, Sch Social & Community Med, Integrat Epidemiol Unit, Bristol, Avon, England

[17] Univ Copenhagen, Ctr GeoGenet, Nat Hist Museum Denmark, Copenhagen, Denmark

[18] Univ Copenhagen, Dept Food Sci, Copenhagen, Denmark

[19] Copenhagen Univ Hosp, Inst Prevent Med, Copenhagen, Denmark

[20] Univ Southern Denmark, Inst Clin Res, Aarhus, Denmark

[21] Aarhus Univ, Dept Publ Hlth, Epidemiol Sect, Aarhus, Denmark

[22] Univ Copenhagen, Novo Nordisk Fdn, Fac Hlth Sci, Ctr Prot Res, Copenhagen, Denmark

[23] Erasmus MC, Dept Pediat, Rotterdam, Netherlands

[24] Erasmus MC, Dept Pediat, Div Neonatol, Rotterdam, Netherlands

[25] ICREA, Barcelona, Spain

[26] Statens Serum Inst, Danish Ctr Neonatal Screening, Dept Clin Biochem & Immunol, DK-2300 Copenhagen, Denmark

来源：

NATURE GENETICS | 2014年 / 46卷 / 01期

关键词：

GENOTYPE IMPUTATION; SEQUENCE VARIANTS; AIRWAY; CHILDREN; EXPRESSION; RESOURCE; GENETICS; SAMPLES; COSTS;

D O I：

10.1038/ng.2830

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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.

引用

页码：51 / +

页数：8

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