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Article: Genome-wide association study identifies NRG1 as a susceptibility locus for Hirschsprung's disease
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TitleGenome-wide association study identifies NRG1 as a susceptibility locus for Hirschsprung's disease
 
AuthorsGarcia-Barcelo, MM6
Tang, CSM
Ngan, ESW6
Lui, VCH6
Chen, Y6
So, MT
Leon, TYY
Miao, XP2
Shum, CKY
Liu, FQ
Yeung, MY
Yuan, ZW4
Guo, WH7
Liu, L
Sun, XB9
Huang, LM8
Tou, JF5
Song, YQ
Chan, D
Cheung, KMC1
Wong, KKY
Cherny, SS3
Sham, PC6
Tam, PKH6
 
KeywordsGWA
RET
 
Issue Date2009
 
PublisherNational Academy of Sciences. The Journal's web site is located at http://www.pnas.org
 
CitationProceedings Of The National Academy Of Sciences Of The United States Of America, 2009, v. 106 n. 8, p. 2694-2699 [How to Cite?]
DOI: http://dx.doi.org/10.1073/pnas.0809630105
 
AbstractHirschsprung's disease (HSCR), or aganglionic megacolon, is a congenital disorder characterized by the absence of enteric ganglia in variable portions of the distal intestine. RET is a well-established susceptibility locus, although existing evidence strongly suggests additional loci contributing to sporadic HSCR. To identify these additional genetic loci, we carried out a genome-wide association study using the Affymetrix 500K marker set. We successfully genotyped 293,836 SNPs in 181 Chinese subjects with sporadic HSCR and 346 ethnically matched control subjects. The SNPs most associated with HSCR were genotyped in an independent set of 190 HSCR and 510 control subjects. Aside from SNPs in RET, the strongest overall associations in plausible candidate genes were found for 2 SNPs located in intron 1 of the neuregulin 1 gene (NRG1) on 8p12, with rs16879552 and rs7835688 yielding odds ratios of 1.68 [Cl 95%:(1.40, 2.00), P= 1.80 × 10-8] and 1.98 [Cl 95%:(1.59, 2.47), P = 1.12 × 10-9], respectively, for the heterozygous risk genotypes under an additive model. There was also a significant interaction between RET and NRG1 (P = 0.0095), increasing the odds ratio 2.3-fold to 19.53 for the RET rs2435357 risk genotype (TT) in the presence of the NRG1 rs7835688 heterozygote, indicating that NRG1 is a modifier of HSRC penetrance. Our highly significant association findings are backed-up by the important role of NRG1 as regulator of the development of the enteric ganglia precursors. The identification of NRG1 as an additional HSCR susceptibility locus not only opens unique fields of investigation into the mechanisms underlying the HSCR pathology, but also the mechanisms by which a discrete number of loci interact with each other to cause disease. © 2009 by The National Academy of Sciences of the USA.
 
ISSN0027-8424
2013 Impact Factor: 9.809
 
DOIhttp://dx.doi.org/10.1073/pnas.0809630105
 
PubMed Central IDPMC2650328
 
ISI Accession Number IDWOS:000263652900042
Funding AgencyGrant Number
Hong Kong Research Grants CouncilHKU 765407M
HKU 775907M
University Grants Committee of Hong KongAoE/M-04/04
National Institutes of HealthEY-12562
Funding Information:

We thank all subjects who participated in the study. We also thank the Genome Research Centre of the University of Hong Kong, and in particular to Dr. Agnes Chan and Prof. Kathryn S. E. Cheah for their assistance. This work was supported by research Grants HKU 765407M (to M.-M. G.-B.) and HKU 775907M (to P. K. T.) from the Hong Kong Research Grants Council, the University Grants Committee of Hong Kong Grant AoE/M-04/04 and National Institutes of Health Grant EY-12562 (to S. S. C. and P. C. S.).

 
ReferencesReferences in Scopus
 
GrantsGenetic dissection of Hirschsprung's disease
Developmental genomics and skeletal research
Functional evaluation of RET coding and non-coding sequence mutations in Hirschsprung's disease
 
DC FieldValue
dc.contributor.authorGarcia-Barcelo, MM
 
dc.contributor.authorTang, CSM
 
dc.contributor.authorNgan, ESW
 
dc.contributor.authorLui, VCH
 
dc.contributor.authorChen, Y
 
dc.contributor.authorSo, MT
 
dc.contributor.authorLeon, TYY
 
dc.contributor.authorMiao, XP
 
dc.contributor.authorShum, CKY
 
dc.contributor.authorLiu, FQ
 
dc.contributor.authorYeung, MY
 
dc.contributor.authorYuan, ZW
 
dc.contributor.authorGuo, WH
 
dc.contributor.authorLiu, L
 
dc.contributor.authorSun, XB
 
dc.contributor.authorHuang, LM
 
dc.contributor.authorTou, JF
 
dc.contributor.authorSong, YQ
 
dc.contributor.authorChan, D
 
dc.contributor.authorCheung, KMC
 
dc.contributor.authorWong, KKY
 
dc.contributor.authorCherny, SS
 
dc.contributor.authorSham, PC
 
dc.contributor.authorTam, PKH
 
dc.date.accessioned2010-09-17T10:36:42Z
 
dc.date.available2010-09-17T10:36:42Z
 
dc.date.issued2009
 
dc.description.abstractHirschsprung's disease (HSCR), or aganglionic megacolon, is a congenital disorder characterized by the absence of enteric ganglia in variable portions of the distal intestine. RET is a well-established susceptibility locus, although existing evidence strongly suggests additional loci contributing to sporadic HSCR. To identify these additional genetic loci, we carried out a genome-wide association study using the Affymetrix 500K marker set. We successfully genotyped 293,836 SNPs in 181 Chinese subjects with sporadic HSCR and 346 ethnically matched control subjects. The SNPs most associated with HSCR were genotyped in an independent set of 190 HSCR and 510 control subjects. Aside from SNPs in RET, the strongest overall associations in plausible candidate genes were found for 2 SNPs located in intron 1 of the neuregulin 1 gene (NRG1) on 8p12, with rs16879552 and rs7835688 yielding odds ratios of 1.68 [Cl 95%:(1.40, 2.00), P= 1.80 × 10-8] and 1.98 [Cl 95%:(1.59, 2.47), P = 1.12 × 10-9], respectively, for the heterozygous risk genotypes under an additive model. There was also a significant interaction between RET and NRG1 (P = 0.0095), increasing the odds ratio 2.3-fold to 19.53 for the RET rs2435357 risk genotype (TT) in the presence of the NRG1 rs7835688 heterozygote, indicating that NRG1 is a modifier of HSRC penetrance. Our highly significant association findings are backed-up by the important role of NRG1 as regulator of the development of the enteric ganglia precursors. The identification of NRG1 as an additional HSCR susceptibility locus not only opens unique fields of investigation into the mechanisms underlying the HSCR pathology, but also the mechanisms by which a discrete number of loci interact with each other to cause disease. © 2009 by The National Academy of Sciences of the USA.
 
dc.description.naturelink_to_OA_fulltext
 
dc.identifier.citationProceedings Of The National Academy Of Sciences Of The United States Of America, 2009, v. 106 n. 8, p. 2694-2699 [How to Cite?]
DOI: http://dx.doi.org/10.1073/pnas.0809630105
 
dc.identifier.doihttp://dx.doi.org/10.1073/pnas.0809630105
 
dc.identifier.eissn1091-6490
 
dc.identifier.epage2699
 
dc.identifier.isiWOS:000263652900042
Funding AgencyGrant Number
Hong Kong Research Grants CouncilHKU 765407M
HKU 775907M
University Grants Committee of Hong KongAoE/M-04/04
National Institutes of HealthEY-12562
Funding Information:

We thank all subjects who participated in the study. We also thank the Genome Research Centre of the University of Hong Kong, and in particular to Dr. Agnes Chan and Prof. Kathryn S. E. Cheah for their assistance. This work was supported by research Grants HKU 765407M (to M.-M. G.-B.) and HKU 775907M (to P. K. T.) from the Hong Kong Research Grants Council, the University Grants Committee of Hong Kong Grant AoE/M-04/04 and National Institutes of Health Grant EY-12562 (to S. S. C. and P. C. S.).

 
dc.identifier.issn0027-8424
2013 Impact Factor: 9.809
 
dc.identifier.issue8
 
dc.identifier.pmcidPMC2650328
 
dc.identifier.pmid19196962
 
dc.identifier.scopuseid_2-s2.0-62449175742
 
dc.identifier.spage2694
 
dc.identifier.urihttp://hdl.handle.net/10722/92121
 
dc.identifier.volume106
 
dc.languageeng
 
dc.publisherNational Academy of Sciences. The Journal's web site is located at http://www.pnas.org
 
dc.publisher.placeUnited States
 
dc.relation.ispartofProceedings of the National Academy of Sciences of the United States of America
 
dc.relation.projectGenetic dissection of Hirschsprung's disease
 
dc.relation.projectDevelopmental genomics and skeletal research
 
dc.relation.projectFunctional evaluation of RET coding and non-coding sequence mutations in Hirschsprung's disease
 
dc.relation.referencesReferences in Scopus
 
dc.subjectGWA
 
dc.subjectRET
 
dc.titleGenome-wide association study identifies NRG1 as a susceptibility locus for Hirschsprung's disease
 
dc.typeArticle
 
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Author Affiliations
  1. The University of Hong Kong Li Ka Shing Faculty of Medicine
  2. Shenzhen Children's Hospital
  3. Genome Research Centre
  4. China Medical University Shenyang
  5. Zhejiang Children's Hospital
  6. Centre for Reproduction, Development, and Growth
  7. Beijing Children's Hospital
  8. Peking University
  9. Shandong University School of Medicine