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Article: Fine mapping of the NRG1 hirschsprung's disease locus
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TitleFine mapping of the NRG1 hirschsprung's disease locus
 
AuthorsTang, CSM2
Tang, WK2
So, MT2
Miao, XP3
Leung, BMC2
Yip, BHK2
Leon, TYY2
Ngan, ESW2
Lui, VCH2
Chen, Y2
Chan, IHY2
Chung, PHY2
Liu, XL2
Wu, XZ1
Wong, KKY2
Sham, PC2
Cherny, SS2
Tam, PKH2
GarciaBarceló, MM2
 
KeywordsChinese
Controlled Study
Ethnic Group
Gene Expression
Gene Identification
Gene Locus
Gene Mapping
Gene Mutation
Genetic Association
Genetic Predisposition
Genotype
Hirschsprung Disease
Human
Human Tissue
Major Clinical Study
Nucleotide Sequence
Single Nucleotide Polymorphism
 
Issue Date2011
 
PublisherPublic Library of Science. The Journal's web site is located at http://www.plosone.org/home.action
 
CitationPlos One, 2011, v. 6 n. 1 [How to Cite?]
DOI: http://dx.doi.org/10.1371/journal.pone.0016181
 
AbstractThe primary pathology of Hirschsprung's disease (HSCR, colon aganglionosis) is the absence of ganglia in variable lengths of the hindgut, resulting in functional obstruction. HSCR is attributed to a failure of migration of the enteric ganglion precursors along the developing gut. RET is a key regulator of the development of the enteric nervous system (ENS) and the major HSCR-causing gene. Yet the reduced penetrance of RET DNA HSCR-associated variants together with the phenotypic variability suggest the involvement of additional genes in the disease. Through a genome-wide association study, we uncovered a ~350 kb HSCR-associated region encompassing part of the neuregulin-1 gene (NRG1). To identify the causal NRG1 variants contributing to HSCR, we genotyped 243 SNPs variants on 343 ethnic Chinese HSCR patients and 359 controls. Genotype analysis coupled with imputation narrowed down the HSCR-associated region to 21 kb, with four of the most associated SNPs (rs10088313, rs10094655, rs4624987, and rs3884552) mapping to the NRG1 promoter. We investigated whether there was correlation between the genotype at the rs10088313 locus and the amount of NRG1 expressed in human gut tissues (40 patients and 21 controls) and found differences in expression as a function of genotype. We also found significant differences in NRG1 expression levels between diseased and control individuals bearing the same rs10088313 risk genotype. This indicates that the effects of NRG1 common variants are likely to depend on other alleles or epigenetic factors present in the patients and would account for the variability in the genetic predisposition to HSCR. © 2011 Tang et al.
 
ISSN1932-6203
2012 Impact Factor: 3.73
2012 SCImago Journal Rankings: 1.512
 
DOIhttp://dx.doi.org/10.1371/journal.pone.0016181
 
PubMed Central IDPMC3024406
 
ISI Accession Number IDWOS:000286522200033
Funding AgencyGrant Number
Hong Kong Research Grants CouncilHKU 765609M
University of Hong Kong200911159071
200811159006
University of Hong Kong Genomics Strategic Research Theme
Funding Information:

This work was supported by research grants from the Hong Kong Research Grants Council HKU 765609M to MGB and from The University of Hong Kong Seed Funding 200911159071 and 200811159006 to PT and MGB respectively. Support was also obtained from The University of Hong Kong Genomics Strategic Research Theme. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

 
ReferencesReferences in Scopus
 
GrantsIdentification of functional variants in Neuregulin-1 (NRG1), a newly discovered Hirschsprungs disease gene
 
DC FieldValue
dc.contributor.authorTang, CSM
 
dc.contributor.authorTang, WK
 
dc.contributor.authorSo, MT
 
dc.contributor.authorMiao, XP
 
dc.contributor.authorLeung, BMC
 
dc.contributor.authorYip, BHK
 
dc.contributor.authorLeon, TYY
 
dc.contributor.authorNgan, ESW
 
dc.contributor.authorLui, VCH
 
dc.contributor.authorChen, Y
 
dc.contributor.authorChan, IHY
 
dc.contributor.authorChung, PHY
 
dc.contributor.authorLiu, XL
 
dc.contributor.authorWu, XZ
 
dc.contributor.authorWong, KKY
 
dc.contributor.authorSham, PC
 
dc.contributor.authorCherny, SS
 
dc.contributor.authorTam, PKH
 
dc.contributor.authorGarciaBarceló, MM
 
dc.date.accessioned2010-10-31T11:24:38Z
 
dc.date.available2010-10-31T11:24:38Z
 
dc.date.issued2011
 
dc.description.abstractThe primary pathology of Hirschsprung's disease (HSCR, colon aganglionosis) is the absence of ganglia in variable lengths of the hindgut, resulting in functional obstruction. HSCR is attributed to a failure of migration of the enteric ganglion precursors along the developing gut. RET is a key regulator of the development of the enteric nervous system (ENS) and the major HSCR-causing gene. Yet the reduced penetrance of RET DNA HSCR-associated variants together with the phenotypic variability suggest the involvement of additional genes in the disease. Through a genome-wide association study, we uncovered a ~350 kb HSCR-associated region encompassing part of the neuregulin-1 gene (NRG1). To identify the causal NRG1 variants contributing to HSCR, we genotyped 243 SNPs variants on 343 ethnic Chinese HSCR patients and 359 controls. Genotype analysis coupled with imputation narrowed down the HSCR-associated region to 21 kb, with four of the most associated SNPs (rs10088313, rs10094655, rs4624987, and rs3884552) mapping to the NRG1 promoter. We investigated whether there was correlation between the genotype at the rs10088313 locus and the amount of NRG1 expressed in human gut tissues (40 patients and 21 controls) and found differences in expression as a function of genotype. We also found significant differences in NRG1 expression levels between diseased and control individuals bearing the same rs10088313 risk genotype. This indicates that the effects of NRG1 common variants are likely to depend on other alleles or epigenetic factors present in the patients and would account for the variability in the genetic predisposition to HSCR. © 2011 Tang et al.
 
dc.description.naturepublished_or_final_version
 
dc.identifier.citationPlos One, 2011, v. 6 n. 1 [How to Cite?]
DOI: http://dx.doi.org/10.1371/journal.pone.0016181
 
dc.identifier.doihttp://dx.doi.org/10.1371/journal.pone.0016181
 
dc.identifier.eissn1932-6203
 
dc.identifier.hkuros175675
 
dc.identifier.hkuros184635
 
dc.identifier.isiWOS:000286522200033
Funding AgencyGrant Number
Hong Kong Research Grants CouncilHKU 765609M
University of Hong Kong200911159071
200811159006
University of Hong Kong Genomics Strategic Research Theme
Funding Information:

This work was supported by research grants from the Hong Kong Research Grants Council HKU 765609M to MGB and from The University of Hong Kong Seed Funding 200911159071 and 200811159006 to PT and MGB respectively. Support was also obtained from The University of Hong Kong Genomics Strategic Research Theme. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

 
dc.identifier.issn1932-6203
2012 Impact Factor: 3.73
2012 SCImago Journal Rankings: 1.512
 
dc.identifier.issue1
 
dc.identifier.openurl
 
dc.identifier.pmcidPMC3024406
 
dc.identifier.pmid21283760
 
dc.identifier.scopuseid_2-s2.0-79251616918
 
dc.identifier.urihttp://hdl.handle.net/10722/125323
 
dc.identifier.volume6
 
dc.languageeng
 
dc.publisherPublic Library of Science. The Journal's web site is located at http://www.plosone.org/home.action
 
dc.publisher.placeUnited States
 
dc.relation.ispartofPLoS ONE
 
dc.relation.projectIdentification of functional variants in Neuregulin-1 (NRG1), a newly discovered Hirschsprungs disease gene
 
dc.relation.referencesReferences in Scopus
 
dc.rightsCreative Commons: Attribution 3.0 Hong Kong License
 
dc.subjectChinese
 
dc.subjectControlled Study
 
dc.subjectEthnic Group
 
dc.subjectGene Expression
 
dc.subjectGene Identification
 
dc.subjectGene Locus
 
dc.subjectGene Mapping
 
dc.subjectGene Mutation
 
dc.subjectGenetic Association
 
dc.subjectGenetic Predisposition
 
dc.subjectGenotype
 
dc.subjectHirschsprung Disease
 
dc.subjectHuman
 
dc.subjectHuman Tissue
 
dc.subjectMajor Clinical Study
 
dc.subjectNucleotide Sequence
 
dc.subjectSingle Nucleotide Polymorphism
 
dc.titleFine mapping of the NRG1 hirschsprung's disease locus
 
dc.typeArticle
 
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<subject>Chinese</subject>
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Author Affiliations
  1. Guiyang Medical College
  2. The University of Hong Kong
  3. Huazhong University of Science and Technology