Article: Fine mapping of the NRG1 hirschsprung's disease locus
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- Publisher Website: 10.1371/journal.pone.0016181
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- PMID: 21283760
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| Title | Fine mapping of the NRG1 hirschsprung's disease locus | ||||||||
|---|---|---|---|---|---|---|---|---|---|
| Authors | Tang, 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 | ||||||||
| Keywords | Chinese 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 Date | 2011 | ||||||||
| Publisher | Public Library of Science. The Journal's web site is located at http://www.plosone.org/home.action | ||||||||
| Citation | Plos One, 2011, v. 6 n. 1 [How to Cite?] DOI: http://dx.doi.org/10.1371/journal.pone.0016181 | ||||||||
| Abstract | The 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. | ||||||||
| ISSN | 1932-6203 2011 Impact Factor: 4.092 2011 SCImago Journal Rankings: 0.519 | ||||||||
| DOI | http://dx.doi.org/10.1371/journal.pone.0016181 | ||||||||
| ISI Accession Number ID | WOS:000286522200033
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. | ||||||||
| PubMed Central ID | PMC3024406 | ||||||||
| References | References in Scopus | ||||||||
| Grants | Identification of functional variants in Neuregulin-1 (NRG1), a newly discovered Hirschsprungs disease gene NRG1 intron 1 SNPs in Hirschsprung's disease Sequencing of the neuregulin-1 (NRG1) gene in Hisrchprung's disease patients |
| dc.contributor.author | Tang, CSM | ||||||||
|---|---|---|---|---|---|---|---|---|---|
| dc.contributor.author | Tang, WK | ||||||||
| dc.contributor.author | So, MT | ||||||||
| dc.contributor.author | Miao, XP | ||||||||
| dc.contributor.author | Leung, BMC | ||||||||
| dc.contributor.author | Yip, BHK | ||||||||
| dc.contributor.author | Leon, TYY | ||||||||
| dc.contributor.author | Ngan, ESW | ||||||||
| dc.contributor.author | Lui, VCH | ||||||||
| dc.contributor.author | Chen, Y | ||||||||
| dc.contributor.author | Chan, IHY | ||||||||
| dc.contributor.author | Chung, PHY | ||||||||
| dc.contributor.author | Liu, XL | ||||||||
| dc.contributor.author | Wu, XZ | ||||||||
| dc.contributor.author | Wong, KKY | ||||||||
| dc.contributor.author | Sham, PC | ||||||||
| dc.contributor.author | Cherny, SS | ||||||||
| dc.contributor.author | Tam, PKH | ||||||||
| dc.contributor.author | GarciaBarceló, MM | ||||||||
| dc.date.accessioned | 2010-10-31T11:24:38Z | ||||||||
| dc.date.available | 2010-10-31T11:24:38Z | ||||||||
| dc.date.issued | 2011 | ||||||||
| dc.description.abstract | The 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.grant | Identification of functional variants in Neuregulin-1 (NRG1), a newly discovered Hirschsprungs disease gene | ||||||||
| dc.description.grant | NRG1 intron 1 SNPs in Hirschsprung's disease | ||||||||
| dc.description.grant | Sequencing of the neuregulin-1 (NRG1) gene in Hisrchprung's disease patients | ||||||||
| dc.description.grantcode | 100485 | ||||||||
| dc.description.grantcode | 101817 | ||||||||
| dc.description.grantcode | 99882 | ||||||||
| dc.description.nature | published_or_final_version | ||||||||
| dc.identifier.citation | Plos One, 2011, v. 6 n. 1 [How to Cite?] DOI: http://dx.doi.org/10.1371/journal.pone.0016181 | ||||||||
| dc.identifier.doi | http://dx.doi.org/10.1371/journal.pone.0016181 | ||||||||
| dc.identifier.hkuros | 175675 | ||||||||
| dc.identifier.hkuros | 184635 | ||||||||
| dc.identifier.isi | WOS:000286522200033
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.issn | 1932-6203 2011 Impact Factor: 4.092 2011 SCImago Journal Rankings: 0.519 | ||||||||
| dc.identifier.issue | 1 | ||||||||
| dc.identifier.openurl | | ||||||||
| dc.identifier.pmcid | PMC3024406 | ||||||||
| dc.identifier.pmid | 21283760 | ||||||||
| dc.identifier.scopus | eid_2-s2.0-79251616918 | ||||||||
| dc.identifier.uri | http://hdl.handle.net/10722/125323 | ||||||||
| dc.identifier.volume | 6 | ||||||||
| dc.language | eng | ||||||||
| dc.publisher | Public Library of Science. The Journal's web site is located at http://www.plosone.org/home.action | ||||||||
| dc.publisher.place | United States | ||||||||
| dc.relation.ispartof | PLoS ONE | ||||||||
| dc.relation.references | References in Scopus | ||||||||
| dc.rights | Creative Commons: Attribution 3.0 Hong Kong License | ||||||||
| dc.subject | Chinese | ||||||||
| dc.subject | Controlled Study | ||||||||
| dc.subject | Ethnic Group | ||||||||
| dc.subject | Gene Expression | ||||||||
| dc.subject | Gene Identification | ||||||||
| dc.subject | Gene Locus | ||||||||
| dc.subject | Gene Mapping | ||||||||
| dc.subject | Gene Mutation | ||||||||
| dc.subject | Genetic Association | ||||||||
| dc.subject | Genetic Predisposition | ||||||||
| dc.subject | Genotype | ||||||||
| dc.subject | Hirschsprung Disease | ||||||||
| dc.subject | Human | ||||||||
| dc.subject | Human Tissue | ||||||||
| dc.subject | Major Clinical Study | ||||||||
| dc.subject | Nucleotide Sequence | ||||||||
| dc.subject | Single Nucleotide Polymorphism | ||||||||
| dc.title | Fine mapping of the NRG1 hirschsprung's disease locus | ||||||||
| dc.type | Article |
Author Affiliations
- Guiyang Medical College
- The University of Hong Kong
- Huazhong University of Science and Technology