Conference Paper: 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
AuthorsTam, PKH
Tang, CSM
Ngan, ESW
Lui, VCH
Chen, Y
So, MT
Leon, TYY
Miao, XP
Shum, CKY
Liu, FQ
Yeung, MY
Yuan, ZW
Guo, WH
Liu, L
Sun, XB
Huang, LM
Tou, JF
Song, YQ
Chan, D
Cheung, KMC
Wong, KKY
Cherny, SS
Sham, PC
Garcia-Barcelo, MM
Issue Date2009
PublisherWiley-Blackwell. The Journal's web site is located at http://www.wiley.com/bw/journal.asp?ref=1350-1925&site=1
CitationThe Second International Symposium on Development of the Enteric Nervous System: Cells, Signals and Genes, London, 22-25 February 2009. In Neurogastroenterology & Motility, 2009, v. 21 n.2, p. XXVII [How to Cite?]
DOI: http://dx.doi.org/10.1111/j.1365-2982.2008.01253.x
AbstractBackground and objectives: Hirschsprung’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. Methods: We genotyped 4 93 840 single-nucleotide polymorphisms (SNPs) in 200 Chinese subjects with sporadic HSCR and 306 ethnically matched control subjects. The SNPs most associated with HSCR were genotyped in an independent set of 190 HSCR and 510 control subjects. Results: Aside from SNPs in RET, the strongest overall associations were found for two SNPs located in intron 1 of the neuregulin1 gene (NRG1) on 8p12, with rs16879552 and rs7835688 yielding odds ratios of 1.68 [CI 95%:(1.40, 2.00), P = 1.80 · 10–8] and 1.98 [CI 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. Conclusions: 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 a new HSCR susceptibility locus not only opens new 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.
ISSN1350-1925
2011 Impact Factor: 3.414
2011 SCImago Journal Rankings: 0.280
DOIhttp://dx.doi.org/10.1111/j.1365-2982.2008.01253.x
ISI Accession Number IDWOS:000262688300109
DC Field
Value
dc.contributor.authorTam, PKH
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.authorGarcia-Barcelo, MM
dc.date.accessioned2011-12-16T08:09:51Z
dc.date.available2011-12-16T08:09:51Z
dc.date.issued2009
dc.description.abstractBackground and objectives: Hirschsprung’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. Methods: We genotyped 4 93 840 single-nucleotide polymorphisms (SNPs) in 200 Chinese subjects with sporadic HSCR and 306 ethnically matched control subjects. The SNPs most associated with HSCR were genotyped in an independent set of 190 HSCR and 510 control subjects. Results: Aside from SNPs in RET, the strongest overall associations were found for two SNPs located in intron 1 of the neuregulin1 gene (NRG1) on 8p12, with rs16879552 and rs7835688 yielding odds ratios of 1.68 [CI 95%:(1.40, 2.00), P = 1.80 · 10–8] and 1.98 [CI 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. Conclusions: 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 a new HSCR susceptibility locus not only opens new 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.
dc.description.naturelink_to_subscribed_fulltext
dc.description.otherThe Second International Symposium on Development of the Enteric Nervous System: Cells, Signals and Genes, London, 22-25 February 2009. In Neurogastroenterology & Motility, 2009, v. 21 n.2, p. XXVII
dc.identifier.citationThe Second International Symposium on Development of the Enteric Nervous System: Cells, Signals and Genes, London, 22-25 February 2009. In Neurogastroenterology & Motility, 2009, v. 21 n.2, p. XXVII [How to Cite?]
DOI: http://dx.doi.org/10.1111/j.1365-2982.2008.01253.x
dc.identifier.doihttp://dx.doi.org/10.1111/j.1365-2982.2008.01253.x
dc.identifier.epageXXVII
dc.identifier.isiWOS:000262688300109
dc.identifier.issn1350-1925
2011 Impact Factor: 3.414
2011 SCImago Journal Rankings: 0.280
dc.identifier.spageXXVII
dc.identifier.urihttp://hdl.handle.net/10722/143705
dc.identifier.volume21
dc.publisherWiley-Blackwell. The Journal's web site is located at http://www.wiley.com/bw/journal.asp?ref=1350-1925&site=1
dc.relation.ispartofNEUROGASTROENTEROLOGY AND MOTILITY
dc.titleGenome-wide association study identifies NRG1 as a susceptibility locus for Hirschsprung's disease
dc.typeConference_Paper