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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
2013 Impact Factor: 3.424
 
DOIhttp://dx.doi.org/10.1111/j.1365-2982.2008.01253.x
 
ISI Accession Number IDWOS:000262688300109
 
DC FieldValue
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
2013 Impact Factor: 3.424
 
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
 
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<item><contributor.author>Tam, PKH</contributor.author>
<contributor.author>Tang, CSM</contributor.author>
<contributor.author>Ngan, ESW</contributor.author>
<contributor.author>Lui, VCH</contributor.author>
<contributor.author>Chen, Y</contributor.author>
<contributor.author>So, MT</contributor.author>
<contributor.author>Leon, TYY</contributor.author>
<contributor.author>Miao, XP</contributor.author>
<contributor.author>Shum, CKY</contributor.author>
<contributor.author>Liu, FQ</contributor.author>
<contributor.author>Yeung, MY</contributor.author>
<contributor.author>Yuan, ZW</contributor.author>
<contributor.author>Guo, WH</contributor.author>
<contributor.author>Liu, L</contributor.author>
<contributor.author>Sun, XB</contributor.author>
<contributor.author>Huang, LM</contributor.author>
<contributor.author>Tou, JF</contributor.author>
<contributor.author>Song, YQ</contributor.author>
<contributor.author>Chan, D</contributor.author>
<contributor.author>Cheung, KMC</contributor.author>
<contributor.author>Wong, KKY</contributor.author>
<contributor.author>Cherny, SS</contributor.author>
<contributor.author>Sham, PC</contributor.author>
<contributor.author>Garcia-Barcelo, MM</contributor.author>
<date.accessioned>2011-12-16T08:09:51Z</date.accessioned>
<date.available>2011-12-16T08:09:51Z</date.available>
<date.issued>2009</date.issued>
<identifier.citation>The Second International Symposium on Development of the Enteric Nervous System: Cells, Signals and Genes, London, 22-25 February 2009. In Neurogastroenterology &amp; Motility, 2009, v. 21  n.2, p. XXVII</identifier.citation>
<identifier.issn>1350-1925</identifier.issn>
<identifier.uri>http://hdl.handle.net/10722/143705</identifier.uri>
<description.abstract>Background and objectives: Hirschsprung&#8217;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 &#183; 10&#8211;8] and
1.98 [CI 95%:(1.59, 2.47), P = 1.12 &#183; 10&#8211;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.</description.abstract>
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