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Article: Genome-wide association study identifies NRG1 as a susceptibility locus for Hirschsprung's disease

TitleGenome-wide association study identifies NRG1 as a susceptibility locus for Hirschsprung's disease
Authors
KeywordsGWA
RET
Issue Date2009
PublisherNational Academy of Sciences. The Journal's web site is located at http://www.pnas.org
Citation
Proceedings Of The National Academy Of Sciences Of The United States Of America, 2009, v. 106 n. 8, p. 2694-2699 How to Cite?
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.
Persistent Identifierhttp://hdl.handle.net/10722/92121
ISSN
2014 Impact Factor: 9.674
2014 SCImago Journal Rankings: 5.781
PubMed Central ID
ISI Accession Number ID
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.).

References
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DC FieldValueLanguage
dc.contributor.authorGarcia-Barcelo, MMen_HK
dc.contributor.authorTang, CSMen_HK
dc.contributor.authorNgan, ESWen_HK
dc.contributor.authorLui, VCHen_HK
dc.contributor.authorChen, Yen_HK
dc.contributor.authorSo, MTen_HK
dc.contributor.authorLeon, TYYen_HK
dc.contributor.authorMiao, XPen_HK
dc.contributor.authorShum, CKYen_HK
dc.contributor.authorLiu, FQen_HK
dc.contributor.authorYeung, MYen_HK
dc.contributor.authorYuan, ZWen_HK
dc.contributor.authorGuo, WHen_HK
dc.contributor.authorLiu, Len_HK
dc.contributor.authorSun, XBen_HK
dc.contributor.authorHuang, LMen_HK
dc.contributor.authorTou, JFen_HK
dc.contributor.authorSong, YQen_HK
dc.contributor.authorChan, Den_HK
dc.contributor.authorCheung, KMCen_HK
dc.contributor.authorWong, KKYen_HK
dc.contributor.authorCherny, SSen_HK
dc.contributor.authorSham, PCen_HK
dc.contributor.authorTam, PKHen_HK
dc.date.accessioned2010-09-17T10:36:42Z-
dc.date.available2010-09-17T10:36:42Z-
dc.date.issued2009en_HK
dc.identifier.citationProceedings Of The National Academy Of Sciences Of The United States Of America, 2009, v. 106 n. 8, p. 2694-2699en_HK
dc.identifier.issn0027-8424en_HK
dc.identifier.urihttp://hdl.handle.net/10722/92121-
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.en_HK
dc.languageengen_HK
dc.publisherNational Academy of Sciences. The Journal's web site is located at http://www.pnas.orgen_HK
dc.relation.ispartofProceedings of the National Academy of Sciences of the United States of Americaen_HK
dc.subjectGWAen_HK
dc.subjectRETen_HK
dc.titleGenome-wide association study identifies NRG1 as a susceptibility locus for Hirschsprung's diseaseen_HK
dc.typeArticleen_HK
dc.identifier.emailGarciaBarcelo, MM: mmgarcia@hku.hken_HK
dc.identifier.emailNgan, ESW: engan@hku.hken_HK
dc.identifier.emailLui, VCH: vchlui@hku.hken_HK
dc.identifier.emailChen, Y: ychenc@hku.hken_HK
dc.identifier.emailSong, YQ: songy@hku.hken_HK
dc.identifier.emailChan, D: chand@hku.hken_HK
dc.identifier.emailCheung, KMC: cheungmc@hku.hken_HK
dc.identifier.emailWong, KKY: kkywong@hku.hken_HK
dc.identifier.emailCherny, SS: cherny@hku.hken_HK
dc.identifier.emailSham, PC: pcsham@hku.hken_HK
dc.identifier.emailTam, PKH: paultam@hku.hken_HK
dc.identifier.authorityGarciaBarcelo, MM=rp00445en_HK
dc.identifier.authorityNgan, ESW=rp00422en_HK
dc.identifier.authorityLui, VCH=rp00363en_HK
dc.identifier.authorityChen, Y=rp01318en_HK
dc.identifier.authoritySong, YQ=rp00488en_HK
dc.identifier.authorityChan, D=rp00540en_HK
dc.identifier.authorityCheung, KMC=rp00387en_HK
dc.identifier.authorityWong, KKY=rp01392en_HK
dc.identifier.authorityCherny, SS=rp00232en_HK
dc.identifier.authoritySham, PC=rp00459en_HK
dc.identifier.authorityTam, PKH=rp00060en_HK
dc.description.naturelink_to_OA_fulltexten_US
dc.identifier.doi10.1073/pnas.0809630105en_HK
dc.identifier.pmid19196962-
dc.identifier.pmcidPMC2650328-
dc.identifier.scopuseid_2-s2.0-62449175742en_HK
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-62449175742&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume106en_HK
dc.identifier.issue8en_HK
dc.identifier.spage2694en_HK
dc.identifier.epage2699en_HK
dc.identifier.eissn1091-6490-
dc.identifier.isiWOS:000263652900042-
dc.publisher.placeUnited Statesen_HK
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.identifier.scopusauthoridGarciaBarcelo, MM=6701767303en_HK
dc.identifier.scopusauthoridTang, CSM=35764635500en_HK
dc.identifier.scopusauthoridNgan, ESW=22234827500en_HK
dc.identifier.scopusauthoridLui, VCH=7004231344en_HK
dc.identifier.scopusauthoridChen, Y=36463185300en_HK
dc.identifier.scopusauthoridSo, MT=8748542200en_HK
dc.identifier.scopusauthoridLeon, TYY=10641704600en_HK
dc.identifier.scopusauthoridMiao, XP=7102585391en_HK
dc.identifier.scopusauthoridShum, CKY=35286215500en_HK
dc.identifier.scopusauthoridLiu, FQ=36067266700en_HK
dc.identifier.scopusauthoridYeung, MY=16029841800en_HK
dc.identifier.scopusauthoridYuan, ZW=8672008500en_HK
dc.identifier.scopusauthoridGuo, WH=35285430300en_HK
dc.identifier.scopusauthoridLiu, L=26643573300en_HK
dc.identifier.scopusauthoridSun, XB=16833911300en_HK
dc.identifier.scopusauthoridHuang, LM=12647222900en_HK
dc.identifier.scopusauthoridTou, JF=7006759358en_HK
dc.identifier.scopusauthoridSong, YQ=7404921212en_HK
dc.identifier.scopusauthoridChan, D=7402216545en_HK
dc.identifier.scopusauthoridCheung, KMC=7402406754en_HK
dc.identifier.scopusauthoridWong, KKY=24438686400en_HK
dc.identifier.scopusauthoridCherny, SS=7004670001en_HK
dc.identifier.scopusauthoridSham, PC=34573429300en_HK
dc.identifier.scopusauthoridTam, PKH=7202539421en_HK

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