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U.S.A."],"published-print":{"date-parts":[[2009,2,24]]},"abstract":"<jats:p>\n                    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.\n                    <jats:italic>RET<\/jats:italic>\n                    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\n                    <jats:italic>Affymetrix<\/jats:italic>\n                    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\n                    <jats:italic>RET<\/jats:italic>\n                    , the strongest overall associations in plausible candidate genes were found for 2 SNPs located in intron 1 of the neuregulin1 gene (\n                    <jats:italic>NRG1<\/jats:italic>\n                    ) on 8p12, with rs16879552 and rs7835688 yielding odds ratios of 1.68 [CI\n                    <jats:sub>95%<\/jats:sub>\n                    :(1.40, 2.00),\n                    <jats:italic>P<\/jats:italic>\n                    = 1.80 \u00d7 10\n                    <jats:sup>\u22128<\/jats:sup>\n                    ] and 1.98 [CI\n                    <jats:sub>95%<\/jats:sub>\n                    :(1.59, 2.47),\n                    <jats:italic>P<\/jats:italic>\n                    = 1.12 \u00d7 10\n                    <jats:sup>\u22129<\/jats:sup>\n                    ], respectively, for the heterozygous risk genotypes under an additive model. There was also a significant interaction between\n                    <jats:italic>RET<\/jats:italic>\n                    and\n                    <jats:italic>NRG1<\/jats:italic>\n                    (\n                    <jats:italic>P<\/jats:italic>\n                    = 0.0095), increasing the odds ratio 2.3-fold to 19.53 for the\n                    <jats:italic>RET<\/jats:italic>\n                    rs2435357 risk genotype (TT) in the presence of the\n                    <jats:italic>NRG1<\/jats:italic>\n                    rs7835688 heterozygote, indicating that\n                    <jats:italic>NRG1<\/jats:italic>\n                    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\n                    <jats:italic>NRG1<\/jats:italic>\n                    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.\n                  <\/jats:p>","DOI":"10.1073\/pnas.0809630105","type":"journal-article","created":{"date-parts":[[2009,2,7]],"date-time":"2009-02-07T00:06:11Z","timestamp":1233965171000},"page":"2694-2699","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":177,"title":["Genome-wide association study identifies\n                    <i>NRG1<\/i>\n                    as a susceptibility locus for Hirschsprung's disease"],"prefix":"10.1073","volume":"106","author":[{"given":"Maria-Merc\u00e8","family":"Garcia-Barcelo","sequence":"first","affiliation":[{"name":"Departments of aSurgery,"},{"name":"Centre for Reproduction, Development, and Growth,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clara Sze-man","family":"Tang","sequence":"additional","affiliation":[{"name":"Department of Psychiatry,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elly Sau-wai","family":"Ngan","sequence":"additional","affiliation":[{"name":"Departments of aSurgery,"},{"name":"Centre for Reproduction, Development, and Growth,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincent Chi-hang","family":"Lui","sequence":"additional","affiliation":[{"name":"Departments of aSurgery,"},{"name":"Centre for Reproduction, Development, and Growth,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Chen","sequence":"additional","affiliation":[{"name":"Departments of aSurgery,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Man-ting","family":"So","sequence":"additional","affiliation":[{"name":"Departments of aSurgery,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas Yuk-yu","family":"Leon","sequence":"additional","affiliation":[{"name":"Departments of aSurgery,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao-ping","family":"Miao","sequence":"additional","affiliation":[{"name":"Departments of aSurgery,"},{"name":"Department of Surgery, Shenzhen Children's Hospital, Shenzhen, China;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cathy Ka-yee","family":"Shum","sequence":"additional","affiliation":[{"name":"Departments of aSurgery,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feng-qin","family":"Liu","sequence":"additional","affiliation":[{"name":"Departments of aSurgery,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming-yiu","family":"Yeung","sequence":"additional","affiliation":[{"name":"Department of Psychiatry,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhen-wei","family":"Yuan","sequence":"additional","affiliation":[{"name":"Department of Paediatric Surgery, Shengjing Hospital, China Medical University, Shenyang, China;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei-hong","family":"Guo","sequence":"additional","affiliation":[{"name":"Department of Surgery, Beijing Children's Hospital, Beijing, China;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Psychiatry,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao-bing","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Pediatric Surgery, Shandong Medical University, Shandong, China;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liu-ming","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Surgery, Beijing University, Beijing, China; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin-fa","family":"Tou","sequence":"additional","affiliation":[{"name":"Department of Surgery, Zhejiang Children's Hospital, Zhejiang, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"You-qiang","family":"Song","sequence":"additional","affiliation":[{"name":"Departments of jBiochemistry and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danny","family":"Chan","sequence":"additional","affiliation":[{"name":"Departments of jBiochemistry and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenneth M. 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