{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T13:58:53Z","timestamp":1787320733821,"version":"build-2736575974"},"reference-count":75,"publisher":"Oxford University Press (OUP)","issue":"7","license":[{"start":{"date-parts":[[2025,1,16]],"date-time":"2025-01-16T00:00:00Z","timestamp":1736985600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"name":"Project of Shenzhen San Ming"},{"name":"Science and Technology Innovation Base Platform"},{"DOI":"10.13039\/501100002858","name":"The China Postdoctoral Science Foundation","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100002858","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Hubei Provincial Key Research and Development Program"},{"name":"Clinical Research Pilot Project of Tongji Hospital"},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,3,20]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Hirschsprung\u2019s disease (HSCR) is a congenital enteric neuropathic disorder characterized by high heritability (&amp;gt;80%) and polygenic inheritance (&amp;gt;20 genes). The previous genome-wide association studies (GWAS) identified several common variants associated with HSCR and demonstrated increased predictive performance for HSCR risk in Europeans using a genetic risk score, there remains a notable gap in knowledge regarding Chinese populations. We conducted whole exome sequencing in a HSCR case cohort in Chinese. By using the common controls (505 controls from 1KG EAS and 10\u2009588 controls from ChinaMAP), we conducted GWAS for the common variants in the exome and gene-based association for rare variants. We further validated the associated variants and genes in replicated samples and in vitro and vivo experiments. We identified one novel gene PLK5 by GWAS and suggested 45 novel putative genes based the gene-based test. By using genetic variant at RET and PLK5, we constructed a genetic risk score that could identify the individuals with very high genetic risk for HSCR. Compared with patients with zero or one risk allele from the three variants, the risk for HSCR was 36.61 times higher with six alleles. In addition, we delineated a HSCR risk gene landscape that encompasses 57 genes, which explains 88.5% and 54.5% of HSCR in Chinese and European, respectively. In summary, this study improved the understanding of genetic architecture of HSCR and provided a risk prediction approach for HSCR in the Chinese.<\/jats:p>","DOI":"10.1093\/hmg\/ddae205","type":"journal-article","created":{"date-parts":[[2024,12,26]],"date-time":"2024-12-26T23:27:37Z","timestamp":1735255657000},"page":"586-598","source":"Crossref","is-referenced-by-count":5,"title":["Rare and common genetic variants underlying the risk of Hirschsprung\u2019s disease"],"prefix":"10.1093","volume":"34","author":[{"given":"Jun","family":"Xiao","sequence":"first","affiliation":[{"name":"Department of Pediatric Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology , No. 1095 Jiefang Avenue, Qiaokou District, Wuhan, Hubei 430030 ,","place":["China"]},{"name":"Hubei Clinical Center of Hirschsprung\u2019s disease and allied disorders , No. 1095 Jiefang Avenue, Qiaokou District, Wuhan, Hubei 430030 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenzhao","family":"Feng","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology , No. 1095 Jiefang Avenue, Qiaokou District, Wuhan, Hubei 430030 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tianqi","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Pediatric Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology , No. 1095 Jiefang Avenue, Qiaokou District, Wuhan, Hubei 430030 ,","place":["China"]},{"name":"Hubei Clinical Center of Hirschsprung\u2019s disease and allied disorders , No. 1095 Jiefang Avenue, Qiaokou District, Wuhan, Hubei 430030 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Pediatric Surgery, Pingshan District Maternal & Child Healthcare Hospital of Shenzhen , No. 6 Longtian South Road, Longtian Subdistrict, Pingshan District, Shenzhen, Guangdong 518122 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuyong","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Pediatric Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology , No. 1095 Jiefang Avenue, Qiaokou District, Wuhan, Hubei 430030 ,","place":["China"]},{"name":"Hubei Clinical Center of Hirschsprung\u2019s disease and allied disorders , No. 1095 Jiefang Avenue, Qiaokou District, Wuhan, Hubei 430030 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Wuhan, Hubei 430030 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiong","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pediatric Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology , No. 1095 Jiefang Avenue, Qiaokou District, Wuhan, Hubei 430030 ,","place":["China"]},{"name":"Hubei Clinical Center of Hirschsprung\u2019s disease and allied disorders , No. 1095 Jiefang Avenue, Qiaokou District, Wuhan, Hubei 430030 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Didi","family":"Zhuansun","sequence":"additional","affiliation":[{"name":"Department of Pediatric Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology , No. 1095 Jiefang Avenue, Qiaokou District, Wuhan, Hubei 430030 ,","place":["China"]},{"name":"Hubei Clinical Center of Hirschsprung\u2019s disease and allied disorders , No. 1095 Jiefang Avenue, Qiaokou District, Wuhan, Hubei 430030 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyao","family":"Meng","sequence":"additional","affiliation":[{"name":"Department of Pediatric Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology , No. 1095 Jiefang Avenue, Qiaokou District, Wuhan, Hubei 430030 ,","place":["China"]},{"name":"Hubei Clinical Center of Hirschsprung\u2019s disease and allied disorders , No. 1095 Jiefang Avenue, Qiaokou District, Wuhan, Hubei 430030 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pediatric Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology , No. 1095 Jiefang Avenue, Qiaokou District, Wuhan, Hubei 430030 ,","place":["China"]},{"name":"Hubei Clinical Center of Hirschsprung\u2019s disease and allied disorders , No. 1095 Jiefang Avenue, Qiaokou District, Wuhan, Hubei 430030 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Xiang","sequence":"additional","affiliation":[{"name":"Department of Pediatric Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology , No. 1095 Jiefang Avenue, Qiaokou District, Wuhan, Hubei 430030 ,","place":["China"]},{"name":"Hubei Clinical Center of Hirschsprung\u2019s disease and allied disorders , No. 1095 Jiefang Avenue, Qiaokou District, Wuhan, Hubei 430030 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaosi","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Pediatric Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology , No. 1095 Jiefang Avenue, Qiaokou District, Wuhan, Hubei 430030 ,","place":["China"]},{"name":"Hubei Clinical Center of Hirschsprung\u2019s disease and allied disorders , No. 1095 Jiefang Avenue, Qiaokou District, Wuhan, Hubei 430030 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bingyan","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Pediatric Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology , No. 1095 Jiefang Avenue, Qiaokou District, Wuhan, Hubei 430030 ,","place":["China"]},{"name":"Hubei Clinical Center of Hirschsprung\u2019s disease and allied disorders , No. 1095 Jiefang Avenue, Qiaokou District, Wuhan, Hubei 430030 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weibing","family":"Tang","sequence":"additional","affiliation":[{"name":"Department of Pediatric Surgery, Children\u2019s Hospital of Nanjing Medical University , No. 72 Guangzhou Road, Gulou District, Nanjing, Jiangsu 210008 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of Pediatric Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology , No. 1095 Jiefang Avenue, Qiaokou District, Wuhan, Hubei 430030 ,","place":["China"]},{"name":"Hubei Clinical Center of Hirschsprung\u2019s disease and allied disorders , No. 1095 Jiefang Avenue, Qiaokou District, Wuhan, Hubei 430030 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jixin","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Pediatric Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology , No. 1095 Jiefang Avenue, Qiaokou District, Wuhan, Hubei 430030 ,","place":["China"]},{"name":"Hubei Clinical Center of Hirschsprung\u2019s disease and allied disorders , No. 1095 Jiefang Avenue, Qiaokou District, Wuhan, Hubei 430030 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,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9596-2330","authenticated-orcid":false,"given":"Jiexiong","family":"Feng","sequence":"additional","affiliation":[{"name":"Department of Pediatric Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology , No. 1095 Jiefang Avenue, Qiaokou District, Wuhan, Hubei 430030 ,","place":["China"]},{"name":"Hubei Clinical Center of Hirschsprung\u2019s disease and allied disorders , No. 1095 Jiefang Avenue, Qiaokou District, Wuhan, Hubei 430030 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2025,1,16]]},"reference":[{"key":"2025032012271254400_ref1","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1038\/s41572-023-00465-y","article-title":"Hirschsprung disease","volume":"9","author":"Montalva","year":"2023","journal-title":"Nat Rev Dis 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disease","volume":"15","author":"Kyrklund","year":"2020","journal-title":"Orphanet J Rare Dis"},{"key":"2025032012271254400_ref6","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1038\/367377a0","article-title":"Point mutations affecting the tyrosine kinase domain of the RET proto-oncogene in Hirschsprung's disease","volume":"367","author":"Romeo","year":"1994","journal-title":"Nature"},{"key":"2025032012271254400_ref7","doi-asserted-by":"crossref","first-page":"644","DOI":"10.1007\/s12519-023-00686-x","article-title":"Comprehensive characterization of the genetic landscape of familial Hirschsprung's disease","volume":"19","author":"Xiao","year":"2023","journal-title":"World J Pediatr"},{"key":"2025032012271254400_ref8","doi-asserted-by":"crossref","first-page":"1267","DOI":"10.1016\/0092-8674(94)90017-5","article-title":"Targeted and natural (piebald-lethal) mutations of endothelin-B receptor gene produce megacolon associated with spotted coat color in 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