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Only a few genetic studies of growth retardation associated with the KBD have been carried out by now. In this study, we conducted a two-stage bivariate genome-wide association study (BGWAS) of the KBD using joint deformities and body height as study phenotypes, totally involving 2,417 study subjects. Articular cartilage specimens from 8 subjects were collected for immunohistochemistry. In the BGWAS, <jats:italic>ADAM12<\/jats:italic> gene achieved the most significant association (rs1278300 p-value\u2009=\u20099.25\u2009\u00d7\u200910<jats:sup>\u22129<\/jats:sup>) with the KBD. Replication study observed significant association signal at rs1278300 (p-value\u2009=\u20090.007) and rs1710287 (p-value\u2009=\u20090.002) of A<jats:italic>DAM12<\/jats:italic> after Bonferroni correction. Immunohistochemistry revealed significantly decreased expression level of ADAM12 protein in the KBD articular cartilage (average positive chondrocyte rate\u2009=\u200947.59\u2009\u00b1\u20097.79%) compared to healthy articular cartilage (average positive chondrocyte rate\u2009=\u200964.73\u2009\u00b1\u20095.05%). Our results suggest that <jats:italic>ADAM12<\/jats:italic> gene is a novel susceptibility gene underlying both joint destruction and growth retardation of the KBD.<\/jats:p>","DOI":"10.1038\/srep31792","type":"journal-article","created":{"date-parts":[[2016,8,22]],"date-time":"2016-08-22T09:41:25Z","timestamp":1471858885000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["A bivariate genome-wide association study identifies ADAM12 as a novel susceptibility gene for Kashin-Beck disease"],"prefix":"10.1038","volume":"6","author":[{"given":"Jingcan","family":"Hao","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wenyu","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yan","family":"Wen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiao","family":"Xiao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Awen","family":"He","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiong","family":"Guo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tielin","family":"Yang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaogang","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hui","family":"Shen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiangding","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qing","family":"Tian","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hong-Wen","family":"Deng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Feng","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2016,8,22]]},"reference":[{"key":"BFsrep31792_CR1","doi-asserted-by":"publisher","first-page":"1112","DOI":"10.1056\/NEJM199810153391604","volume":"339","author":"R Moreno-Reyes","year":"1998","unstructured":"Moreno-Reyes, R. et al. 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