title: A bivariate genome-wide association study identifies ADAM12 as a novel susceptibility gene for Kashin-Beck disease.
abstract: Kashin-Beck disease (KBD) is a chronic osteoarthropathy, which manifests as joint deformities and growth retardation. 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, ADAM12 gene achieved the most significant association (rs1278300 p-value = 9.25 × 10(-9)) with the KBD. Replication study observed significant association signal at rs1278300 (p-value = 0.007) and rs1710287 (p-value = 0.002) of ADAM12 after Bonferroni correction. Immunohistochemistry revealed significantly decreased expression level of ADAM12 protein in the KBD articular cartilage (average positive chondrocyte rate = 47.59 ± 7.79%) compared to healthy articular cartilage (average positive chondrocyte rate = 64.73 ± 5.05%). Our results suggest that ADAM12 gene is a novel susceptibility gene underlying both joint destruction and growth retardation of the KBD.
authors.affiliation: Key Laboratory of Trace Elements and Endemic Diseases of National Health and Family Planning Commission, School of Public Health, Health Science center, Xi'an Jiaotong University, Xi'an, P. R. China.
authors.forename: Jingcan
authors.initials: J
authors.lastname: Hao
authors.affiliation: Key Laboratory of Trace Elements and Endemic Diseases of National Health and Family Planning Commission, School of Public Health, Health Science center, Xi'an Jiaotong University, Xi'an, P. R. China.
authors.forename: Wenyu
authors.initials: W
authors.lastname: Wang
authors.affiliation: Key Laboratory of Trace Elements and Endemic Diseases of National Health and Family Planning Commission, School of Public Health, Health Science center, Xi'an Jiaotong University, Xi'an, P. R. China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Wen
authors.affiliation: Key Laboratory of Trace Elements and Endemic Diseases of National Health and Family Planning Commission, School of Public Health, Health Science center, Xi'an Jiaotong University, Xi'an, P. R. China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Xiao
authors.affiliation: Key Laboratory of Trace Elements and Endemic Diseases of National Health and Family Planning Commission, School of Public Health, Health Science center, Xi'an Jiaotong University, Xi'an, P. R. China.
authors.forename: Awen
authors.initials: A
authors.lastname: He
authors.affiliation: Key Laboratory of Trace Elements and Endemic Diseases of National Health and Family Planning Commission, School of Public Health, Health Science center, Xi'an Jiaotong University, Xi'an, P. R. China.
authors.forename: Xiong
authors.initials: X
authors.lastname: Guo
authors.affiliation: Key Laboratory of Biomedical Information Engineering of Ministry of Education, and Institute of Molecular Genetics, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, P.R. China.
authors.forename: Tielin
authors.initials: T
authors.lastname: Yang
authors.affiliation: Key Laboratory of Biomedical Information Engineering of Ministry of Education, and Institute of Molecular Genetics, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, P.R. China.
authors.forename: Xiaogang
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Biostatistics and Bioinformatics, Tulane University School of Public Health and Tropical Medicine, New Orleans, Louisiana, USA.|Center for Bioinformatics and Genomics, Tulane University, New Orleans, Louisiana, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Shen
authors.affiliation: Laboratory of Molecular and Statistical Genetics, College of Life Sciences, Hunan Normal University, Changsha, P. R. China.
authors.forename: Xiangding
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Biostatistics and Bioinformatics, Tulane University School of Public Health and Tropical Medicine, New Orleans, Louisiana, USA.|Center for Bioinformatics and Genomics, Tulane University, New Orleans, Louisiana, USA.
authors.forename: Qing
authors.initials: Q
authors.lastname: Tian
authors.affiliation: Department of Biostatistics and Bioinformatics, Tulane University School of Public Health and Tropical Medicine, New Orleans, Louisiana, USA.|Center for Bioinformatics and Genomics, Tulane University, New Orleans, Louisiana, USA.
authors.forename: Hong-Wen
authors.initials: HW
authors.lastname: Deng
authors.affiliation: Key Laboratory of Trace Elements and Endemic Diseases of National Health and Family Planning Commission, School of Public Health, Health Science center, Xi'an Jiaotong University, Xi'an, P. R. China.
authors.forename: Feng
authors.initials: F
authors.lastname: Zhang
mesh_terms: D000072199:ADAM12 Protein / Q000235:genetics* / Q000378:metabolism; D000328:Adult; D000368:Aged; D044466:Asian People / Q000235:genetics; D002681:China; D005260:Female; D020022:Genetic Predisposition to Disease / Q000208:ethnology / Q000235:genetics*; D055106:Genome-Wide Association Study / Q000379:methods*; D005838:Genotype; D006801:Humans; D057767:Kashin-Beck Disease / Q000208:ethnology / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D020641:Polymorphism, Single Nucleotide; D055815:Young Adult
chemical_list: D000072199:ADAM12 Protein; C000606480:ADAM12 protein, human