Exome sequencing identified FGF12 as a novel candidate gene for Kashin-Beck disease.
The objective of this study was to identify novel causal genes involved in the pathogenesis of Kashin-Beck disease (KBD). A representative grade III KBD sib pair with serious skeletal growth and development failure was subjected to exome sequencing using the Illumina Hiseq2000 platform. The detected gene mutations were then filtered against the data of 1000 Genome Project, dbSNP database, and BGI inhouse database, and replicated by a genome-wide association study (GWAS) of KBD. Ninety grade II or III KBD patients with extreme KBD phenotypes and 1627 healthy controls were enrolled in the GWAS. Affymetrix Genome-Wide Human SNP Array 6.0 was applied for genotyping. PLINK software was used for association analysis. We identified a novel 106T>C at the 3'UTR of the FGF12 gene, which has not been reported by now. Sequence alignment observed high conversation at the mutated 3'UTR+106T>C locus across various vertebrates. In the GWAS of KBD, we detected nine SNPs of the FGF12 gene showing association evidence (P value < 0.05) with KBD. The most significant association signal was observed at rs1847340 (P value = 1.90 × 10(-5)). This study suggests that FGF12 was a susceptibility gene of KBD. Our results provide novel clues for revealing the pathogenesis of KBD and the biological function of FGF12.
Key Laboratory of Trace Elements and Endemic Diseases of Ministry of Health, School of Public Health, Health Science Center, Xi'an Jiaotong University, Xi'an, People's Republic of China.
Feng
F
Zhang
BGI-Shenzhen, Shenzhen, 518083, China.
Lanlan
L
Dai
Department of Nephrology and Traditional Chinese Medicine, The People's Liberating Army 451 Hospital, Xi'an, People's Republic of China.
Weimin
W
Lin
Key Laboratory of Trace Elements and Endemic Diseases of Ministry of Health, School of Public Health, Health Science Center, Xi'an Jiaotong University, Xi'an, People's Republic of China.
Wenyu
W
Wang
BGI-Shenzhen, Shenzhen, 518083, China.
Xuanzhu
X
Liu
BGI-Shenzhen, Shenzhen, 518083, China.
Jianguo
J
Zhang
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, People's Republic of China.
Tielin
T
Yang
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, People's Republic of China.
Xiaogang
X
Liu
Department of Biostatistics and Bioinformatics, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA, USA.|Center for Bioinformatics and Genomics, Tulane University, New Orleans, LA, USA.
Hui
H
Shen
Laboratory of Molecular and Statistical Genetics, College of Life Sciences, Hunan Normal University, Changsha, People's Republic of China.
Xiangding
X
Chen
Laboratory of Molecular and Statistical Genetics, College of Life Sciences, Hunan Normal University, Changsha, People's Republic of China.
Lijun
L
Tan
Department of Biostatistics and Bioinformatics, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA, USA.|Center for Bioinformatics and Genomics, Tulane University, New Orleans, LA, USA.
Qing
Q
Tian
Department of Biostatistics and Bioinformatics, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA, USA.|Center for Bioinformatics and Genomics, Tulane University, New Orleans, LA, USA.
Hong-Wen
HW
Deng
BGI-Shenzhen, Shenzhen, 518083, China. xuxun@genomics.org.cn.
Xun
X
Xu
Key Laboratory of Trace Elements and Endemic Diseases of Ministry of Health, School of Public Health, Health Science Center, Xi'an Jiaotong University, Xi'an, People's Republic of China. guox@mail.xjtu.edu.cn.
Xiong
X
Guo
D020413:3' Untranslated Regions; D016022:Case-Control Studies; D059472:Exome; D005260:Female; D005346:Fibroblast Growth Factors / Q000235:genetics*; D006801:Humans; D057767:Kashin-Beck Disease / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide
D020413:3' Untranslated Regions; C486356:FGF12 protein, human; D005346:Fibroblast Growth Factors
Exome sequencing; Fibroblast growth factor; Genome-wide association study; Kashin-Beck disease