Whole-exome sequencing for the identification of susceptibility genes of Kashin-Beck disease.
OBJECTIVE
To identify and investigate the susceptibility genes of Kashin-Beck disease (KBD) in Chinese population.


METHODS
Whole-exome capturing and sequencing technology was used for the detection of genetic variations in 19 individuals from six families with high incidence of KBD. A total of 44 polymorphisms from 41 genes were genotyped from a total of 144 cases and 144 controls by using MassARRAY under the standard protocol from Sequenom. Association was applied on the data by using PLINK1.07.


RESULTS
In the sequencing stage, each sample showed approximately 70-fold coverage, thus covering more than 99% of the target regions. Among the single nucleotide polymorphisms (SNPs) used in the transmission disequilibrium test, 108 had a p-value of <0.01, whereas 1056 had a p-value of <0.05. Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway analysis indicates that these SNPs focus on three major pathways: regulation of actin cytoskeleton, focal adhesion, and metabolic pathways. In the validation stage, single locus effects revealed that two of these polymorphisms (rs7745040 and rs9275295) in the human leukocyte antigen (HLA)-DRB1 gene and one polymorphism (rs9473132) in CD2-associated protein (CD2AP) gene have a significant statistical association with KBD.


CONCLUSIONS
HLA-DRB1 and CD2AP gene were identified to be among the susceptibility genes of KBD, thus supporting the role of the autoimmune response in KBD and the possibility of shared etiology between osteoarthritis, rheumatoid arthritis, and KBD.
Psychiatric Laboratory & Department of Psychiatry, West China Hospital, Sichuan University, Chengdu, Sichuan, P R China; State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, P R China.
Zhenxing
Z
Yang
BGI-Shenzhen, Shenzhen, Guangdong, P R China.
Yu
Y
Xu
Psychiatric Laboratory & Department of Psychiatry, West China Hospital, Sichuan University, Chengdu, Sichuan, P R China; State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, P R China.
Hongrong
H
Luo
Psychiatric Laboratory & Department of Psychiatry, West China Hospital, Sichuan University, Chengdu, Sichuan, P R China; State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, P R China.
Xiaohong
X
Ma
Psychiatric Laboratory & Department of Psychiatry, West China Hospital, Sichuan University, Chengdu, Sichuan, P R China; State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, P R China.
Qiang
Q
Wang
Psychiatric Laboratory & Department of Psychiatry, West China Hospital, Sichuan University, Chengdu, Sichuan, P R China; State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, P R China.
Yingcheng
Y
Wang
Psychiatric Laboratory & Department of Psychiatry, West China Hospital, Sichuan University, Chengdu, Sichuan, P R China; State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, P R China.
Wei
W
Deng
BGI-Shenzhen, Shenzhen, Guangdong, P R China.
Tao
T
Jiang
BGI-Shenzhen, Shenzhen, Guangdong, P R China.
Guangqing
G
Sun
BGI-Shenzhen, Shenzhen, Guangdong, P R China.
Tingting
T
He
BGI-Shenzhen, Shenzhen, Guangdong, P R China.
Jingchu
J
Hu
BGI-Shenzhen, Shenzhen, Guangdong, P R China.
Yingrui
Y
Li
BGI-Shenzhen, Shenzhen, Guangdong, P R China.
Jun
J
Wang
Psychiatric Laboratory & Department of Psychiatry, West China Hospital, Sichuan University, Chengdu, Sichuan, P R China; State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, P R China.
Tao
T
Li
State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, P R China; Biobank Center, West China Hospital, Sichuan University, Chengdu, Sichuan, P R China.
Xun
X
Hu
D000293:Adolescent; D000328:Adult; D000368:Aged; D044466:Asian People / Q000235:genetics; D016022:Case-Control Studies; D059472:Exome / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D060005:Genotyping Techniques; D006801:Humans; D057767:Kashin-Beck Disease / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D017421:Sequence Analysis; D055815:Young Adult