Dataset Information

Genome-wide association study identifies new susceptibility loci for adolescent idiopathic scoliosis in Chinese girls.

ABSTRACT: Adolescent idiopathic scoliosis (AIS) is a structural deformity of the spine affecting millions of children. As a complex disease, the genetic aetiology of AIS remains obscure. Here we report the results of a four-stage genome-wide association study (GWAS) conducted in a sample of 4,317 AIS patients and 6,016 controls. Overall, we identify three new susceptibility loci at 1p36.32 near AJAP1 (rs241215, Pcombined=2.95 × 10(-9)), 2q36.1 between PAX3 and EPHA4 (rs13398147, Pcombined=7.59 × 10(-13)) and 18q21.33 near BCL-2 (rs4940576, Pcombined=2.22 × 10(-12)). In addition, we refine a previously reported region associated with AIS at 10q24.32 (rs678741, Pcombined=9.68 × 10(-37)), which suggests LBX1AS1, encoding an antisense transcript of LBX1, might be a functional variant of AIS. This is the first GWAS investigating genetic variants associated with AIS in Chinese population, and the findings provide new insight into the multiple aetiological mechanisms of AIS.

SUBMITTER: Zhu Z

PROVIDER: S-EPMC4595747 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Genome-wide association study identifies new susceptibility loci for adolescent idiopathic scoliosis in Chinese girls.

Zhu Zezhang Z Tang Nelson Leung-Sang NL Xu Leilei L Qin Xiaodong X Mao Saihu S Song Yueming Y Liu Limin L Li Fangcai F Liu Peng P Yi Long L Chang Jiang J Jiang Long L Ng Bobby Kin-Wah BK Shi Benlong B Zhang Wen W Qiao Jun J Sun Xu X Qiu Xusheng X Wang Zhou Z Wang Fei F Xie Dingding D Chen Ling L Chen Zhonghui Z Jin Mengran M Han Xiao X Hu Zongshan Z Zhang Zhen Z Liu Zhen Z Zhu Feng F Qian Bang-Ping BP Yu Yang Y Wang Bing B Lee K M KM Lee Wayne Y W WYW Lam T P TP Qiu Yong Y Cheng Jack Chun-Yiu JC

Nature communications 20150922

Adolescent idiopathic scoliosis (AIS) is a structural deformity of the spine affecting millions of children. As a complex disease, the genetic aetiology of AIS remains obscure. Here we report the results of a four-stage genome-wide association study (GWAS) conducted in a sample of 4,317 AIS patients and 6,016 controls. Overall, we identify three new susceptibility loci at 1p36.32 near AJAP1 (rs241215, Pcombined=2.95 × 10(-9)), 2q36.1 between PAX3 and EPHA4 (rs13398147, Pcombined=7.59 × 10(-13)) ...[more]

PMID: 26394188

Similar Datasets

Project description:To investigate the underlying mechanisms of low metabolic activity of primary chondrocytes obtained from girls with adolescent idiopathic scoliosis (AIS); AIS is a spine-deforming disease that often occurs in girls. AIS is associated with a lower bone mass than that of healthy individuals and osteopenia. Leptin was shown to play an important role in bone growth. It can also regulate the function of chondrocytes. Changes in leptin and Ob-R levels in AIS patients have been reported in several studies. The underlying mechanisms between the dysfunction of peripheral leptin signaling and abnormal chondrocytes remain unclear; The following parameters were evaluated in AIS patients and the control groups: total serum leptin levels; Ob-R expression in the plasma membrane of primary chondrocytes; JAK2 and STAT3 phosphorylation status. Then, we inhibited the lysosome and proteasome and knocked down clathrin heavy chain (CHC) expression in primary chondrocytes isolated from girls with AIS and evaluated Ob-R expression. We investigated the effects of leptin combined with a lysosome inhibitor or CHC knockdown in primary chondrocytes obtained from AIS patients; Compared with the controls, AIS patients showed similar total serum leptin levels, reduced JAK2 and STAT3 phosphorylation, and decreased cartilage matrix synthesis in the facet joint. Lower metabolic activity and lower membrane expression of Ob-R were observed in primary chondrocytes from the AIS group than in the controls. Lysosome inhibition increased the total Ob-R content but had no effect on the membrane expression of Ob-R or leptin's effects on AIS primary chondrocytes. CHC knockdown upregulated the membrane Ob-R levels and enhanced leptin's effects on AIS primary chondrocytes; The underlying mechanism of chondrocytes that are hyposensitive to leptin in some girls with AIS is low plasma membrane Ob-R expression that results from an imbalance between the rate of receptor endocytosis and the insertion of newly synthesized receptors into the membrane.

Project description:Adolescent idiopathic scoliosis (AIS) is a well characterized spinal deformity that affects millions of children world-wide. The role of genetic factor in the development of AIS has been of great interest, since obvious hereditary trend has been observed in AIS families. In a recent study of Chinese population, a novel mutation of AKAP2 was observed in a family with AIS, which was believed to play a role in the aetiopathogenesis of AIS. The purpose of this study was to investigate whether genetic variants of AKAP2 are associated with the susceptibility of AIS in Chinese population.SNV c.2645A > C of AKAP2 was genotyped in 1254 AIS patients and 1232 normal controls using allelic-specific multiple ligase detection reactions. SNPs located within 5' untranslated regions (UTR) and 3' UTR of AKAP2 gene were selected using Haploview (v2.6). The GWAS database composed of 961 AIS patients and 1499 controls was referred to for the genotyping information. Relative mRNA expression of AKAP2 in peripheral blood was analyzed for 33 patients and 18 age-matched controls. Comparison between the cases and controls were performed using the Student's t test. PLINK (v1.90) was used to calculate the association of each SNP with the disease by Cochran-Armitage trend test.All the patients and the controls presented a genotype of AA in c.2645A > C of AKAP2, and there was no case of mutation in any subject. A total of 116 SNPs covering AKAP2 were analyzed, and none of these SNPs was found to have significantly different allele frequency between the cases and the controls. The mRNA expression of AKAP2 in patients was comparable with that in the controls (1.9 ± 0.8 vs. 1.8 ± 0.7, p = 0.66).Our large-scale replication study of the variants in AKAP2 gene did not support its association with the susceptibility of AIS in the Chinese population. In future study, functional studies of the previously reported rare variant are warranted to clarify whether the variant can regulate the expression of AKAP2. The whole AKAP2 gene can be sequenced in larger AIS cohorts to identify potentially missing mutations.

Project description:Age at menarche is closely related to scoliosis progression during adolescence. Current data concerning the timing of menarche between scoliotic and non-scoliotic girls in the literature are conflicting, with inconclusive results. The aim of this study was to investigate the distribution difference of age at menarche for adolescent idiopathic scoliosis (AIS) girls and normal control population and to subsequently elucidate the menarche age difference through literature reviewing. Moreover, menarche age of AIS girls with Cobb angle <40°, 40-60°, >60° were compared to estimate its association with curve severity. Menstrual status data were available for 6,376 healthy female adolescents and 2,196 AIS girls. We notice that less than 10% of healthy Chinese girls experienced onset of menses before 11.38 years, and approximately 90% of healthy Chinese girls were menstruating by 13.88 years, with a median age of 12.63 years. As for AIS girls, less than 10% started to menstruate before 11.27 years, and approximately 90% were menstruating by 14.38 years, with a median age of 12.83 years. Average menarche age in AIS (12.83 ± 1.22 years) was significantly later than that of normal control girls (12.63 ± 0.98 years) (p < 0.001). Age at menarche for AIS affected girls was significantly greater than that of normal control girls at 75%, 90% of whom had attained menarche (p = 0.001, p < 0.001). Proportion of girls starting to menstruate after 14 years was significantly higher in AIS population compared with normal controls (16.3 vs. 8.1%, p < 0.001). In addition, AIS girls with Cobb angle >60° experienced onset of menses at an average age of 13.25 years, which was significantly later than AIS girls with Cobb angle <40° (12.81 years, p < 0.05) and marginally significantly later than AIS girls with Cobb angle between 40 and 60° (12.86 years, p = 0.053). In conclusion, a tendency of delayed onset of menarche was observed in Chinese idiopathic scoliotic girls in this large sample study, especially for girls with Cobb angle >60°, which is supported by multiple previously established positive linkages on AIS etiology studies. Accordingly it is believed that late menarche may contribute importantly to abnormal pubertal growth and subsequently modulate curve behavior in AIS.

Dataset Information

Genome-wide association study identifies new susceptibility loci for adolescent idiopathic scoliosis in Chinese girls.

Publications

Genome-wide association study identifies new susceptibility loci for adolescent idiopathic scoliosis in Chinese girls.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets