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Adolescent idiopathic scoliosis (AIS) is the most common spinal deformity. We previously conducted a genome-wide association study (GWAS) and detected two loci associated with AIS. To identify additional loci, we extended our GWAS by increasing the number of cohorts (2,109 affected subjects and 11,140 control subjects in total) and conducting a whole-genome imputation. Through the extended GWAS and replication studies using independent Japanese and Chinese populations, we identified a susceptibility locus on chromosome 9p22.2 (p = 2.46 × 10(-13); odds ratio = 1.21). The most significantly associated SNPs were in intron 3 of BNC2, which encodes a zinc finger transcription factor, basonuclin-2. Expression quantitative trait loci data suggested that the associated SNPs have the potential to regulate the BNC2 transcriptional activity and that the susceptibility alleles increase BNC2 expression. We identified a functional SNP, rs10738445 in BNC2, whose susceptibility allele showed both higher binding to a transcription factor, YY1 (yin and yang 1), and higher BNC2 enhancer activity than the non-susceptibility allele. BNC2 overexpression produced body curvature in developing zebrafish in a gene-dosage-dependent manner. Our results suggest that increased BNC2 expression is implicated in the etiology of AIS.

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.

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The sagittal morphology of the pelvis in patients with severe HOA was normal and might not be involved in the development and progression of this disorder. Although the whole spine was involved in compensating for the flexed hip joint, the poor ability resulted in severely unbalanced spinal-pelvic alignment in these patients. The forward inclined spine and retroverted femur would contribute to the poor physical activities in these patients. However, the abnormal sagittal spine-pelvis-leg alignment in patients with severe HOA might not be involved in the pathogenesis of low back pain.

Purpose To investigate the prevalence of degenerative lumbar scoliosis (DLS) in Chinese Han population, as well as its correlation with age, gender, bone mineral density (BMD), and body mass index (BMI); and to determine factors that might affect the curve severity. Methods A prospective study was performed on adults visiting the dual-energy X-ray absorption clinics for physical examination from January 2011 to March 2012. 2,395 subjects aged older than 40 years and having no history of previous spinal trauma, surgeries or scoliosis, were enrolled in this study. A logistic regression analysis was performed to determine the independent variables related to the presence of scoliosis. Besides, the relationship between curve severity and these variables was also analyzed with partial linear correlation analysis. Results The prevalence of DLS was approximately 13.3 %. The logistic regression analysis showed that age, T score, and gender all had remarkable correlation with the occurrence of DLS, with the odd ratios being 4.2, 1.5, and 1.6, respectively. According to the receiver operating characteristics curve, the best dividing point for age and T score of female subjects was 65 and -2.0, respectively. Partial linear correlation analysis indicated that there existed no obvious correlation between the above variables and the severity of scoliosis. Conclusion The prevalence of DLS in Chinese Han population aged older than 40 years was approximately 13.3 %, which had a significant correlation with age, gender, and BMD. Osteopenia, gender of female, and aged older than 65 years could contribute to the presence of DLS. The curve severity was not associated with age, gender, BMI, or BMD.

No abstract

The spindle assembly checkpoint (SAC) is a conserved signaling pathway that monitors faithful chromosome segregation during mitosis. As a core component of SAC, the evolutionarily conserved kinase monopolar spindle 1 (Mps1) has been implicated in regulating chromosome alignment, but the underlying molecular mechanism remains unclear. Our molecular delineation of Mps1 activity in SAC led to discovery of a previously unidentified structural determinant underlying Mps1 function at the kinetochores. Here, we show that Mps1 contains an internal region for kinetochore localization (IRK) adjacent to the tetratricopeptide repeat domain. Importantly, the IRK region determines the kinetochore localization of inactive Mps1, and an accumulation of inactive Mps1 perturbs accurate chromosome alignment and mitotic progression. Mechanistically, the IRK region binds to the nuclear division cycle 80 complex (Ndc80C), and accumulation of inactive Mps1 at the kinetochores prevents a dynamic interaction between Ndc80C and spindle microtubules (MTs), resulting in an aberrant kinetochore attachment. Thus, our results present a previously undefined mechanism by which Mps1 functions in chromosome alignment by orchestrating Ndc80C-MT interactions and highlight the importance of the precise spatiotemporal regulation of Mps1 kinase activity and kinetochore localization in accurate mitotic progression.Mps1 kinase | spindle assembly checkpoint | chromosome alignment | kinetochore-microtubule attachment | reversine