Aims. Lumbar spinal stenosis (LSS) is a common skeletal system disease that has been partly attributed to
Degenerative cervical spondylosis (DCS) is a common musculoskeletal disease that encompasses a wide range of progressive degenerative changes and affects all components of the cervical spine. DCS imposes very large social and economic burdens. However, its genetic basis remains elusive. Predicted whole-blood and skeletal muscle gene expression and genome-wide association study (GWAS) data from a DCS database were integrated, and functional summary-based imputation (FUSION) software was used on the integrated data. A transcriptome-wide association study (TWAS) was conducted using FUSION software to assess the association between predicted gene expression and DCS risk. The TWAS-identified genes were verified via comparison with differentially expressed genes (DEGs) in DCS RNA expression profiles in the Gene Expression Omnibus (GEO) (Accession Number: GSE153761). The Functional Mapping and Annotation (FUMA) tool for genome-wide association studies and Meta tools were used for gene functional enrichment and annotation analysis.Aims
Methods
Introduction. Adolescent idiopathic scoliosis (AIS) is the most common paediatric spinal deformity, affecting about 3% of school-aged children worldwide. This disorder occurs in otherwise healthy children who bear no obvious deficiencies in the components of the spinal column itself. The cause of AIS is poorly understood, as is implied by the name. Lesions of the bony composition of the vertebrae, the vertebral endplates, the paraspinous muscles, or the neurological system each have been proposed to explain disease pathogenesis. Progress has been hampered by the absence of an obvious AIS animal model. Consequently we have used genetic studies in human populations to identify factors underlying AIS susceptibility. The complex inheritance and population frequency of AIS suggest that many genetic factors are involved in this disease. To search comprehensively for such factors we previously undertook the first genome-wide association study (GWAS) of AIS susceptibility in a cohort of 419 families in Texas, USA. We found that chromosome 3 SNPs in the proximity of the CHL1 gene yielded strongest results, which we replicated in additional cohorts (rs10510181 OR 1·49, 95% CI 1·29–173, p=2·58×10–8). CHL1 is of interest because it encodes an axon guidance protein and is functionally related to the ROBO3 gene that causes hereditary gaze palsy with progressive scoliosis (HGPPS), a rare disease marked by severe scoliosis. Here we expanded the study to 702 Texas families. Methods. We tested more than 327 000 single-nucleotide polymorphisms (SNPs) across all human autosomes for association with disease. Results. Results of the study in 702 Texas families yielded evidence for association with SNPs in a second axon guidance gene, DSCAM, which encodes a protein in the same structural and functional class with Chl1 and Robo3 (rs2222973 combined OR 0·59, 95% CI 0·48–0·74; p=1·46×10–6). We additionally found AIS associations with loci in CNTNAP2, whose protein product interacts directly with L1 and Robo class proteins and participates in axon pathfinding. Conclusions. These data support
Introduction. Idiopathic scoliosis (IS) has been associated with several genetic loci in varying study populations, reflecting the disorder's genetic complexity. One region of interest is on chromosome 17, flanking regions linked to neurofibromatosis type 1 (NF1). This region is of particular relevance because the most common osseous manifestation in NF1 is scoliosis (10–30% of patients). This alludes to a potential genetic correlation within this region affecting spinal development or stability. The objective of this research is to identify candidate genes within this region that are statistically linked to IS. Methods. An initial population of IS families recruited through approval by the institutional review board (202 families; 1198 individuals) had DNA harvested from blood, and underwent genomic screening, finemapping, and statistical analyses. We identified a specific familial subset: families with males having undergone surgery for scoliosis (17 families, 147 individuals). The initial genome-wide scan indicated that this subset was linked to chromosome 17q.11.2. The most prominent marker, D17s975, (p=0·0003) at 25.12 Mb is adjacent to the NF1 deletional region. We then analysed a custom panel of single-nucleotide polymorphisms (SNPs) extending from 18·30–31·47 Mb for linkage through Taqman SNP assay protocol. With allele specific fluorescent tags, allelic discrimination was done with real-time PCR. Results. Findings show two regions with two or more contiguous SNPs of significance (p<0·05), confirming significant linkage adjacent to the NF1 locus (table). The most significant results lie within the serotonin transporter gene SLC6A4, whose product is a modulator of serotonin (5-HT) activity. Conclusions. IS is a disorder of variable phenotypic expression that has been related to several regions on the genome. Although NF1 has been definitively associated with a region on chromosome 17, the phenotypic expression is not understood at the molecular level. The elucidation of shared
