Candidate gene analysis and exome sequencing confirm LBX1 as a susceptibility gene for idiopathic scoliosis.

BACKGROUND CONTEXT: Idiopathic scoliosis is a spinal deformity affecting approximately 3% of otherwise healthy children or adolescents. The etiology is still largely unknown but has an important genetic component. Genome-wide association studies have identified a number of common genetic variants that are significantly associated with idiopathic scoliosis in Asian and Caucasian populations, rs11190870 close to the LBX1 gene being the most replicated finding. PURPOSE: The aim of the present study was to investigate the genetics of idiopathic scoliosis in a Scandinavian cohort by performing a candidate gene study of four variants previously shown to be associated with idiopathic scoliosis and exome sequencing of idiopathic scoliosis patients with a severe phenotype to identify possible novel scoliosis risk variants. STUDY DESIGN: This was a case control study. PATIENT SAMPLE: A total of 1,739 patients with idiopathic scoliosis and 1,812 controls were included. OUTCOME MEASURE: The outcome measure was idiopathic scoliosis. METHODS: The variants rs10510181, rs11190870, rs12946942, and rs6570507 were genotyped in 1,739 patients with idiopathic scoliosis and 1,812 controls. Exome sequencing was performed on pooled samples from 100 surgically treated idiopathic scoliosis patients. Novel or rare missense, nonsense, or splice site variants were selected for individual genotyping in the 1,739 cases and 1,812 controls. In addition, the 5'UTR, noncoding exon and promoter regions of LBX1, not covered by exome sequencing, were Sanger sequenced in the 100 pooled samples. RESULTS: Of the four candidate genes, an intergenic variant, rs11190870, downstream of the LBX1 gene, showed a highly significant association to idiopathic scoliosis in 1,739 cases and 1,812 controls (p=7.0×10(-18)). We identified 20 novel variants by exome sequencing after filtration and an initial genotyping validation. However, we could not verify any association to idiopathic scoliosis in the large cohort of 1,739 cases and 1,812 controls. We did not find any variants in the 5'UTR, noncoding exon and promoter regions of LBX1. CONCLUSIONS: Here, we confirm LBX1 as a susceptibility gene for idiopathic scoliosis in a Scandinavian population and report that we are unable to find evidence of other genes of similar or stronger effect.

Variation in the PTH2R gene is associated with age-related degenerative changes in the lumbar spine.

In the elderly, degenerative changes in the lumbar spine are common, contributing to falsely elevated bone mineral density (BMD) values. The parathyroid hormone (PTH) system plays an important role in the regulation of bone turnover and we explore the hypothesis that polymorphisms (SNPs) within genes in this pathway (PTH, PTHLH, PTH1R and PTH2R) contribute to degenerative manifestations of the spine in elderly women. The study included 1,004 Swedish women aged 75 years from the population-based OPRA cohort who attended follow-up at 5 and 10 years. Lumbar spine BMD was assessed by dual energy X-ray absorptiometry (DXA) and each individual vertebra was evaluated visually on the DXA image for apparent degenerative manifestations. Six SNPs in PTH and 3 SNPs each in PTH1R, PTH2R and PTHLH were analysed. Among women with degenerative manifestations at the lumbar spine, there was an over-representation at baseline of those carrying the PTH2R SNP rs897083 A-allele (p = 0.0021; odds ratio 1.5 95 % CI 1.2-2.0) and across the duration of follow-up (p = 0.0008). No association was observed between degenerative manifestations and variation in the other genes. None of the PTH hormone system genes were associated with vertebral fracture. Variation in the PTH2R gene (Chr2q34, rs897083) may contribute to the age-associated degenerative manifestations that develop at the lumbar spine.