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Candidate gene analysis and exome sequencing confirm LBX1 as a susceptibility gene for Idiopathic Scoliosis.

Grauers, A; Wang, J; Einarsdottir, E; Simony, A; Danielsson, A; Åkesson, Kristina LU ; Ohlin, Acke LU ; Halldin, K; Grabowski, P and Tenne, Max LU , et al. (2015) In The Spine Journal 15(10). p.2239-2246
Abstract
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 (GWAS) 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... (More)
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 (GWAS) 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. (Less)
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publishing date
type
Contribution to journal
publication status
published
subject
in
The Spine Journal
volume
15
issue
10
pages
2239 - 2246
publisher
Elsevier
external identifiers
  • pmid:25987191
  • scopus:84942504402
ISSN
1878-1632
DOI
10.1016/j.spinee.2015.05.013
language
English
LU publication?
yes
id
4a65be88-5e4b-4153-8381-4a8be0cc79b1 (old id 5448857)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/25987191?dopt=Abstract
date added to LUP
2015-06-04 22:12:42
date last changed
2019-08-14 03:00:48
@article{4a65be88-5e4b-4153-8381-4a8be0cc79b1,
  abstract     = {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 (GWAS) 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. <br/>Purpose<br/>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.<br/>Study design<br/>This was a case control study.<br/>Patient sample<br/>A total of 1,739 patients with idiopathic scoliosis and 1,812 controls were included.<br/>Outcome measure<br/><br/>The outcome measure was idiopathic scoliosis.<br/>Methods<br/>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.<br/>Results<br/>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.<br/>Conclusions<br/>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.},
  author       = {Grauers, A and Wang, J and Einarsdottir, E and Simony, A and Danielsson, A and Åkesson, Kristina and Ohlin, Acke and Halldin, K and Grabowski, P and Tenne, Max and Laivuori, H and Dahlman, I and Andersen, M and Christensen, S B and Karlsson, Magnus and Jiao, H and Kere, J and Gerdhem, Paul},
  issn         = {1878-1632},
  language     = {eng},
  month        = {05},
  number       = {10},
  pages        = {2239--2246},
  publisher    = {Elsevier},
  series       = {The Spine Journal},
  title        = {Candidate gene analysis and exome sequencing confirm LBX1 as a susceptibility gene for Idiopathic Scoliosis.},
  url          = {http://dx.doi.org/10.1016/j.spinee.2015.05.013},
  volume       = {15},
  year         = {2015},
}