title: Candidate gene analysis and exome sequencing confirm LBX1 as a susceptibility gene for idiopathic scoliosis.
abstract: BACKGROUND
  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.
  
  
  OBJECTIVE
  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.
  
  
  METHODS
  This was a case control study.
  
  
  METHODS
  A total of 1,739 patients with idiopathic scoliosis and 1,812 controls were included.
  
  
  METHODS
  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.
authors.affiliation: Department of Orthopedics, Sundsvall and Härnösand County Hospital, SE-85186, Sundsvall, Sweden; Department of Orthopedics, Karolinska University Hospital, K54, SE-14186, Stockholm, Sweden; Department of Clinical Sciences, Intervention and Technology (CLINTEC) Karolinska Institutet, SE-14186, Stockholm, Sweden.
authors.forename: Anna
authors.initials: A
authors.lastname: Grauers
authors.affiliation: Department of Biosciences and Nutrition, Karolinska Institutet, Novum, Hälsovägen 7-9, SE-14183, Huddinge, Sweden; Center for Innovative Medicine, Karolinska Institutet, Novum, Hälsovägen 7-9, SE-14183, Huddinge, Sweden.
authors.forename: Jingwen
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Biosciences and Nutrition, Karolinska Institutet, Novum, Hälsovägen 7-9, SE-14183, Huddinge, Sweden; Center for Innovative Medicine, Karolinska Institutet, Novum, Hälsovägen 7-9, SE-14183, Huddinge, Sweden.
authors.forename: Elisabet
authors.initials: E
authors.lastname: Einarsdottir
authors.affiliation: Sector for Spine Surgery and Research, Middelfart Hospital, Middelfart, Denmark.
authors.forename: Ane
authors.initials: A
authors.lastname: Simony
authors.affiliation: Department of Orthopedics, Sahlgren University Hospital, Gothenburg, Sweden.
authors.forename: Aina
authors.initials: A
authors.lastname: Danielsson
authors.affiliation: Department of Orthopedics and Clinical Sciences, Lund University, Skane University Hospital, Malmö, Sweden.
authors.forename: Kristina
authors.initials: K
authors.lastname: Åkesson
authors.affiliation: Department of Orthopedics and Clinical Sciences, Lund University, Skane University Hospital, Malmö, Sweden.
authors.forename: Acke
authors.initials: A
authors.lastname: Ohlin
authors.affiliation: Department of Orthopedics, Sahlgren University Hospital, Gothenburg, Sweden.
authors.forename: Klas
authors.initials: K
authors.lastname: Halldin
authors.affiliation: Department of Orthopedics, University Hospital of Umeå, Umeå, Sweden.
authors.forename: Pawel
authors.initials: P
authors.lastname: Grabowski
authors.affiliation: Department of Orthopedics and Clinical Sciences, Lund University, Skane University Hospital, Malmö, Sweden.
authors.forename: Max
authors.initials: M
authors.lastname: Tenne
authors.affiliation: Department of Medical Genetics and Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland; Institute for Molecular Medicine Finland, University of Helsinki, Tukholmankatu 8, Helsinki, Finland.
authors.forename: Hannele
authors.initials: H
authors.lastname: Laivuori
authors.affiliation: Department of Medicine, Lipid Laboratory, Karolinska Institutet, SE-14186, Stockholm, Sweden.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Dahlman
authors.affiliation: Sector for Spine Surgery and Research, Middelfart Hospital, Middelfart, Denmark.
authors.forename: Mikkel
authors.initials: M
authors.lastname: Andersen
authors.affiliation: Sector for Spine Surgery and Research, Middelfart Hospital, Middelfart, Denmark.
authors.forename: Steen Bach
authors.initials: SB
authors.lastname: Christensen
authors.affiliation: Department of Orthopedics and Clinical Sciences, Lund University, Skane University Hospital, Malmö, Sweden.
authors.forename: Magnus K
authors.initials: MK
authors.lastname: Karlsson
authors.affiliation: Department of Biosciences and Nutrition, Karolinska Institutet, Novum, Hälsovägen 7-9, SE-14183, Huddinge, Sweden; Center for Innovative Medicine, Karolinska Institutet, Novum, Hälsovägen 7-9, SE-14183, Huddinge, Sweden.
authors.forename: Hong
authors.initials: H
authors.lastname: Jiao
authors.affiliation: Department of Biosciences and Nutrition, Karolinska Institutet, Novum, Hälsovägen 7-9, SE-14183, Huddinge, Sweden; Center for Innovative Medicine, Karolinska Institutet, Novum, Hälsovägen 7-9, SE-14183, Huddinge, Sweden; Molecular Neurology Research Program, University of Helsinki and Folkhälsan Institute of Genetics, Helsinki, Finland. Electronic address: Juha.kere@ki.se.
authors.forename: Juha
authors.initials: J
authors.lastname: Kere
authors.affiliation: Department of Orthopedics, Karolinska University Hospital, K54, SE-14186, Stockholm, Sweden; Department of Clinical Sciences, Intervention and Technology (CLINTEC) Karolinska Institutet, SE-14186, Stockholm, Sweden. Electronic address: Paul.gerdhem@karolinska.se.
authors.forename: Paul
authors.initials: P
authors.lastname: Gerdhem
mesh_terms: D000293:Adolescent; D016022:Case-Control Studies; D002648:Child; D059472:Exome; D005260:Female; D055106:Genome-Wide Association Study; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide; D012600:Scoliosis / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D018398:Homeodomain Proteins; C542809:LBX1 protein, human; D014157:Transcription Factors
keywords: Adolescent; Association study; Ethiology; Exome sequencing; Genetics; Idiopathic scoliosis; Juvenile; LBX1