Anna Grauers1, Jingwen Wang2, Elisabet Einarsdottir2, Ane Simony3, Aina Danielsson4, Kristina Åkesson5, Acke Ohlin5, Klas Halldin4, Pawel Grabowski6, Max Tenne5, Hannele Laivuori7, Ingrid Dahlman8, Mikkel Andersen3, Steen Bach Christensen3, Magnus K Karlsson5, Hong Jiao2, Juha Kere9, Paul Gerdhem10. 1. 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. 2. 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. 3. Sector for Spine Surgery and Research, Middelfart Hospital, Middelfart, Denmark. 4. Department of Orthopedics, Sahlgren University Hospital, Gothenburg, Sweden. 5. Department of Orthopedics and Clinical Sciences, Lund University, Skane University Hospital, Malmö, Sweden. 6. Department of Orthopedics, University Hospital of Umeå, Umeå, Sweden. 7. 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. 8. Department of Medicine, Lipid Laboratory, Karolinska Institutet, SE-14186, Stockholm, Sweden. 9. 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. 10. 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.
Abstract
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.
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 scoliosispatients 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 scoliosispatients. 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: Elizabeth A Terhune; Anna M Monley; Melissa T Cuevas; Cambria I Wethey; Ryan S Gray; Nancy Hadley-Miller Journal: Spine Deform Date: 2022-04-16
Authors: Elizabeth A Terhune; Melissa T Cuevas; Anna M Monley; Cambria I Wethey; Xiaomi Chen; Maria V Cattell; Melisa N Bayrak; Morgan R Bland; Brittan Sutphin; George Devon Trahan; Matthew R G Taylor; Lee A Niswander; Kenneth L Jones; Erin E Baschal; Lilian Antunes; Matthew Dobbs; Christina Gurnett; Bruce Appel; Ryan Gray; Nancy Hadley Miller Journal: Hum Mutat Date: 2021-02-07 Impact factor: 4.878