Abstract
Adolescent idiopathic scoliosis (AIS) is the most common pediatric skeletal disease1. We previously reported a locus on chromosome 10q24.31 associated with AIS susceptibility in Japanese using a genome-wide association study (GWAS) consisting of 1,033 cases and 1,473 controls2. To identify additional AIS-associated loci, we expanded the study by adding X-chromosome SNPs in the GWAS and increasing the size of the replication cohorts. Through a stepwise association study including 1,819 cases and 25,939 controls, we identified a new susceptibility locus on chromosome 6q24.1 in Japanese (P = 2.25 × 10−10; odds ratio (OR) = 1.28). The most significantly associated SNP, rs6570507, was in GPR126 (encoding G protein–coupled receptor 126). Its association was replicated in Han Chinese and European-ancestry populations (combined P = 1.27 × 10−14; OR = 1.27). GPR126 was highly expressed in cartilage, and the knockdown of gpr126 in zebrafish caused delayed ossification of the developing spine. Our results should provide insights into the etiology and pathogenesis of AIS.
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References
Weinstein, S.L. Natural history. Spine (Phila Pa 1976) 24, 2592–2600 (1999).
Takahashi, Y. et al. A genome-wide association study identifies common variants near LBX1 associated with adolescent idiopathic scoliosis. Nat. Genet. 43, 1237–1240 (2011).
Wynne-Davies, R. Genetic aspects of idiopathic scoliosis. Dev. Med. Child Neurol. 15, 809–811 (1973).
Ward, K. et al. Polygenic inheritance of adolescent idiopathic scoliosis: a study of extended families in Utah. Am. J. Med. Genet. A. 152A, 1178–1188 (2010).
Fan, Y.H. et al. SNP rs11190870 near LBX1 is associated with adolescent idiopathic scoliosis in southern Chinese. J. Hum. Genet. 57, 244–246 (2012).
Jiang, H. et al. Association of rs11190870 near LBX1 with adolescent idiopathic scoliosis susceptibility in a Han Chinese population. Eur. Spine J. 22, 282–286 (2013).
Lango Allen, H. et al. Hundreds of variants clustered in genomic loci and biological pathways affect human height. Nature 467, 832–838 (2010).
Yang, T.P. et al. Genevar: a database and Java application for the analysis and visualization of SNP-gene associations in eQTL studies. Bioinformatics 26, 2474–2476 (2010).
Heinzen, E.L. et al. Tissue-specific genetic control of splicing: implications for the study of complex traits. PLoS Biol. 6, e1 (2008).
Dunham, I. et al. An integrated encyclopedia of DNA elements in the human genome. Nature 489, 57–74 (2012).
Stehlik, C., Kroismayr, R., Dorfleutner, A., Binder, B.R. & Lipp, J. VIGR—a novel inducible adhesion family G-protein coupled receptor in endothelial cells. FEBS Lett. 569, 149–155 (2004).
Henry, S.P., Liang, S., Akdemir, K.C. & de Crombrugghe, B. The postnatal role of Sox9 in cartilage. J. Bone Miner. Res. 27, 2511–2525 (2012).
Kouwenhoven, J.W. & Castelein, R.M. The pathogenesis of adolescent idiopathic scoliosis: review of the literature. Spine (Phila Pa 1976) 33, 2898–2908 (2008).
Guo, X., Chau, W.W., Chan, Y.L. & Cheng, J.C. Relative anterior spinal overgrowth in adolescent idiopathic scoliosis. Results of disproportionate endochondral-membranous bone growth. J. Bone Joint Surg. Br. 85, 1026–1031 (2003).
Burwell, R.G., Dangerfield, P.H. & Freeman, B.J. Concepts on the pathogenesis of adolescent idiopathic scoliosis. Bone growth and mass, vertebral column, spinal cord, brain, skull, extra-spinal left-right skeletal length asymmetries, disproportions and molecular pathogenesis. Stud. Health Technol. Inform. 135, 3–52 (2008).
Burwell, R.G. et al. Pathogenesis of adolescent idiopathic scoliosis in girls—a double neuro-osseous theory involving disharmony between two nervous systems, somatic and autonomic expressed in the spine and trunk: possible dependency on sympathetic nervous system and hormones with implications for medical therapy. Scoliosis 4, 24 (2009).
Monk, K.R., Oshima, K., Jors, S., Heller, S. & Talbot, W.S. Gpr126 is essential for peripheral nerve development and myelination in mammals. Development 138, 2673–2680 (2011).
Zhao, J. et al. The role of height-associated loci identified in genome wide association studies in the determination of pediatric stature. BMC Med. Genet. 11, 96 (2010).
Soranzo, N. et al. Meta-analysis of genome-wide scans for human adult stature identifies novel loci and associations with measures of skeletal frame size. PLoS Genet. 5, e1000445 (2009).
Sovio, U. et al. Genetic determinants of height growth assessed longitudinally from infancy to adulthood in the northern Finland birth cohort 1966. PLoS Genet. 5, e1000409 (2009).
Lettre, G. et al. Identification of ten loci associated with height highlights new biological pathways in human growth. Nat. Genet. 40, 584–591 (2008).
Sharma, S. & Wise, C. Current understanding of genetic factors in idiopathic scoliosis. in The Genetics and Development of Scoliosis (eds. Katsumi, K. & Dunwoodie, S.L.) 167–190 (Springer, New York, 2010).
Nave, K.A. Myelination and support of axonal integrity by glia. Nature 468, 244–252 (2010).
Monk, K.R. et al. A G protein–coupled receptor is essential for Schwann cells to initiate myelination. Science 325, 1402–1405 (2009).
Pogoda, H.M. et al. A genetic screen identifies genes essential for development of myelinated axons in zebrafish. Dev. Biol. 298, 118–131 (2006).
Carter, G.T. et al. Profiles of neuromuscular diseases. Hereditary motor and sensory neuropathy, types I and II. Am. J. Phys. Med. Rehabil. 74, S140–S149 (1995).
Martin, A.G., Foguet, P.R., Marks, D.S., Thompson, A.G. & Child, A.H. Infantile scoliosis in Beals syndrome: the use of a non-fusion technique for surgical correction. Eur. Spine J. 15, 433–439 (2006).
Yingsakmongkol, W. & Kumar, S.J. Scoliosis in arthrogryposis multiplex congenita: results after nonsurgical and surgical treatment. J. Pediatr. Orthop. 20, 656–661 (2000).
Hancock, D.B. et al. Meta-analyses of genome-wide association studies identify multiple loci associated with pulmonary function. Nat. Genet. 42, 45–52 (2010).
Boyer, J., Amin, N., Taddonio, R. & Dozor, A.J. Evidence of airway obstruction in children with idiopathic scoliosis. Chest 109, 1532–1535 (1996).
Ohnishi, Y. et al. A high-throughput SNP typing system for genome-wide association studies. J. Hum. Genet. 46, 471–477 (2001).
Takahashi, Y. et al. Lack of association between adolescent idiopathic scoliosis and previously reported single nucleotide polymorphisms in MATN1, MTNR1B, TPH1, and IGF1 in a Japanese population. J. Orthop. Res. 29, 1055–1058 (2011).
Sharma, S. et al. Genome-wide association studies of adolescent idiopathic scoliosis suggest candidate susceptibility genes. Hum. Mol. Genet. 20, 1456–1466 (2011).
Purcell, S. et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am. J. Hum. Genet. 81, 559–575 (2007).
Falconer, D.S. & Mackay, T.F.C. Introduction to Quantitative Genetics, 4th edn (Longman, Harlow, UK, 1996).
Shukunami, C., Takimoto, A., Miura, S., Nishizaki, Y. & Hiraki, Y. Chondromodulin-I and tenomodulin are differentially expressed in the avascular mesenchyme during mouse and chick development. Cell Tissue Res. 332, 111–122 (2008).
Fleming, A., Keynes, R. & Tannahill, D. A central role for the notochord in vertebral patterning. Development 131, 873–880 (2004).
Acknowledgements
We thank all participating individuals with AIS and the doctors and staff of the collaborating institutes. We especially thank N. Suzuki, M. Saito, M. Kamata, N. Hosogane, E. Okada and H. Hase for their help in collecting samples. We also thank S. Tominaga and T. Isono for technical assistance. This work was supported by a grant-in-aid to M.M. from the Japanese Orthopaedic Association (JOA–Subsidized Science Project Research 2009-1) and by funding from the US National Institutes of Health (R01052973), the Crystal Charity Ball, the Scoliosis Research Society and the Texas Scottish Rite Hospital Research Fund to C.A.W.
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I.K., Y. Takahashi, M.M., K.C. and S.I. designed the study. M.K. and N. Kamatani contributed to overall GWAS design. I.K., M.M. and S.I. drafted the manuscript. T.A.J., A. Takahashi and T. Tsunoda analyzed the GWAS data. I.K., Y. Takahashi, N.H. and M.K. performed the genotyping for the GWAS and replication study. M.M., K.K., K.W., N. Kawakami, T. Tsuji, K.U., T.S., M.I., H.S., S.M., T.K., H. Yanagida, I.Y., Y.O., H.T. and Y. Toyama managed DNA samples from individuals with AIS and clinical data. M.K. managed DNA samples from control individuals. J.D., X.Q., H.J., H. Yan, Y.Q. and Q.J. designed and carried out the Han Chinese replication study. S.S., D.L., D.G., J.A.H. and C.A.W. designed and carried out the replication study in individuals of European ancestry. I.K., L.G., A. Takimoto, C.S. and Y.H. designed and performed the functional studies. I.K. and S.I. summarized the results.
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Kou, I., Takahashi, Y., Johnson, T. et al. Genetic variants in GPR126 are associated with adolescent idiopathic scoliosis. Nat Genet 45, 676–679 (2013). https://doi.org/10.1038/ng.2639
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DOI: https://doi.org/10.1038/ng.2639
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