Abstract
Adolescent idiopathic scoliosis is a pediatric spinal deformity affecting 2–3% of school-age children worldwide1. Genetic factors have been implicated in its etiology2. Through a genome-wide association study (GWAS) and replication study involving a total of 1,376 Japanese females with adolescent idiopathic scoliosis and 11,297 female controls, we identified a locus at chromosome 10q24.31 associated with adolescent idiopathic scoliosis susceptibility. The most significant SNP (rs11190870; combined P = 1.24 × 10−19; odds ratio (OR) = 1.56) is located near LBX1 (encoding ladybird homeobox 1). The identification of this susceptibility locus provides new insights into the pathogenesis of adolescent idiopathic scoliosis.
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References
Weinstein, S.L. Natural history. Spine 24, 2592–2600 (1999).
Wise, C.A., Gao, X., Shoemaker, S., Gordon, D. & Herring, J.A. Understanding genetic factors in idiopathic scoliosis, a complex disease of childhood. Curr. Genomics 9, 51–59 (2008).
Ward, K. et al. Validation of DNA-based prognostic testing to predict spinal curve progression in adolescent idiopathic scoliosis. Spine 35, E1455–E1464 (2010).
Kouwenhoven, J.W. & Castelein, R.M. The pathogenesis of adolescent idiopathic scoliosis: review of the literature. Spine 33, 2898–2908 (2008).
Riseborough, E.J. & Wynne-Davies, R.A. Genetic survey of idiopathic scoliosis in Boston, Massachusetts. J. Bone Joint Surg. Am. 55, 974–982 (1973).
Kesling, K.L. & Reinker, K.A. Scoliosis in twins. A meta-analysis of the literature and report of six cases. Spine 22, 2009–2014 (1997).
Raggio, C.L. et al. A novel locus for adolescent idiopathic scoliosis on chromosome 12p. J. Orthop. Res. 27, 1366–1372 (2009).
Wu, J. et al. Association of estrogen receptor gene polymorphisms with susceptibility to adolescent idiopathic scoliosis. Spine 31, 1131–1136 (2006).
Zhang, H.Q. et al. Association of estrogen receptor beta gene polymorphisms with susceptibility to adolescent idiopathic scoliosis. Spine 34, 760–764 (2009).
Chen, Z. et al. Promoter polymorphism of matrilin-1 gene predisposes to adolescent idiopathic scoliosis in a Chinese population. Eur. J. Hum. Genet. 17, 525–532 (2009).
Qiu, X.S. et al. Melatonin receptor 1B (MTNR1B) gene polymorphism is associated with the occurrence of adolescent idiopathic scoliosis. Spine 32, 1748–1753 (2007).
Wang, H. et al. Association study of tryptophan hydroxylase 1 and arylalkylamine N-acetyltransferase polymorphisms with adolescent idiopathic scoliosis in Han Chinese. Spine 33, 2199–2203 (2008).
Inoue, M. et al. Prediction of curve progression in idiopathic scoliosis from gene polymorphic analysis. Stud. Health Technol. Inform. 91, 90–96 (2002).
Yeung, H.Y. et al. Genetic association study of insulin-like growth factor-I (IGF-I) gene with curve severity and osteopenia in adolescent idiopathic scoliosis. Stud. Health Technol. Inform. 123, 18–24 (2006).
Takahashi, Y. et al. Replication study of the association between adolescent idiopathic scoliosis and two estrogen receptor genes. J. Orthop. Res. 29, 834–837 (2011).
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).
Ueno, M. et al. A 5-year epidemiological study on the prevalence rate of idiopathic scoliosis in Tokyo: school screening of more than 250,000 children. J. Orthop. Sci. 16, 1–6 (2011).
Cha, P.C. et al. A genome-wide association study identifies three loci associated with susceptibility to uterine fibroids. Nat. Genet. 43, 447–450 (2011).
Jagla, K. et al. Mouse Lbx1 and human LBX1 define a novel mammalian homeobox gene family related to the Drosophila lady bird genes. Mech. Dev. 53, 345–356 (1995).
Cheng, L. et al. Lbx1 and Tlx3 are opposing switches in determining GABAergic versus glutamatergic transmitter phenotypes. Nat. Neurosci. 8, 1510–1515 (2005).
Schäfer, K., Neuhaus, P., Kruse, J. & Braun, T. The homeobox gene Lbx1 specifies a subpopulation of cardiac neural crest necessary for normal heart development. Circ. Res. 92, 73–80 (2003).
Gross, M.K., Dottori, M. & Goulding, M. Lbx1 specifies somatosensory association interneurons in the dorsal spinal cord. Neuron 34, 535–549 (2002).
Müller, T. et al. The homeodomain factor Lbx1 distinguishes two major programs of neuronal differentiation in the dorsal spinal cord. Neuron 34, 551–562 (2002).
Sieber, M.A. et al. Lbx1 acts as a selector gene in the fate determination of somatosensory and viscerosensory relay neurons in the hindbrain. J. Neurosci. 27, 4902–4909 (2007).
Huang, M. et al. Ptf1a, Lbx1 and Pax2 coordinate glycinergic and peptidergic transmitter phenotypes in dorsal spinal inhibitory neurons. Dev. Biol. 322, 394–405 (2008).
Pincott, J.R. & Taffs, L.F. Experimental scoliosis in primates: a neurological cause. J. Bone Joint Surg. Br. 64, 503–507 (1982).
Guo, X. et al. Balance control in adolescents with idiopathic scoliosis and disturbed somatosensory function. Spine 31, E437–E440 (2006).
Langerak, N.G. et al. Incidence of spinal abnormalities in patients with spastic diplegia 17 to 26 years after selective dorsal rhizotomy. J. Rehabil. Med. 43, 330–337 (2011).
Ohtsuka, Y., Yamagata, M., Arai, S., Kitahara, H. & Minami, S. School screening for scoliosis by the Chiba University Medical School screening program. Results of 1.24 million students over an 8-year period. Spine 13, 1251–1257 (1988).
Ohnishi, Y. et al. A high-throughput SNP typing system for genome-wide association studies. J. Hum. Genet. 46, 471–477 (2001).
Acknowledgements
We thank the individuals who participated in this study. We thank N. Suzuki, M. Saito, M. Kamata, N. Hosogane, E. Okada, H. Hase, I. Karasugi, M. Nakajima and A. Miyake for their help in collecting samples and conducting the experimental study and T. Isono for technical assistance. This work was supported by a grant-in-aid from the Japanese Orthopaedic Association (JOA-Subsidized Science Project Research 2009-1) and by BioBank Japan.
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Y. Takahashi, K.C., M.M. and S.I. designed the study. M.K. and N. Kamatani contributed to overall GWAS design. Y. Takahashi, Y. Toyama, M.M. and S.I. drafted the manuscript. A.T., T.A.J. and T. Tsunoda analyzed the GWAS data. N.H. and M.K. performed the genotyping for the GWAS. M.M., K.K., K.W., N. Kawakami, T. Tsuji, K.U., T.S., M.I., H.S., S.M., T.K., H.Y. and H.T. managed DNA samples from individuals with adolescent idiopathic scoliosis and clinical data. M.K. managed DNA samples from control individuals. Y. Takahashi, I.K., M.M. and S.I. summarized the results.
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Takahashi, Y., Kou, I., Takahashi, A. et al. A genome-wide association study identifies common variants near LBX1 associated with adolescent idiopathic scoliosis. Nat Genet 43, 1237–1240 (2011). https://doi.org/10.1038/ng.974
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DOI: https://doi.org/10.1038/ng.974
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