Genetic variants in GPR126 are associated with adolescent idiopathic scoliosis

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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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Figure 1: Regional association plots and recombination rates at the AIS susceptibility locus on chromosome 6q24.1.
Figure 2: Phenotypes of gpr126 zebrafish morphants.

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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.

Author information

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.

Correspondence to Morio Matsumoto or Shiro Ikegawa.

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The authors declare no competing financial interests.

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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) doi:10.1038/ng.2639

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