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A meta-analysis identifies adolescent idiopathic scoliosis association with LBX1 locus in multiple ethnic groups
  1. Douglas Londono1,
  2. Ikuyo Kou2,
  3. Todd A Johnson3,
  4. Swarkar Sharma4,5,
  5. Yoji Ogura2,6,
  6. Tatsuhiko Tsunoda3,
  7. Atsushi Takahashi7,
  8. Morio Matsumoto6,
  9. John A Herring8,9,
  10. Tsz-Ping Lam10,11,
  11. Xingyan Wang12,13,
  12. Elisa M S Tam10,11,
  13. You-Qiang Song14,
  14. Yan-Hui Fan14,
  15. Danny Chan14,
  16. Kathryn S E Cheah14,
  17. Xusheng Qiu15,
  18. Hua Jiang15,
  19. Dongsheng Huang16,
  20. Japanese Scoliosis Clinical Research Group, TSRHC IS Clinical Group, the International Consortium for Scoliosis Genetics,
  21. Peiqiang Su17,
  22. Pak Sham18,
  23. Kenneth M C Cheung19,
  24. Keith D K Luk19,
  25. Derek Gordon1,
  26. Yong Qiu15,
  27. Jack Cheng10,11,
  28. Nelson Tang12,13,
  29. Shiro Ikegawa2,
  30. Carol A Wise4,9,20,21
  1. 1Department of Genetics, Rutgers, The State University of New Jersey, Piscataway, USA
  2. 2Laboratory for Bone and Joint Diseases, Center for Integrative Medical Sciences, RIKEN, Tokyo, Japan
  3. 3Laboratory for Medical Science Mathematics, Center for Integrative Medical Sciences, RIKEN, Yokohama, Japan
  4. 4Seay Center for Musculoskeletal Research, Texas Scottish Rite Hospital for Children, Dallas, USA
  5. 5School of Biotechnology, SMVDU, Katra, India
  6. 6Department of Orthopaedic Surgery, School of Medicine, Keio University, Tokyo, Japan
  7. 7Laboratory for Statistical Analysis, Center for Integrative Medical Sciences, Riken, Yokohama, Japan
  8. 8Department of Orthopedic Surgery, Texas Scottish Rite Hospital for Children, Dallas, USA
  9. 9Department of Orthopaedics, University of Texas Southwestern Medical Center at Dallas, Dallas, USA
  10. 10Department of Orthopaedics and Traumatology, The Chinese University of Hong Kong, Hong Kong, China
  11. 11Joint Scoliosis Research Center, The Chinese University of Hong Kong and Nanjing University, Hong Kong, China
  12. 12Functional Genomics and Biostatistical Computing Laboratory, Shenzhen Research Institute of the Chinese University of Hong Kong, Hong Kong, China
  13. 13Department of Chemical Pathology, the Chinese University of Hong Kong, Shatin, Hong Kong SAR, China
  14. 14Department of Biochemistry, University of Hong Kong, Hong Kong, China
  15. 15Department of Spine Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China
  16. 16Department of Orthopedics, The Memorial Hospital of Sun Yat-Sen University, Guangzhou, China
  17. 17Department of Spine Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
  18. 18Department of Psychiatry, University of Hong Kong, Hong Kong, China
  19. 19Department of Orthopaedics and Traumatology, University of Hong Kong, Hong Kong, China
  20. 20Department of Pediatrics, University of Texas Southwestern Medical Center at Dallas, Dallas, USA
  21. 21McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center at Dallas, Dallas, USA
  1. Correspondence to Dr Carol Ann Wise, Sarah M and Charles E Seay, Seay Center for Musculoskeletal Research, Texas Scottish Rite Hospital for Children, Dallas, TX 75219, USA; carol.wise{at}tsrh.org Dr Shiro Ikegawa, Laboratory for Bone and Joint Diseases, Center for Integrative Medical Sciences, RIKEN, Tokyo, Japan; sikegawa{at}ims.u-tokyo.ac.jp

Abstract

Background Adolescent idiopathic scoliosis (AIS) is a common rotational deformity of the spine that presents in children worldwide, yet its etiology is poorly understood. Recent genome-wide association studies (GWAS) have identified a few candidate risk loci. One locus near the chromosome 10q24.31 LBX1 gene (OMIM #604255) was originally identified by a GWAS of Japanese subjects and replicated in additional Asian populations. To extend this result, and to create larger AIS cohorts for the purpose of large-scale meta-analyses in multiple ethnicities, we formed a collaborative group called the International Consortium for Scoliosis Genetics (ICSG).

Methods Here, we report the first ICSG study, a meta-analysis of the LBX1 locus in six Asian and three non-Asian cohorts.

Results We find significant evidence for association of this locus with AIS susceptibility in all nine cohorts. Results for seven cohorts containing both genders yielded P=1.22×10–43 for rs11190870, and P=2.94×10–48 for females in all nine cohorts. Comparing the regional haplotype structures for three populations, we refined the boundaries of association to a ∼25 kb block encompassing the LBX1 gene. The LBX1 protein, a homeobox transcription factor that is orthologous to the Drosophila ladybird late gene, is involved in proper migration of muscle precursor cells, specification of cardiac neural crest cells, and neuronal determination in developing neural tubes.

Conclusions Our results firmly establish the LBX1 region as the first major susceptibility locus for AIS in Asian and non-Hispanic white groups, and provide a platform for larger studies in additional ancestral groups.

  • meta-analysis
  • scoliosis
  • LBX1
  • 10q24.31

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