Douglas Londono1, Ikuyo Kou2, Todd A Johnson3, Swarkar Sharma4, Yoji Ogura5, Tatsuhiko Tsunoda3, Atsushi Takahashi6, Morio Matsumoto7, John A Herring8, Tsz-Ping Lam9, Xingyan Wang10, Elisa M S Tam9, You-Qiang Song11, Yan-Hui Fan11, Danny Chan11, Kathryn S E Cheah11, Xusheng Qiu12, Hua Jiang12, Dongsheng Huang13, Peiqiang Su14, Pak Sham15, Kenneth M C Cheung16, Keith D K Luk16, Derek Gordon1, Yong Qiu12, Jack Cheng9, Nelson Tang10, Shiro Ikegawa2, Carol A Wise17. 1. Department of Genetics, Rutgers, The State University of New Jersey, Piscataway, USA. 2. Laboratory for Bone and Joint Diseases, Center for Integrative Medical Sciences, RIKEN, Tokyo, Japan. 3. Laboratory for Medical Science Mathematics, Center for Integrative Medical Sciences, RIKEN, Yokohama, Japan. 4. Seay Center for Musculoskeletal Research, Texas Scottish Rite Hospital for Children, Dallas, USA School of Biotechnology, SMVDU, Katra, India. 5. Laboratory for Bone and Joint Diseases, Center for Integrative Medical Sciences, RIKEN, Tokyo, Japan Department of Orthopaedic Surgery, School of Medicine, Keio University, Tokyo, Japan. 6. Laboratory for Statistical Analysis, Center for Integrative Medical Sciences, Riken, Yokohama, Japan. 7. Department of Orthopaedic Surgery, School of Medicine, Keio University, Tokyo, Japan. 8. Department of Orthopedic Surgery, Texas Scottish Rite Hospital for Children, Dallas, USA Department of Orthopaedics, University of Texas Southwestern Medical Center at Dallas, Dallas, USA. 9. Department of Orthopaedics and Traumatology, The Chinese University of Hong Kong, Hong Kong, China Joint Scoliosis Research Center, The Chinese University of Hong Kong and Nanjing University, Hong Kong, China. 10. Functional Genomics and Biostatistical Computing Laboratory, Shenzhen Research Institute of the Chinese University of Hong Kong, Hong Kong, China Department of Chemical Pathology, the Chinese University of Hong Kong, Shatin, Hong Kong SAR, China. 11. Department of Biochemistry, University of Hong Kong, Hong Kong, China. 12. Department of Spine Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China. 13. Department of Orthopedics, The Memorial Hospital of Sun Yat-Sen University, Guangzhou, China. 14. Department of Spine Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China. 15. Department of Psychiatry, University of Hong Kong, Hong Kong, China. 16. Department of Orthopaedics and Traumatology, University of Hong Kong, Hong Kong, China. 17. Seay Center for Musculoskeletal Research, Texas Scottish Rite Hospital for Children, Dallas, USA Department of Orthopaedics, University of Texas Southwestern Medical Center at Dallas, Dallas, USA Department of Pediatrics, University of Texas Southwestern Medical Center at Dallas, Dallas, USA McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center at Dallas, Dallas, USA.
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. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
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 Drosophilaladybird 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. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
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: Swarkar Sharma; Douglas Londono; Walter L Eckalbar; Xiaochong Gao; Dongping Zhang; Kristen Mauldin; Ikuyo Kou; Atsushi Takahashi; Morio Matsumoto; Nobuhiro Kamiya; Karl K Murphy; Reuel Cornelia; John A Herring; Dennis Burns; Nadav Ahituv; Shiro Ikegawa; Derek Gordon; Carol A Wise Journal: Nat Commun Date: 2015-03-18 Impact factor: 14.919