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      Genome-wide association study identifies 14 previously unreported susceptibility loci for adolescent idiopathic scoliosis in Japanese

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      1 , 1 , 2 , 1 , 2 , 3 , 1 , 4 , 3 , 5 , 6 , 2 , 2 , 1 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 2 , 2 , 2 , 22 , 2 , 23 , 2 , 24 , 2 , 2 , 23 , 7 , 7 , 7 , 8 , 25 , 25 , 9 , 26 , 27 , 11 , 15 , 2 , 5 , , 2 , , 1 ,
      Nature Communications
      Nature Publishing Group UK
      Bone, Disease genetics, Genome-wide association studies

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          Abstract

          Adolescent idiopathic scoliosis (AIS) is the most common pediatric spinal deformity. Several AIS susceptibility loci have been identified; however, they could explain only a small proportion of AIS heritability. To identify additional AIS susceptibility loci, we conduct a meta-analysis of the three genome-wide association studies consisting of 79,211 Japanese individuals. We identify 20 loci significantly associated with AIS, including 14 previously not reported loci. These loci explain 4.6% of the phenotypic variance of AIS. We find 21 cis-expression quantitative trait loci-associated genes in seven of the fourteen loci. By a female meta-analysis, we identify additional three significant loci. We also find significant genetic correlations of AIS with body mass index and uric acid. The cell-type specificity analyses show the significant heritability enrichment for AIS in multiple cell-type groups, suggesting the heterogeneity of etiology and pathogenesis of AIS. Our findings provide insights into etiology and pathogenesis of AIS.

          Abstract

          Adolescent idiopathic scoliosis (AIS) is a common pediatric disease leading to spinal deformities. Here, the authors report GWAS followed by genome-wide meta-analysis in up to 79,211 Japanese individuals, identifying 20 genetic loci for AIS, 14 of which were previously unreported, and perform in vitro validation for rs1978060.

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          Most cited references36

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          Tbx1 haploinsufficieny in the DiGeorge syndrome region causes aortic arch defects in mice.

          DiGeorge syndrome is characterized by cardiovascular, thymus and parathyroid defects and craniofacial anomalies, and is usually caused by a heterozygous deletion of chromosomal region 22q11.2 (del22q11) (ref. 1). A targeted, heterozygous deletion, named Df(16)1, encompassing around 1 megabase of the homologous region in mouse causes cardiovascular abnormalities characteristic of the human disease. Here we have used a combination of chromosome engineering and P1 artificial chromosome transgenesis to localize the haploinsufficient gene in the region, Tbx1. We show that Tbx1, a member of the T-box transcription factor family, is required for normal development of the pharyngeal arch arteries in a gene dosage-dependent manner. Deletion of one copy of Tbx1 affects the development of the fourth pharyngeal arch arteries, whereas homozygous mutation severely disrupts the pharyngeal arch artery system. Our data show that haploinsufficiency of Tbx1 is sufficient to generate at least one important component of the DiGeorge syndrome phenotype in mice, and demonstrate the suitability of the mouse for the genetic dissection of microdeletion syndromes.
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            DiGeorge syndrome phenotype in mice mutant for the T-box gene, Tbx1.

            The DiGeorge/velocardiofacial syndrome (DGS/VCFS) is a relatively common human disorder, usually associated with deletions of chromosome 22q11. The genetic basis for the wide range of developmental anomalies in the heart, glands and facial structures has been elusive. We have investigated the potential role of one candidate gene, Tbx1, which encodes a transcription factor of the T-box family, by producing a null mutation in mice. We found that mice heterozygous for the mutation had a high incidence of cardiac outflow tract anomalies, thus modeling one of the major abnormalities of the human syndrome. Moreover, Tbx1-/- mice displayed a wide range of developmental anomalies encompassing almost all of the common DGS/VCFS features, including hypoplasia of the thymus and parathyroid glands, cardiac outflow tract abnormalities, abnormal facial structures, abnormal vertebrae and cleft palate. On the basis of this phenotype in mice, we propose that TBX1 in humans is a key gene in the etiology of DGS/VCFS.
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              Adolescent idiopathic scoliosis.

              Adolescent idiopathic scoliosis (AIS) is the most common form of structural spinal deformities that have a radiological lateral Cobb angle - a measure of spinal curvature - of ≥10(°). AIS affects between 1% and 4% of adolescents in the early stages of puberty and is more common in young women than in young men. The condition occurs in otherwise healthy individuals and currently has no recognizable cause. In the past few decades, considerable progress has been made towards understanding the clinical patterns and the three-dimensional pathoanatomy of AIS. Advances in biomechanics and technology and their clinical application, supported by limited evidence-based research, have led to improvements in the safety and outcomes of surgical and non-surgical treatments. However, the definite aetiology and aetiopathogenetic mechanisms that underlie AIS are still unclear. Thus, at present, both the prevention of AIS and the treatment of its direct underlying cause are not possible.
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                Author and article information

                Contributors
                chikashi.terao@riken.jp
                watakota@gmail.com
                sikegawa@ims.u-tokyo.ac.jp
                Journal
                Nat Commun
                Nat Commun
                Nature Communications
                Nature Publishing Group UK (London )
                2041-1723
                15 August 2019
                15 August 2019
                2019
                : 10
                : 3685
                Affiliations
                [1 ]ISNI 0000000094465255, GRID grid.7597.c, Laboratory for Bone and Joint Diseases, , Center for Integrative Medical Sciences, RIKEN, ; Tokyo, 108-8639 Japan
                [2 ]ISNI 0000 0004 1936 9959, GRID grid.26091.3c, Department of Orthopedic Surgery, , Keio University School of Medicine, ; Tokyo, 160-8582 Japan
                [3 ]ISNI 0000000094465255, GRID grid.7597.c, Laboratory for Genotyping Development, , Center for Integrative Medical Sciences, RIKEN, ; Yokohama, 230-0045 Japan
                [4 ]ISNI 0000 0000 9337 0481, GRID grid.412896.0, School of Pharmacy, , Taipei Medical University, ; Taipei, 11042 Taiwan
                [5 ]ISNI 0000000094465255, GRID grid.7597.c, Laboratory for Statistical Analysis, , Center for Integrative Medical Sciences, RIKEN, ; Yokohama, 230-0045 Japan
                [6 ]ISNI 0000 0004 0372 2033, GRID grid.258799.8, Kyoto-McGill International Collaborative School in Genomic Medicine, , Kyoto University Graduate School of Medicine, ; Kyoto, 606-8501 Japan
                [7 ]GRID grid.440137.5, Department of Orthopedic Surgery, , Seirei Sakura Citizen Hospital, ; Sakura, 285-8765 Japan
                [8 ]ISNI 0000 0004 0569 2501, GRID grid.440116.6, Department of Orthopedic Surgery, National Hospital Organization, , Kobe Medical Center, ; Kobe, 654-0155 Japan
                [9 ]GRID grid.410782.8, Department of Orthopedic Surgery, , Meijo Hospital, ; Nagoya, 460-0001 Japan
                [10 ]Department of Orthopedic Surgery, National Hospital Organization, Hokkaido Medical Center, Sapporo, 063-0005 Japan
                [11 ]ISNI 0000 0004 1762 2738, GRID grid.258269.2, Department of Orthopedic Surgery, , Juntendo University School of Medicine, ; Tokyo, 113-8421 Japan
                [12 ]ISNI 0000 0001 0671 5144, GRID grid.260975.f, Department of Orthopedic Surgery, , Niigata University Medical and Dental General Hospital, ; Niigata, 951-8510 Japan
                [13 ]ISNI 0000 0004 0373 3971, GRID grid.136593.b, Department of Orthopedic Surgery, , Osaka University Graduate School of Medicine, ; Suita, 565-0871 Japan
                [14 ]ISNI 0000 0004 1764 8161, GRID grid.410810.c, Department of Orthopedic Surgery, , Fukuoka Children’s Hospital, ; Fukuoka, 813-0017 Japan
                [15 ]ISNI 0000 0001 0702 8004, GRID grid.255137.7, Department of Orthopedic Surgery, , Dokkyo Medical University School of Medicine, ; Mibu, 321-0293 Japan
                [16 ]ISNI 0000 0004 0642 121X, GRID grid.459691.6, Department of Orthopedic Surgery, , Kyushu University Beppu Hospital, ; Beppu, 874-0838 Japan
                [17 ]ISNI 0000 0001 2151 536X, GRID grid.26999.3d, Department of Orthopedic Surgery, Faculty of Medicine, , The University of Tokyo, ; Tokyo, 113-8655 Japan
                [18 ]ISNI 0000 0004 0372 782X, GRID grid.410814.8, Department of Orthopedic Surgery, , Nara Medical University, ; Kashihara, 634-8522 Japan
                [19 ]GRID grid.470088.3, Department of Orthopedic Surgery, , Dokkyo Medical University Koshigaya Hospital, ; Koshigaya, 343-8555 Japan
                [20 ]ISNI 0000 0004 0615 9100, GRID grid.412002.5, Department of Orthopedic Surgery, , Kanazawa University Hospital, ; Kanazawa, 920-8641 Japan
                [21 ]ISNI 0000000123090000, GRID grid.410804.9, Department of Orthopedic Surgery, , Jichi Medical University, ; Shimotsuke, 329-0468 Japan
                [22 ]ISNI 0000 0000 9225 8957, GRID grid.270560.6, Department of Orthopedic Surgery, , Saiseikai Central Hospital, ; Tokyo, 108-0073 Japan
                [23 ]ISNI 0000 0004 0374 0880, GRID grid.416614.0, Department of Orthopedic Surgery, , National Defense Medical College, ; Tokorozawa, 359-8513 Japan
                [24 ]GRID grid.414414.0, Department of Orthopedic Surgery, , Eiju General Hospital, ; Tokyo, 110-8645 Japan
                [25 ]ISNI 0000 0001 1092 3077, GRID grid.31432.37, Department of Orthopedic Surgery, , Kobe University Graduate School of Medicine, ; Kobe, 650-0017 Japan
                [26 ]ISNI 0000 0001 2173 7691, GRID grid.39158.36, Department of Advanced Medicine for Spine and Spinal Cord Disorders, , Hokkaido University Graduate School of Medicine, ; Sapporo, 060-8638 Japan
                [27 ]ISNI 0000 0001 2173 7691, GRID grid.39158.36, Department of Preventive and Therapeutic Research for Metastatic Bone Tumor, Faculty of Medicine and Graduate School of Medicine, , Hokkaido University, ; Sapporo, 060-8638 Japan
                Author information
                http://orcid.org/0000-0003-3857-4985
                http://orcid.org/0000-0001-8748-5597
                http://orcid.org/0000-0003-2007-6881
                http://orcid.org/0000-0002-8743-7074
                http://orcid.org/0000-0003-4882-2997
                http://orcid.org/0000-0003-2014-2922
                http://orcid.org/0000-0002-0892-3382
                http://orcid.org/0000-0003-3824-6682
                http://orcid.org/0000-0002-6452-4095
                http://orcid.org/0000-0003-0316-2147
                Article
                11596
                10.1038/s41467-019-11596-w
                6695451
                31417091
                2152b573-95b5-40aa-a5a6-7771c4da3b54
                © The Author(s) 2019

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 3 February 2019
                : 24 July 2019
                Funding
                Funded by: FundRef https://doi.org/10.13039/501100001691, MEXT | Japan Society for the Promotion of Science (JSPS);
                Award ID: 18H02932
                Award ID: 18H02931
                Award ID: 16H05453
                Award Recipient :
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                © The Author(s) 2019

                Uncategorized
                bone,disease genetics,genome-wide association studies
                Uncategorized
                bone, disease genetics, genome-wide association studies

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