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Hum Mol Genet. 2018 Nov 15;27(22):3986-3998. doi: 10.1093/hmg/ddy306.

Genome-wide meta-analysis and replication studies in multiple ethnicities identify novel adolescent idiopathic scoliosis susceptibility loci.

Author information

1
Sarah M. & Charles E. Seay Center for Musculoskeletal Research, Texas Scottish Rite Hospital for Children, Dallas, TX, USA.
2
Laboratory of Bone & Joint Diseases, RIKEN Center for Integrative Medical Sciences, Tokyo, Japan.
3
School of Biomedical Sciences, The University of Hong Kong, Hong Kong, China.
4
Folkhälsan Institute of Genetics, University of Helsinki, 00014 University of Helsinki, Finland.
5
Molecular Neurology Research Program, University of Helsinki, 00014 University of Helsinki, Finland.
6
Department of Biosciences & Nutrition, Karolinska Institutet, Huddinge, Sweden.
7
Department of Bioengineering & Therapeutic Sciences, University of California San Francisco, San Francisco, CA, USA.
8
Institute for Human Genetics, University of California San Francisco, San Francisco, CA, USA.
9
Department of Medical & Molecular Genetics, King's College London, Guy's Hospital, London SE1 9RT, UK.
10
Department of Clinical Science, Intervention & Technology (CLINTEC), Karolinska Institutet, K54 Huddinge, Stockholm, Sweden.
11
Department of Orthopedics, Sundsvall and Härnösand County Hospital, Sundsvall, Sweden.
12
McDermott Center for Human Growth & Development, University of Texas Southwestern Medical Center, Dallas, TX, USA.
13
Sports Medicine, Tenri University, Nara Prefecture , Japan.
14
Department of Orthopaedic Surgery, Keio University School of Medicine, Tokyo, Japan.
15
Department of Orthopaedics & Traumatology, The University of Hong Kong, Hong Kong, China.
16
Department of Orthopaedic Surgery, Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, USA.
17
Department of Orthopedics, Karolinska University Hospital, K54 Huddinge, Stockholm, Sweden.
18
Department of Neurology, School of Medicine, Washington University, St. Louis, MO, USA.

Abstract

Adolescent idiopathic scoliosis (AIS) is the most common musculoskeletal disorder of childhood development. The genetic architecture of AIS is complex, and the great majority of risk factors are undiscovered. To identify new AIS susceptibility loci, we conducted the first genome-wide meta-analysis of AIS genome-wide association studies, including 7956 cases and 88 459 controls from 3 ancestral groups. Three novel loci that surpassed genome-wide significance were uncovered in intragenic regions of the CDH13 (P-value_rs4513093 = 1.7E-15), ABO (P-value_ rs687621 = 7.3E-10) and SOX6 (P-value_rs1455114 = 2.98E-08) genes. Restricting the analysis to females improved the associations at multiple loci, most notably with variants within CDH13 despite the reduction in sample size. Genome-wide gene-functional enrichment analysis identified significant perturbation of pathways involving cartilage and connective tissue development. Expression of both SOX6 and CDH13 was detected in cartilage chondrocytes and chromatin immunoprecipitation sequencing experiments in that tissue revealed multiple HeK27ac-positive peaks overlapping associated loci. Our results further define the genetic architecture of AIS and highlight the importance of vertebral cartilage development in its pathogenesis.

PMID:
30395268
PMCID:
PMC6488972
DOI:
10.1093/hmg/ddy306
[Indexed for MEDLINE]

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