Genome-wide meta-analysis and replication studies in multiple ethnicities identify novel adolescent idiopathic scoliosis susceptibility loci
Year: 2018
Type: review
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.
Source: Human Molecular Genetics
DOI: 10.1093/hmg/ddy306
Authors: Anas M Khanshour, Ikuyo Kou, Yanhui Fan, Elisabet Einarsdottir, Nadja Makki, Yared H Kidane, Juha Kere, Anna Grauers, Todd A Johnson, Nandina Paria, Chandreshkumar Patel, Richa Singhania, Nobuhiro Kamiya, Kazuki Takeda, Nao Otomo, Kota Watanabe, Keith D K Luk, Kenneth M C Cheung, John A Herring, Jonathan J Rios, Nadav Ahituv, Paul Gerdhem, Christina A Gurnett, You-Qiang Song, Shiro Ikegawa, Carol A Wise
Institutions: Texas Scottish Rite Hospital for Children, RIKEN Center for Integrative Medical Sciences, University of Hong Kong, University of Helsinki, Karolinska Institutet, University of California, San Francisco, Guy's Hospital, King's College London, Sundsvall Municipality, Länssjukhuset Sundsvall-Härnösand, The University of Texas Southwestern Medical Center, Tenri University, Keio University, Karolinska University Hospital, Washington University in St. Louis
Language: English
Subfield: Surgery
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funders: American Liver Foundation, Scoliosis Research Society, University of Texas Southwestern Medical Center, Japan Agency for Medical Research and Development, Svenska Forskningsrådet Formas, Karolinska Institutet, Stockholms Läns Landsting, Svenska Läkaresällskapet, National Institutes of Health, Japan Society for the Promotion of Science, National Institute on Aging, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Eunice Kennedy Shriver National Institute of Child Health and Human Development
Awards: G373022865, G418774079, WASHINGTON UNIVERSITY INTELLECTUAL AND DEVELOPMENTAL DISABILITIES RESEARCH CENTER, G5950848594, G6463282482, Establishment of prediction model of onset and progression of adolescent idiopathic scoliosis for personalized medicine, Genetic risk factors for severe scoliosis, G9000095795, Developmental Mechanisms of Human Idiopathic Scoliosis
OpenAlex ID: W2889631667