A polygenic burden of rare variants across extracellular matrix genes among individuals with adolescent idiopathic scoliosis
Year: 2015
Type: article
Study design: Observational Study
Abstract: Adolescent idiopathic scoliosis (AIS) is a complex inherited spinal deformity whose etiology has been elusive. While common genetic variants are associated with AIS, they explain only a small portion of disease risk. To explore the role of rare variants in AIS susceptibility, exome sequence data of 391 severe AIS cases and 843 controls of European ancestry were analyzed using a pathway burden analysis in which variants are first collapsed at the gene level then by Gene Ontology terms. Novel non-synonymous/splice-site variants in extracellular matrix genes were significantly enriched in AIS cases compared with controls (P = 6 × 10(-9), OR = 1.7, CI = 1.4-2.0). Specifically, novel variants in musculoskeletal collagen genes were present in 32% (126/391) of AIS cases compared with 17% (146/843) of in-house controls and 18% (780/4300) of EVS controls (P = 1 × 10(-9), OR = 1.9, CI = 1.6-2.4). Targeted resequencing of six collagen genes replicated this association in combined 919 AIS cases (P = 3 × 10(-12), OR = 2.2, CI = 1.8-2.7) and revealed a highly significant single-gene association with COL11A2 (P = 6 × 10(-9), OR = 3.8, CI = 2.6-7.2). Importantly, AIS cases harbor mainly non-glycine missense mutations and lack the clinical features of monogenic musculoskeletal collagenopathies. Overall, our study reveals a complex genetic architecture of AIS in which a polygenic burden of rare variants across extracellular matrix genes contributes strongly to risk.
Source: Human Molecular Genetics
DOI: 10.1093/hmg/ddv463
Language: English
Subfield: Surgery
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funders: National Institutes of Health, National Institute on Aging, National Heart, Lung, and Blood Institute, National Cancer Institute, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Center for Research Resources, National Center for Advancing Translational Sciences, Eunice Kennedy Shriver National Institute of Child Health and Human Development
Awards: G1019374866, Identifying Rare Variants that Increase Risk for Alzheimer's Disease, G140944187, G1704182483, G2032172404, HIGH PERFORMANCE BIOMEDICAL IMAGING COMPUTER RESOURCES, G475171617, Use of Endophenotypes in the Search for Alzheimer's Disease Risk Genes, WASHINGTON UNIVERSITY INTELLECTUAL AND DEVELOPMENTAL DISABILITIES RESEARCH CENTER, Colorado Clinical and Translational Sciences Institute, Washington University Institute of Clinical and Translational Sciences, Genetic risk factors for severe scoliosis, Washington University Institute of Clinical and Translational Sciences (UL1), Washington University Institute of Clinical and Translational Sciences, GPU COMPUTING RESOURCE TO ENABLE INNOVATION IN IMAGING AND NETWORK BIOLOGY, G843766559, Identification of Genetic Susceptibility in Adolescent Idiopathic Scoliosis, G9000310870, Pediatric Gastroenterology Research Training Program, Cancer Center Support Grant
OpenAlex ID: W2199058166