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Hum Mol Genet. 2016 Jan 1;25(1):202-9. doi: 10.1093/hmg/ddv463. Epub 2015 Nov 12.

A polygenic burden of rare variants across extracellular matrix genes among individuals with adolescent idiopathic scoliosis.

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Department of Orthopaedic Surgery.
Department of Psychiatry.
Department of Neurology, and.
Department of Pediatrics, Washington University, St Louis, MO, USA.
Department of Orthopaedics and Rehabilitation, University of Iowa, Iowa City, IA, USA.
Department of Orthopaedic Surgery, University of Colorado, Denver, CO, USA.
Sarah M. and Charles E. Seay Center for Musculoskeletal Research, Texas Scottish Rite Hospital for Children, Dallas, TX, USA, Department of Orthopaedic Surgery, Department of Pediatrics, McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, USA and.
Department of Orthopaedic Surgery, Shriners Hospital for Children, St Louis, MO, USA.
Department of Orthopaedic Surgery, Department of Neurology, and Department of Pediatrics, Washington University, St Louis, MO, USA,


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.

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