title: A polygenic burden of rare variants across extracellular matrix genes among individuals with adolescent idiopathic scoliosis.
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.
authors.affiliation: Department of Orthopaedic Surgery.
authors.forename: Gabe
authors.initials: G
authors.lastname: Haller
authors.affiliation: Department of Orthopaedic Surgery.
authors.forename: David
authors.initials: D
authors.lastname: Alvarado
authors.affiliation: Department of Orthopaedic Surgery.
authors.forename: Kevin
authors.initials: K
authors.lastname: Mccall
authors.affiliation: Department of Orthopaedic Surgery.
authors.forename: Ping
authors.initials: P
authors.lastname: Yang
authors.affiliation: Department of Psychiatry.
authors.forename: Carlos
authors.initials: C
authors.lastname: Cruchaga
authors.affiliation: Department of Neurology, and.
authors.forename: Matthew
authors.initials: M
authors.lastname: Harms
authors.affiliation: Department of Psychiatry.
authors.forename: Alison
authors.initials: A
authors.lastname: Goate
authors.affiliation: Department of Pediatrics, Washington University, St Louis, MO, USA.
authors.forename: Marcia
authors.initials: M
authors.lastname: Willing
authors.affiliation: Department of Orthopaedics and Rehabilitation, University of Iowa, Iowa City, IA, USA.
authors.forename: Jose A
authors.initials: JA
authors.lastname: Morcuende
authors.affiliation: Department of Orthopaedic Surgery, University of Colorado, Denver, CO, USA.
authors.forename: Erin
authors.initials: E
authors.lastname: Baschal
authors.affiliation: Department of Orthopaedic Surgery, University of Colorado, Denver, CO, USA.
authors.forename: Nancy H
authors.initials: NH
authors.lastname: Miller
authors.affiliation: 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.
authors.forename: Carol
authors.initials: C
authors.lastname: Wise
authors.affiliation: Department of Orthopaedic Surgery, Shriners Hospital for Children, St Louis, MO, USA.
authors.forename: Matthew B
authors.initials: MB
authors.lastname: Dobbs
authors.affiliation: Department of Orthopaedic Surgery, Department of Neurology, and Department of Pediatrics, Washington University, St Louis, MO, USA, gurnettc@neuro.wustl.edu.
authors.forename: Christina A
authors.initials: CA
authors.lastname: Gurnett
mesh_terms: D015331:Cohort Studies; D003094:Collagen / Q000235:genetics; D059472:Exome; D005109:Extracellular Matrix / Q000235:genetics*; D005260:Female; D014644:Genetic Variation; D006801:Humans; D007738:Kyphosis / Q000235:genetics; D008297:Male; D020412:Multifactorial Inheritance; D012600:Scoliosis / Q000235:genetics*; D055815:Young Adult
chemical_list: D003094:Collagen