Journal article
A polygenic burden of rare variants across extracellular matrix genes among individuals with adolescent idiopathic scoliosis
Human molecular genetics, Vol.25(1), pp.202-209
01/01/2016
DOI: 10.1093/hmg/ddv463
PMCID: PMC4690498
PMID: 26566670
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.
Details
- Title: Subtitle
- A polygenic burden of rare variants across extracellular matrix genes among individuals with adolescent idiopathic scoliosis
- Creators
- Gabe Haller - Department of Orthopaedic SurgeryDavid Alvarado - Department of Orthopaedic SurgeryKevin Mccall - Department of Orthopaedic SurgeryPing Yang - Department of Orthopaedic SurgeryCarlos Cruchaga - Department of PsychiatryMatthew Harms - Department of Neurology, andAlison Goate - Department of PsychiatryMarcia Willing - Department of Pediatrics, Washington University, St Louis, MO, USAJose A Morcuende - Department of Orthopaedics and Rehabilitation, University of Iowa, Iowa City, IA, USAErin Baschal - Department of Orthopaedic Surgery, University of Colorado, Denver, CO, USANancy H Miller - Department of Orthopaedic Surgery, University of Colorado, Denver, CO, USACarol Wise - 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 andMatthew B Dobbs - Department of Orthopaedic Surgery, Shriners Hospital for Children, St Louis, MO, USAChristina A Gurnett - Department of Orthopaedic Surgery, Department of Neurology, and Department of Pediatrics, Washington University, St Louis, MO, USA, gurnettc@neuro.wustl.edu
- Resource Type
- Journal article
- Publication Details
- Human molecular genetics, Vol.25(1), pp.202-209
- Publisher
- England
- DOI
- 10.1093/hmg/ddv463
- PMID
- 26566670
- PMCID
- PMC4690498
- ISSN
- 0964-6906
- eISSN
- 1460-2083
- Grant note
- T32 DK077653 / NIDDK NIH HHS R01 AR067715 / NIAMS NIH HHS HL-102923 / NHLBI NIH HHS U54 HD087011 / NICHD NIH HHS P30 CA91842 / NCI NIH HHS 1S10OD018091-01 / NIH HHS TL1 TR000449 / NCATS NIH HHS R01HD052973 / NICHD NIH HHS HL-103010 / NHLBI NIH HHS UL1 TR000448 / NCATS NIH HHS HL-102925 / NHLBI NIH HHS 1S10RR022984-01A1 / NCRR NIH HHS UL1 TR001082 / NCATS NIH HHS R01 AG044546 / NIA NIH HHS R01-AG035083 / NIA NIH HHS HL-102926 / NHLBI NIH HHS HL-102924 / NHLBI NIH HHS P30 CA091842 / NCI NIH HHS UL1RR024992 / NCRR NIH HHS
- Language
- English
- Date published
- 01/01/2016
- Academic Unit
- Stead Family Department of Pediatrics; Orthopedics and Rehabilitation
- Record Identifier
- 9984040531502771
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