TY - JOUR
T1 - A polygenic burden of rare variants across extracellular matrix genes among individuals with adolescent idiopathic scoliosis
AU - Haller, Gabe
AU - Alvarado, David
AU - Mccall, Kevin
AU - Yang, Ping
AU - Cruchaga, Carlos
AU - Harms, Matthew
AU - Goate, Alison
AU - Willing, Marcia
AU - Morcuende, Jose A.
AU - Baschal, Erin
AU - Miller, Nancy H.
AU - Wise, Carol
AU - Dobbs, Matthew B.
AU - Gurnett, Christina A.
N1 - Funding Information:
This research was supported by Shriners Hospital for Children Research Grants, the University of Missouri Spinal Cord Injury Research Program, the Victor McKusick Fellowship of the Marfan Foundation (DA), and the Children's Discovery Institute of St Louis Children's Hospital and Washington University (CAG) and by the National Institutes of Health (NICHD award R01HD052973), the TSRHC Research Fund, Crystal Charity Ball and Scoliosis Research Society (CAW). The Center is partially supported by NCI Cancer Center Support Grant #P30 CA91842 to the Siteman Cancer Center and by ICTS/CTSA Grant #UL1RR024992 from the National Center for Research Resources (NCRR), a component of the NIH (National Institute of Health) and NIH Roadmap for Medical Research. Computations were performed using the facilities of the Washington University Center for High Performance Computing, which were partially funded by NIH grants 1S10RR022984-01A1 and 1S10OD018091-01. C.C. and A.G. contributed exomes for use as controls funded under grants R01-AG044546, R01-AG035083 and the Alzheimer Association (NIRG-11-200110). This research was conducted while C.C. was a recipient of a New Investigator Award in Alzheimer's disease from the American Federation for Aging Research. Additional control samples were obtained from the NHLBI GO ESP and its ongoing studies which produced and provided exome variant calls for comparison: the Lung GO Sequencing Project (HL-102923), the WHI Sequencing Project (HL-102924), the BroadGOSequencing Project (HL-102925), the Seattle GO Sequencing Project (HL-102926) and the Heart GO Sequencing Project (HL-103010). The Research reported in this publication was also supported by the Washington University Institute of Clinical and Translational Sciences grant UL1 TR000448 from the National Center for Advancing Translational Sciences (NCATS) of the NIH.
Publisher Copyright:
© The Author 2015. Published by Oxford University Press. All rights reserved.
PY - 2016/1/1
Y1 - 2016/1/1
N2 - 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 nonsynonymous/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 geneswere 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.
AB - 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 nonsynonymous/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 geneswere 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.
UR - http://www.scopus.com/inward/record.url?scp=84962175728&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84962175728&partnerID=8YFLogxK
U2 - 10.1093/hmg/ddv463
DO - 10.1093/hmg/ddv463
M3 - Article
C2 - 26566670
AN - SCOPUS:84962175728
VL - 25
SP - 202
EP - 209
JO - Human Molecular Genetics
JF - Human Molecular Genetics
SN - 0964-6906
IS - 1
ER -