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 - 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.
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U2 - 10.1093/hmg/ddv463
DO - 10.1093/hmg/ddv463
M3 - Article
C2 - 26566670
AN - SCOPUS:84962175728
SN - 0964-6906
VL - 25
SP - 202
EP - 209
JO - Human molecular genetics
JF - Human molecular genetics
IS - 1
ER -