TY - JOUR
T1 - Genome-wide meta-analysis and replication studies in multiple ethnicities identify novel adolescent idiopathic scoliosis susceptibility loci
AU - Khanshour, Anas M.
AU - Kou, Ikuyo
AU - Fan, Yanhui
AU - Einarsdottir, Elisabet
AU - Makki, Nadja
AU - Kidane, Yared H.
AU - Kere, Juha
AU - Grauers, Anna
AU - Johnson, Todd A.
AU - Paria, Nandina
AU - Patel, Chandreshkumar
AU - Singhania, Richa
AU - Kamiya, Nobuhiro
AU - Takeda, Kazuki
AU - Otomo, Nao
AU - Watanabe, Kota
AU - Luk, Keith D.K.
AU - Cheung, Kenneth M.C.
AU - Herring, John A.
AU - Rios, Jonathan J.
AU - Ahituv, Nadav
AU - Gerdhem, Paul
AU - Gurnett, Christina A.
AU - Song, You Qiang
AU - Ikegawa, Shiro
AU - Wise, Carol A.
N1 - Publisher Copyright:
© The Author(s) 2018. Published by Oxford University Press. All rights reserved.
PY - 2018/11/1
Y1 - 2018/11/1
N2 - Adolescent idiopathic scoliosis (AIS) is the most common musculoskeletal disorder of childhood development. The genetic architecture of AIS is complex, and the great majority of risk factors are undiscovered. To identify new AIS susceptibility loci, we conducted the first genome-wide meta-analysis of AIS genome-wide association studies, including 7956 cases and 88 459 controls from 3 ancestral groups. Three novel loci that surpassed genome-wide significance were uncovered in intragenic regions of the CDH13 (P-value_rs4513093 = 1.7E-15), ABO (P-value_ rs687621 = 7.3E-10) and SOX6 (P-value_ rs1455114 = 2.98E-08) genes. Restricting the analysis to females improved the associations at multiple loci, most notably with variants within CDH13 despite the reduction in sample size. Genome-wide gene-functional enrichment analysis identified significant perturbation of pathways involving cartilage and connective tissue development. Expression of both SOX6 and CDH13 was detected in cartilage chondrocytes and chromatin immunoprecipitation sequencing experiments in that tissue revealed multiple HeK27ac-positive peaks overlapping associated loci. Our results further define the genetic architecture of AIS and highlight the importance of vertebral cartilage development in its pathogenesis.
AB - Adolescent idiopathic scoliosis (AIS) is the most common musculoskeletal disorder of childhood development. The genetic architecture of AIS is complex, and the great majority of risk factors are undiscovered. To identify new AIS susceptibility loci, we conducted the first genome-wide meta-analysis of AIS genome-wide association studies, including 7956 cases and 88 459 controls from 3 ancestral groups. Three novel loci that surpassed genome-wide significance were uncovered in intragenic regions of the CDH13 (P-value_rs4513093 = 1.7E-15), ABO (P-value_ rs687621 = 7.3E-10) and SOX6 (P-value_ rs1455114 = 2.98E-08) genes. Restricting the analysis to females improved the associations at multiple loci, most notably with variants within CDH13 despite the reduction in sample size. Genome-wide gene-functional enrichment analysis identified significant perturbation of pathways involving cartilage and connective tissue development. Expression of both SOX6 and CDH13 was detected in cartilage chondrocytes and chromatin immunoprecipitation sequencing experiments in that tissue revealed multiple HeK27ac-positive peaks overlapping associated loci. Our results further define the genetic architecture of AIS and highlight the importance of vertebral cartilage development in its pathogenesis.
UR - http://www.scopus.com/inward/record.url?scp=85056288930&partnerID=8YFLogxK
U2 - 10.1093/hmg/ddy306
DO - 10.1093/hmg/ddy306
M3 - Article
C2 - 30395268
AN - SCOPUS:85056288930
SN - 0964-6906
VL - 27
SP - 3986
EP - 3998
JO - Human molecular genetics
JF - Human molecular genetics
IS - 22
ER -