Genome-wide meta-analysis and replication studies in multiple ethnicities identify novel adolescent idiopathic scoliosis susceptibility loci

Anas M. Khanshour, Ikuyo Kou, Yanhui Fan, Elisabet Einarsdottir, Nadja Makki, Yared H. Kidane, Juha Kere, Anna Grauers, Todd A. Johnson, Nandina Paria, Chandreshkumar Patel, Richa Singhania, Nobuhiro Kamiya, Kazuki Takeda, Nao Otomo, Koota Watanabe, Keith D.K. Luk, Kenneth M.C. Cheung, John A. Herring, Jonathan J. Rios & 6 others Nadav Ahituv, Paul Gerdhem, Christina A. Gurnett, You Qiang Song, Shiro Ikegawa, Carol A. Wise

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)3986-3998
Number of pages13
JournalHuman Molecular Genetics
Volume27
Issue number22
DOIs
Publication statusPublished - 2018 Nov 1

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Scoliosis
Meta-Analysis
Genome
Cartilage
Chromatin Immunoprecipitation
Genome-Wide Association Study
Chondrocytes
Connective Tissue
Sample Size
Genes

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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Genome-wide meta-analysis and replication studies in multiple ethnicities identify novel adolescent idiopathic scoliosis susceptibility loci. / Khanshour, Anas M.; Kou, Ikuyo; Fan, Yanhui; Einarsdottir, Elisabet; Makki, Nadja; Kidane, Yared H.; Kere, Juha; Grauers, Anna; Johnson, Todd A.; Paria, Nandina; Patel, Chandreshkumar; Singhania, Richa; Kamiya, Nobuhiro; Takeda, Kazuki; Otomo, Nao; Watanabe, Koota; Luk, Keith D.K.; Cheung, Kenneth M.C.; Herring, John A.; Rios, Jonathan J.; Ahituv, Nadav; Gerdhem, Paul; Gurnett, Christina A.; Song, You Qiang; Ikegawa, Shiro; Wise, Carol A.

In: Human Molecular Genetics, Vol. 27, No. 22, 01.11.2018, p. 3986-3998.

Research output: Contribution to journalArticle

Khanshour, AM, Kou, I, Fan, Y, Einarsdottir, E, Makki, N, Kidane, YH, Kere, J, Grauers, A, Johnson, TA, Paria, N, Patel, C, Singhania, R, Kamiya, N, Takeda, K, Otomo, N, Watanabe, K, Luk, KDK, Cheung, KMC, Herring, JA, Rios, JJ, Ahituv, N, Gerdhem, P, Gurnett, CA, Song, YQ, Ikegawa, S & Wise, CA 2018, 'Genome-wide meta-analysis and replication studies in multiple ethnicities identify novel adolescent idiopathic scoliosis susceptibility loci', Human Molecular Genetics, vol. 27, no. 22, pp. 3986-3998. https://doi.org/10.1093/hmg/ddy306
Khanshour, Anas M. ; Kou, Ikuyo ; Fan, Yanhui ; Einarsdottir, Elisabet ; Makki, Nadja ; Kidane, Yared H. ; Kere, Juha ; Grauers, Anna ; Johnson, Todd A. ; Paria, Nandina ; Patel, Chandreshkumar ; Singhania, Richa ; Kamiya, Nobuhiro ; Takeda, Kazuki ; Otomo, Nao ; Watanabe, Koota ; Luk, Keith D.K. ; Cheung, Kenneth M.C. ; Herring, John A. ; Rios, Jonathan J. ; Ahituv, Nadav ; Gerdhem, Paul ; Gurnett, Christina A. ; Song, You Qiang ; Ikegawa, Shiro ; Wise, Carol A. / Genome-wide meta-analysis and replication studies in multiple ethnicities identify novel adolescent idiopathic scoliosis susceptibility loci. In: Human Molecular Genetics. 2018 ; Vol. 27, No. 22. pp. 3986-3998.
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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, Koota

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.

PY - 2018/11/1

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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.

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