A PAX1 enhancer locus is associated with susceptibility to idiopathic scoliosis in females

TSRHC Scoliosis Clinical Group, Japan Scoliosis Clinical Research Group

Research output: Contribution to journalArticle

56 Citations (Scopus)

Abstract

Idiopathic scoliosis (IS) is a common paediatric musculoskeletal disease that displays a strong female bias. By performing a genome-wide association study (GWAS) of 3,102 individuals, we identify significant associations with 20p11.22 SNPs for females (P=6.89 × 10 -9) but not males (P=0.71). This association with IS is also found in independent female cohorts from the United States of America and Japan (overall P=2.15 × 10 -10, OR=1.30 (rs6137473)). Unexpectedly, the 20p11.22 IS risk alleles were previously associated with protection from early-onset alopecia, another sexually dimorphic condition. The 174-kb associated locus is distal to PAX1, which encodes paired box 1, a transcription factor involved in spine development. We identify a sequence in the associated locus with enhancer activity in zebrafish somitic muscle and spinal cord, an activity that is abolished by IS-associated SNPs. We thus identify a sexually dimorphic IS susceptibility locus, and propose the first functionally defined candidate mutations in an enhancer that may regulate expression in specific spinal cells.

Original languageEnglish (US)
Article number6452
JournalNature Communications
Volume6
DOIs
StatePublished - 2015

Fingerprint

Pediatrics
Scoliosis
loci
Muscle
Transcription Factors
Genes
magnetic permeability
spinal cord
spine
genome
Single Nucleotide Polymorphism
mutations
muscles
boxes
Musculoskeletal Diseases
Japan
Genome-Wide Association Study
Alopecia
Zebrafish
cells

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Chemistry(all)
  • Physics and Astronomy(all)

Cite this

TSRHC Scoliosis Clinical Group, & Japan Scoliosis Clinical Research Group (2015). A PAX1 enhancer locus is associated with susceptibility to idiopathic scoliosis in females. Nature Communications, 6, [6452]. https://doi.org/10.1038/ncomms7452

A PAX1 enhancer locus is associated with susceptibility to idiopathic scoliosis in females. / TSRHC Scoliosis Clinical Group; Japan Scoliosis Clinical Research Group.

In: Nature Communications, Vol. 6, 6452, 2015.

Research output: Contribution to journalArticle

TSRHC Scoliosis Clinical Group & Japan Scoliosis Clinical Research Group 2015, 'A PAX1 enhancer locus is associated with susceptibility to idiopathic scoliosis in females', Nature Communications, vol. 6, 6452. https://doi.org/10.1038/ncomms7452
TSRHC Scoliosis Clinical Group ; Japan Scoliosis Clinical Research Group. / A PAX1 enhancer locus is associated with susceptibility to idiopathic scoliosis in females. In: Nature Communications. 2015 ; Vol. 6.
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abstract = "Idiopathic scoliosis (IS) is a common paediatric musculoskeletal disease that displays a strong female bias. By performing a genome-wide association study (GWAS) of 3,102 individuals, we identify significant associations with 20p11.22 SNPs for females (P=6.89 × 10 -9) but not males (P=0.71). This association with IS is also found in independent female cohorts from the United States of America and Japan (overall P=2.15 × 10 -10, OR=1.30 (rs6137473)). Unexpectedly, the 20p11.22 IS risk alleles were previously associated with protection from early-onset alopecia, another sexually dimorphic condition. The 174-kb associated locus is distal to PAX1, which encodes paired box 1, a transcription factor involved in spine development. We identify a sequence in the associated locus with enhancer activity in zebrafish somitic muscle and spinal cord, an activity that is abolished by IS-associated SNPs. We thus identify a sexually dimorphic IS susceptibility locus, and propose the first functionally defined candidate mutations in an enhancer that may regulate expression in specific spinal cells.",
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AU - Ikegawa, Shiro

AU - Gordon, Derek

AU - Wise, Carol A.

AU - Karol, L.

AU - Rathjen, K.

AU - Sucato, D.

AU - Birch, J.

AU - Johnston, C.

AU - Richards, B. S.

AU - Mildrant, T.

AU - Talwakar, V.

AU - Iwinski, H.

AU - Muchow, R.

AU - Tassone, J. C.

AU - Liu, X. C.

AU - Shindell, R.

AU - Schrader, W.

AU - Eberson, C.

AU - Lapinsky, A.

AU - Loder, R.

AU - Davey, J.

AU - Hosogane, Naobumi

AU - Ogura, Yoji

AU - Takahashi, Yohei

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AU - Watanabe, Kota

AU - Chiba, Kazuhiro

AU - Toyama, Yoshiaki

AU - Kono, Katsuki

AU - Kawakami, Noriaki

AU - Tsuji, Taichi

AU - Uno, Koki

AU - Suzuki, Teppei

AU - Ito, Manabu

AU - Sudo, Hideki

PY - 2015

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N2 - Idiopathic scoliosis (IS) is a common paediatric musculoskeletal disease that displays a strong female bias. By performing a genome-wide association study (GWAS) of 3,102 individuals, we identify significant associations with 20p11.22 SNPs for females (P=6.89 × 10 -9) but not males (P=0.71). This association with IS is also found in independent female cohorts from the United States of America and Japan (overall P=2.15 × 10 -10, OR=1.30 (rs6137473)). Unexpectedly, the 20p11.22 IS risk alleles were previously associated with protection from early-onset alopecia, another sexually dimorphic condition. The 174-kb associated locus is distal to PAX1, which encodes paired box 1, a transcription factor involved in spine development. We identify a sequence in the associated locus with enhancer activity in zebrafish somitic muscle and spinal cord, an activity that is abolished by IS-associated SNPs. We thus identify a sexually dimorphic IS susceptibility locus, and propose the first functionally defined candidate mutations in an enhancer that may regulate expression in specific spinal cells.

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