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

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  • Swarkar Sharma

    (Sarah M. and Charles E. Seay Center for Musculoskeletal Research, Texas Scottish Rite Hospital for Children
    Present address: School of Biotechnology, Shri Mata Vaishno Devi University, Katra, Jammu and Kashmir 182320, India)

  • Douglas Londono

    (Rutgers University)

  • Walter L. Eckalbar

    (Institute for Human Genetics, University of California San Francisco)

  • Xiaochong Gao

    (Sarah M. and Charles E. Seay Center for Musculoskeletal Research, Texas Scottish Rite Hospital for Children)

  • Dongping Zhang

    (Sarah M. and Charles E. Seay Center for Musculoskeletal Research, Texas Scottish Rite Hospital for Children)

  • Kristen Mauldin

    (Sarah M. and Charles E. Seay Center for Musculoskeletal Research, Texas Scottish Rite Hospital for Children)

  • Ikuyo Kou

    (Laboratory of Bone and Joint Diseases, Center for Integrative Medical Sciences, RIKEN)

  • Atsushi Takahashi

    (Laboratory for Statistical Analysis, Center for Integrative Medical Sciences, RIKEN)

  • Morio Matsumoto

    (School of Medicine, Keio University)

  • Nobuhiro Kamiya

    (Sarah M. and Charles E. Seay Center for Musculoskeletal Research, Texas Scottish Rite Hospital for Children
    Present address: Department of Sports Medicine, Tenri University, Tenri, Nara 632-0071, Japan)

  • Karl K. Murphy

    (Institute for Human Genetics, University of California San Francisco)

  • Reuel Cornelia

    (Sarah M. and Charles E. Seay Center for Musculoskeletal Research, Texas Scottish Rite Hospital for Children)

  • John A. Herring

    (Texas Scottish Rite Hospital for Children
    University of Texas Southwestern Medical Center at Dallas)

  • Dennis Burns

    (University of Texas Southwestern Medical Center at Dallas)

  • Nadav Ahituv

    (Institute for Human Genetics, University of California San Francisco)

  • Shiro Ikegawa

    (Laboratory of Bone and Joint Diseases, Center for Integrative Medical Sciences, RIKEN)

  • Derek Gordon

    (Rutgers University)

  • Carol A. Wise

    (Sarah M. and Charles E. Seay Center for Musculoskeletal Research, Texas Scottish Rite Hospital for Children
    University of Texas Southwestern Medical Center at Dallas
    McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center at Dallas
    University of Texas Southwestern Medical Center at Dallas)

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.

Suggested Citation

  • Swarkar Sharma & Douglas Londono & Walter L. Eckalbar & Xiaochong Gao & Dongping Zhang & Kristen Mauldin & Ikuyo Kou & Atsushi Takahashi & Morio Matsumoto & Nobuhiro Kamiya & Karl K. Murphy & Reuel Co, 2015. "A PAX1 enhancer locus is associated with susceptibility to idiopathic scoliosis in females," Nature Communications, Nature, vol. 6(1), pages 1-10, May.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms7452
    DOI: 10.1038/ncomms7452
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