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

  • Author(s): Sharma, Swarkar
  • Londono, Douglas
  • Eckalbar, Walter L
  • Gao, Xiaochong
  • Zhang, Dongping
  • Mauldin, Kristen
  • Kou, Ikuyo
  • Takahashi, Atsushi
  • Matsumoto, Morio
  • Kamiya, Nobuhiro
  • Murphy, Karl K
  • Cornelia, Reuel
  • TSRHC Scoliosis Clinical Group
  • Japan Scoliosis Clinical Research Group
  • Herring, John A
  • Burns, Dennis
  • Ahituv, Nadav
  • Ikegawa, Shiro
  • Gordon, Derek
  • Wise, Carol A
  • et al.

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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