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

Nat Commun. 2015 Mar 18;6:6452. doi: 10.1038/ncomms7452.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Alleles
  • Animals
  • Chromosome Mapping
  • Cohort Studies
  • Enhancer Elements, Genetic*
  • Female
  • Genetic Predisposition to Disease*
  • Genome-Wide Association Study
  • Genotype
  • Humans
  • Japan
  • Linkage Disequilibrium
  • Male
  • Mutation
  • Paired Box Transcription Factors / genetics*
  • Paired Box Transcription Factors / physiology
  • Phenotype
  • Polymorphism, Single Nucleotide
  • Risk Factors
  • Scoliosis / genetics*
  • Sequence Analysis, DNA
  • Sex Factors
  • United States
  • Zebrafish

Substances

  • Paired Box Transcription Factors
  • PAX1 transcription factor