A PAX1 enhancer locus is associated with susceptibility to idiopathic scoliosis in females.
Swarkar SharmaDouglas LondonoWalter L EckalbarXiaochong GaoDongping ZhangKristen MauldinIkuyo KouAtsushi TakahashiMorio MatsumotoNobuhiro KamiyaKarl K MurphyReuel Cornelianull nullnull nullJohn A HerringDennis BurnsNadav AhituvShiro IkegawaDerek GordonCarol A WisePublished in: Nature communications (2015)
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.
Keyphrases
- genome wide association study
- transcription factor
- early onset
- binding protein
- spinal cord
- late onset
- dna binding
- genome wide
- poor prognosis
- induced apoptosis
- intensive care unit
- skeletal muscle
- spinal cord injury
- emergency department
- neuropathic pain
- cell cycle arrest
- minimally invasive
- dna methylation
- cell proliferation