Format

Send to

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

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

Author information

1
Sarah M. and Charles E. Seay Center for Musculoskeletal Research, Research Department, Texas Scottish Rite Hospital for Children, Dallas, Texas 75219, USA.
2
Department of Genetics and Human Genetics Institute, Rutgers University, Piscataway, New Jersey 08854, USA.
3
Department of Bioengineering and Therapeutic Sciences, Institute for Human Genetics, University of California San Francisco, San Francisco, California 94143, USA.
4
Laboratory of Bone and Joint Diseases, Center for Integrative Medical Sciences, RIKEN, Tokyo 108-8639, Japan.
5
Laboratory for Statistical Analysis, Center for Integrative Medical Sciences, RIKEN, Yokohama 230-0045, Japan.
6
Department of Orthopaedic Surgery, School of Medicine, Keio University, Tokyo 108-8345, Japan.
7
1] Department of Orthopaedics, Texas Scottish Rite Hospital for Children, Dallas, Texas 75219, USA [2] Department of Orthopaedic Surgery, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390, USA.
8
Department of Pathology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390, USA.
9
1] Sarah M. and Charles E. Seay Center for Musculoskeletal Research, Research Department, Texas Scottish Rite Hospital for Children, Dallas, Texas 75219, USA [2] Department of Orthopaedic Surgery, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390, USA [3] McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390, USA [4] McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390, USA.

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.

PMID:
25784220
PMCID:
PMC4365504
DOI:
10.1038/ncomms7452
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center