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

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 Cornelia, John A. Herring, Dennis Burns, Nadav Ahituv, Shiro Ikegawa, Derek Gordon and Carol A. Wise ()
Additional contact information
Swarkar Sharma: Sarah M. and Charles E. Seay Center for Musculoskeletal Research, Texas Scottish Rite Hospital for Children
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
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
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

Nature Communications, 2015, vol. 6, issue 1, 1-10

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms7452

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