title: A PAX1 enhancer locus is associated with susceptibility to idiopathic scoliosis in females.
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.
authors.affiliation: Sarah M. and Charles E. Seay Center for Musculoskeletal Research, Research Department, Texas Scottish Rite Hospital for Children, Dallas, Texas 75219, USA.
authors.forename: Swarkar
authors.identifier: 0000000188575906
authors.initials: S
authors.lastname: Sharma
authors.affiliation: Department of Genetics and Human Genetics Institute, Rutgers University, Piscataway, New Jersey 08854, USA.
authors.forename: Douglas
authors.initials: D
authors.lastname: Londono
authors.affiliation: Department of Bioengineering and Therapeutic Sciences, Institute for Human Genetics, University of California San Francisco, San Francisco, California 94143, USA.
authors.forename: Walter L
authors.initials: WL
authors.lastname: Eckalbar
authors.affiliation: Sarah M. and Charles E. Seay Center for Musculoskeletal Research, Research Department, Texas Scottish Rite Hospital for Children, Dallas, Texas 75219, USA.
authors.forename: Xiaochong
authors.initials: X
authors.lastname: Gao
authors.affiliation: Sarah M. and Charles E. Seay Center for Musculoskeletal Research, Research Department, Texas Scottish Rite Hospital for Children, Dallas, Texas 75219, USA.
authors.forename: Dongping
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Sarah M. and Charles E. Seay Center for Musculoskeletal Research, Research Department, Texas Scottish Rite Hospital for Children, Dallas, Texas 75219, USA.
authors.forename: Kristen
authors.initials: K
authors.lastname: Mauldin
authors.affiliation: Laboratory of Bone and Joint Diseases, Center for Integrative Medical Sciences, RIKEN, Tokyo 108-8639, Japan.
authors.forename: Ikuyo
authors.initials: I
authors.lastname: Kou
authors.affiliation: Laboratory for Statistical Analysis, Center for Integrative Medical Sciences, RIKEN, Yokohama 230-0045, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Takahashi
authors.affiliation: Department of Orthopaedic Surgery, School of Medicine, Keio University, Tokyo 108-8345, Japan.
authors.forename: Morio
authors.initials: M
authors.lastname: Matsumoto
authors.affiliation: Sarah M. and Charles E. Seay Center for Musculoskeletal Research, Research Department, Texas Scottish Rite Hospital for Children, Dallas, Texas 75219, USA.
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Kamiya
authors.affiliation: Department of Bioengineering and Therapeutic Sciences, Institute for Human Genetics, University of California San Francisco, San Francisco, California 94143, USA.
authors.forename: Karl K
authors.initials: KK
authors.lastname: Murphy
authors.affiliation: Sarah M. and Charles E. Seay Center for Musculoskeletal Research, Research Department, Texas Scottish Rite Hospital for Children, Dallas, Texas 75219, USA.
authors.forename: Reuel
authors.initials: R
authors.lastname: Cornelia
authors.affiliation: 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.
authors.forename: John A
authors.initials: JA
authors.lastname: Herring
authors.affiliation: Department of Pathology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390, USA.
authors.forename: Dennis
authors.initials: D
authors.lastname: Burns
authors.affiliation: Department of Bioengineering and Therapeutic Sciences, Institute for Human Genetics, University of California San Francisco, San Francisco, California 94143, USA.
authors.forename: Nadav
authors.initials: N
authors.lastname: Ahituv
authors.affiliation: Laboratory of Bone and Joint Diseases, Center for Integrative Medical Sciences, RIKEN, Tokyo 108-8639, Japan.
authors.forename: Shiro
authors.initials: S
authors.lastname: Ikegawa
authors.affiliation: Department of Genetics and Human Genetics Institute, Rutgers University, Piscataway, New Jersey 08854, USA.
authors.forename: Derek
authors.initials: D
authors.lastname: Gordon
authors.affiliation: 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.
authors.forename: Carol A
authors.initials: CA
authors.lastname: Wise
mesh_terms: D000483:Alleles; D000818:Animals; D002874:Chromosome Mapping; D015331:Cohort Studies; D004742:Enhancer Elements, Genetic; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D007564:Japan; D015810:Linkage Disequilibrium; D008297:Male; D009154:Mutation; D051761:Paired Box Transcription Factors / Q000235:genetics* / Q000502:physiology; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D012600:Scoliosis / Q000235:genetics*; D017422:Sequence Analysis, DNA; D012737:Sex Factors; D014481:United States; D015027:Zebrafish
chemical_list: D051761:Paired Box Transcription Factors; C070835:PAX1 transcription factor