Sarah M. and Charles E. Seay Center for Musculoskeletal Research, Research Department, Texas Scottish Rite Hospital for Children, Dallas, Texas 75219, USA.
Department of Genetics and Human Genetics Institute, Rutgers University, Piscataway, New Jersey 08854, USA.
Nat Commun. 2015 Mar 18;6:6452. doi: 10.1038/ncomms7452.
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.
特发性脊柱侧凸（IS）是一种常见的儿科肌肉骨骼疾病，表现出强烈的女性偏倚。通过对 3102 个人进行全基因组关联研究（GWAS），我们发现女性 20p11.22SNP 与 IS 存在显著关联（P=6.89×10(-9)），但男性没有（P=0.71）。这种与 IS 的关联在来自美国和日本的独立女性队列中也存在（总体 P=2.15×10(-10)，OR=1.30（rs6137473））。出乎意料的是，20p11.22IS 风险等位基因先前与另一种性二态性疾病——早发性脱发的保护有关。与 IS 相关的 174kb 相关基因座位于 PAX1 远端，PAX1 编码配对盒 1，这是一种参与脊柱发育的转录因子。我们在与关联基因座相关的序列中发现了在斑马鱼体节肌肉和脊髓中具有增强子活性的序列，而 IS 相关 SNP 会使这种活性丧失。因此，我们确定了一个性二态的 IS 易感基因座，并提出了第一个在增强子中具有功能定义的候选突变，该增强子可能调节特定脊髓细胞中的表达。
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