Ogura Yoji, Kou Ikuyo, Miura Shigenori, Takahashi Atsushi, Xu Leilei, Takeda Kazuki, Takahashi Yohei, Kono Katsuki, Kawakami Noriaki, Uno Koki, Ito Manabu, Minami Shohei, Yonezawa Ikuho, Yanagida Haruhisa, Taneichi Hiroshi, Zhu Zezhang, Tsuji Taichi, Suzuki Teppei, Sudo Hideki, Kotani Toshiaki, Watanabe Kota, Hosogane Naobumi, Okada Eijiro, Iida Aritoshi, Nakajima Masahiro, Sudo Akihiro, Chiba Kazuhiro, Hiraki Yuji, Toyama Yoshiaki, Qiu Yong, Shukunami Chisa, Kamatani Yoichiro, Kubo Michiaki, Matsumoto Morio, Ikegawa Shiro
Laboratory of Bone and Joint Diseases, Center for Integrative Sciences, RIKEN, Tokyo 108-8639, Japan; Department of Orthopaedic Surgery, School of Medicine, Keio University, Tokyo 160-8582, Japan.
Laboratory of Bone and Joint Diseases, Center for Integrative Sciences, RIKEN, Tokyo 108-8639, Japan.
Am J Hum Genet. 2015 Aug 6;97(2):337-42. doi: 10.1016/j.ajhg.2015.06.012. Epub 2015 Jul 23.
Adolescent idiopathic scoliosis (AIS) is the most common spinal deformity. We previously conducted a genome-wide association study (GWAS) and detected two loci associated with AIS. To identify additional loci, we extended our GWAS by increasing the number of cohorts (2,109 affected subjects and 11,140 control subjects in total) and conducting a whole-genome imputation. Through the extended GWAS and replication studies using independent Japanese and Chinese populations, we identified a susceptibility locus on chromosome 9p22.2 (p = 2.46 × 10(-13); odds ratio = 1.21). The most significantly associated SNPs were in intron 3 of BNC2, which encodes a zinc finger transcription factor, basonuclin-2. Expression quantitative trait loci data suggested that the associated SNPs have the potential to regulate the BNC2 transcriptional activity and that the susceptibility alleles increase BNC2 expression. We identified a functional SNP, rs10738445 in BNC2, whose susceptibility allele showed both higher binding to a transcription factor, YY1 (yin and yang 1), and higher BNC2 enhancer activity than the non-susceptibility allele. BNC2 overexpression produced body curvature in developing zebrafish in a gene-dosage-dependent manner. Our results suggest that increased BNC2 expression is implicated in the etiology of AIS.
青少年特发性脊柱侧凸（AIS）是最常见的脊柱畸形。我们之前进行了一项全基因组关联研究（GWAS），并检测到两个与AIS相关的基因座。为了识别更多基因座，我们通过增加队列数量（总共2109名患病受试者和11140名对照受试者）并进行全基因组推算来扩展我们的GWAS。通过使用独立的日本和中国人群进行扩展GWAS和重复研究，我们在9号染色体p22.2上鉴定出一个易感基因座（p = 2.46×10^(-13)；优势比 = 1.21）。最显著相关的单核苷酸多态性（SNP）位于BNC2的内含子3中，该基因编码锌指转录因子锌指核酸结合蛋白2（basonuclin-2）。表达数量性状基因座数据表明，相关的SNP有可能调节BNC2的转录活性，并且易感等位基因会增加BNC2的表达。我们在BNC2中鉴定出一个功能性SNP，rs10738445, 其易感等位基因与转录因子阴阳1（YY1）的结合力以及BNC2增强子活性均高于非易感等位基因。BNC2过表达在发育中的斑马鱼中以基因剂量依赖的方式产生身体弯曲。我们的结果表明，BNC2表达增加与AIS的病因有关。
