Nakano Masakazu, Ikeda Yoko, Taniguchi Takazumi, Yagi Tomohito, Fuwa Masahiro, Omi Natsue, Tokuda Yuichi, Tanaka Masami, Yoshii Kengo, Kageyama Masaaki, Naruse Shigeta, Matsuda Akira, Mori Kazuhiko, Kinoshita Shigeru, Tashiro Kei
Department of Genomic Medical Sciences, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan.
Proc Natl Acad Sci U S A. 2009 Aug 4;106(31):12838-42. doi: 10.1073/pnas.0906397106. Epub 2009 Jul 22.
Primary open-angle glaucoma (POAG) is the major type of glaucoma. To discover genetic markers associated with POAG, we examined a total of 1,575 Japanese subjects in a genome-wide association study (stage 1) and a subsequent study (stage 2). Both studies were carried out at a single institution. In the stage 1 association study, we compared SNPs between 418 POAG patients and 300 control subjects. First, low-quality data were eliminated by a stringent filter, and 331,838 autosomal SNPs were selected for analysis. Poorly clustered SNPs were eliminated by a visual assessment, leaving 255 that showed a significant deviation (P < 0.001) in the allele frequency comparison. In the stage 2 analysis, we tested these 255 SNPs for association in DNA samples from a separate group of 409 POAG and 448 control subjects. High-quality genotype data were selected and used to calculate the combined P values of stages 1 and 2 by the Mantel-Haenszel test. These analyses yielded 6 SNPs with P < 0.0001. All 6 SNPs showed a significant association (P < 0.05) in stage 2, demonstrating a confirmed association with POAG. Although we could not link the SNPs to the annotated gene(s), it turned out that we have identified 3 genetic loci probably associated with POAG. These findings would provide the foundation for future studies to build on, such as for the metaanalysis, to reveal the molecular mechanism of the POAG pathogenesis.
原发性开角型青光眼（POAG）是青光眼的主要类型。为了发现与POAG相关的遗传标记，我们在一项全基因组关联研究（第1阶段）及后续研究（第2阶段）中对总共1575名日本受试者进行了检查。两项研究均在单一机构开展。在第1阶段的关联研究中，我们比较了418例POAG患者和300名对照受试者之间的单核苷酸多态性（SNP）。首先，通过严格的筛选去除低质量数据，选择331,838个常染色体SNP进行分析。通过视觉评估去除聚类不佳的SNP，剩下255个在等位基因频率比较中显示出显著偏差（P < 0.001）的SNP。在第2阶段分析中，我们在另一组409例POAG患者和448名对照受试者的DNA样本中测试了这255个SNP的关联性。选择高质量的基因型数据，并通过Mantel-Haenszel检验计算第1阶段和第2阶段的合并P值。这些分析产生了6个P < 0.0001的SNP。所有6个SNP在第2阶段均显示出显著关联（P < 0.05），证明与POAG存在确定的关联。尽管我们无法将这些SNP与注释基因联系起来，但结果表明我们已经确定了3个可能与POAG相关的基因位点。这些发现将为未来的研究奠定基础，例如用于荟萃分析，以揭示POAG发病机制的分子机制。
