Genome-wide association study with DNA pooling identifies variants at CNTNAP2 associated with pseudoexfoliation syndrome
Genome-wide association study with DNA pooling identifies variants at CNTNAP2 associated with pseudoexfoliation syndrome
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DOI：
10.1038/ejhg.2010.144
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发表时间：
2011-02-01
影响因子：
5.2
通讯作者：
Reis, Andre
中科院分区：
文献类型：
--
作者：
Krumbiegel, Mandy;Pasutto, Francesca;Reis, Andre
遗传和非遗传因素有助于假性剥脱（PEX）综合征的发展，这是一种复杂的、与年龄相关的、广泛的基质过程，常与青光眼相关。为了确定其病因学的特定遗传变异，我们使用DNA汇集方法进行了全基因组关联研究（GWAS）。因此，将等摩尔量的80名PEX综合征受试者、80名PEX青光眼（PEXG）受试者和80名对照受试者的DNA样品合并到单独的库中，并与500 K SNP阵列（Affytron）杂交。用专门开发的软件工具GPFrontend和GPGraphics结合GenePool软件分析和可视化阵列探针强度数据。对于重复，使用了610例PEX/PEXG无关患者和364例对照的独立德国队列以及249例患者和190例对照的意大利队列。其中17个SNP在DNA池中显示出显著的等位基因频率差异，并通过个体基因分型得到证实。对CNTNAP 2位点的进一步单基因分型揭示了两种SNP的PEX/PEXG之间的关联，这在独立的德国队列中得到了证实，但在意大利队列中没有得到证实。即使在Bonferroni校正后，两种SNP在合并的德国队列中仍然显著（rs 2107856：P-c=0.0108，rs 2141388：P-c=0.0072）。CNTNAP 2被发现在所有人眼组织中普遍表达，特别是在视网膜中，并且定位于上皮细胞、内皮细胞、平滑肌细胞、神经胶质细胞和神经元细胞的细胞膜。通过检测已知的LOXL 1基因座证实了GWAS与DNA合并方法的效率，我们的研究数据显示了CNTNAP 2与德国患者的PEX综合征和PEXG相关的证据。European Journal of Human Genetics（2011）19，186-193; doi：10.1038/ejhg.2010.144; 2010年9月1日在线发表
Genetic and nongenetic factors contribute to development of pseudoexfoliation (PEX) syndrome, a complex, age-related, generalized matrix process frequently associated with glaucoma. To identify specific genetic variants underlying its etiology, we performed a genome-wide association study (GWAS) using a DNA-pooling approach. Therefore, equimolar amounts of DNA samples of 80 subjects with PEX syndrome, 80 with PEX glaucoma (PEXG) and 80 controls were combined into separate pools and hybridized to 500K SNP arrays (Affymetrix). Array probe intensity data were analyzed and visualized with expressly developed software tools GPFrontend and GPGraphics in combination with GenePool software. For replication, independent German cohorts of 610 unrelated patients with PEX/PEXG and 364 controls as well as Italian cohorts of 249 patients and 190 controls were used. Of 19, 17 SNPs showing significant allele frequency difference in DNA pools were confirmed by individual genotyping. Further single genotyping at CNTNAP2 locus revealed association between PEX/PEXG for two SNPs, which was confirmed in an independent German but not the Italian cohort. Both SNPs remained significant in the combined German cohorts even after Bonferroni correction (rs2107856: P-c=0.0108, rs2141388: P-c=0.0072). CNTNAP2 was found to be ubiquitously expressed in all human ocular tissues, particularly in retina, and localized to cell membranes of epithelial, endothelial, smooth muscle, glial and neuronal cells. Confirming efficiency of GWAS with DNA-pooling approach by detection of the known LOXL1 locus, our study data show evidence for association of CNTNAP2 with PEX syndrome and PEXG in German patients. European Journal of Human Genetics (2011) 19, 186-193; doi:10.1038/ejhg.2010.144; published online 1 September 2010