CIDR- Custom Exome Chip Genotyping in POAG (WIGGS)

原发性开角型青光眼（primary open angle glaucoma，POAG）是一种严重的致盲性眼病。原发性开角型青光眼的病因尚不清楚，无法进行一级预防。目前的治疗可以减缓但不能治愈这种进行性神经病。我们研究的总体目标是阐明原发性开角型青光眼（POAG）的发病机制，使其有可能实施有效的筛查和预防策略，并开发新的治疗方法。开角型青光眼是一种临床和遗传学上复杂的疾病，具有显著的遗传性。连锁和关联研究已经确定了有趣的POAG易感基因，然而这些基因仅占整体疾病遗传力的一小部分，并且主要具有相对温和的（如果有的话）功能效应。之前，我们成立了两个合作联盟，为GWA研究提供了3，517例POAG病例和3，631例对照，NEIGHBOR联盟（NEI青光眼人类遗传合作）和GLAUGEN研究（青光眼基因和环境）。 虽然我们的荟萃分析揭示了与POAG相关的重要常见变异，但这些基因组区域中的实际疾病易感性变异尚不清楚。此外，GWAS未检测到的罕见遗传变异也可能导致POAG。本提案的目的是使用Illumina HumanExome BeadChip将整个外显子组数据添加到NEIGHBOR和GLAUGEN数据集，并添加与POAG相关的内容。该提案的近期目标是：1）获得所有可用NEIGHBOR和GLAUGEN样本（3517例病例和3611例对照）的高质量人类外显子组数据; 2）进行关联分析，以识别导致POAG的变异; 3）在独立数据集中并通过适当的体外和动物模型确认新的关联。增加外显子组数据将有可能通过评估常见和罕见遗传变异的贡献来全面分析导致POAG的遗传风险因素。这项工作将是一个重要的一步，发展基因为基础的筛选测试和新的治疗目标的分子事件负责的疾病。 青光眼是一种与眼内压（IOP）相关的进行性视神经病变，最终导致失明。青光眼导致的永久性视野丧失是一种具有全球公共卫生意义的疾病，影响着数百万人。青光眼的病因学知之甚少，没有有效的一级预防和治愈性治疗方法。我们研究的总体目标是阐明青光眼的分子发病机制，使其有可能实施有效的筛查和预防策略，并开发新的治疗方法。该提案的目的是通过添加来自Illumina HumanExome BeadChip的外显子组数据来扩展两个大型青光眼队列（GLAUGEN和NEIGHBOR全基因组关联研究）的遗传分析，这将使得有可能识别导致这种致盲疾病的高影响功能性遗传缺陷。

Primary open angle glaucoma (POAG) is a significant cause of blindness worldwide. The etiology of POAG is poorly understood and primary prevention is not possible. Current treatments can slow but do not cure this progressive neuropathy. The overall goal of our research is to elucidate the pathogenesis of primary openangle glaucoma (POAG) making it possible to implement effective screening and prevention strategies and to develop novel therapies. POAG is a clinically and genetically complex condition with significant heritability. Linkage and association studies have identified interesting POAG susceptibility genes, however these genes only account for a small fraction of the overall disease heritability and mainly have relatively modest (if any) functional effects. Previously we formed two collaborative consortia contributing 3,517 POAG cases and 3,631 controls for GWA studies, the NEIGHBOR consortium (NEI Glaucoma Human genetic collaboration) and the GLAUGEN study (Glaucoma genes and environment). While our meta analysis revealed important common variants associated with POAG the actual disease susceptibility variants in these genomic regions are not yet known. Additionally rare genetic variation, not detected by the GWAS, is also likely to contribute to POAG. The purpose of this proposal is to add whole exome data to the NEIGHBOR and GLAUGEN datasets using the Illumina HumanExome BeadChip with added content relevant to POAG. The immediate goals of this proposal are: 1) Obtain high quality human exome data for all available NEIGHBOR and GLAUGEN samples (3517 cases and 3611 controls); 2) Perform association analyses to identify variants contributing to POAG; 3) Confirm novel associations in an independent dataset and through in vitro and animal models as appropriate. Adding exome data will make it possible to conduct a comprehensive analysis of genetic risk factors contributing to POAG by assessing contributions of both common and rare genetic variants. This work will be an important step toward the development of gene based screening tests and novel therapies targeted to the molecular events responsible for the disease. Public Health Rlevance: Glaucoma is an intraocular pressure (IOP) related progressive optic neuropathy that ultimately leads to blindness. Permanent visual field loss from glaucoma is a condition of public health significance worldwide, affecting millions of people. The etiology of glaucoma is poorly understood and effective means of primary prevention and curative therapies are not available. The overall goal of our research is to elucidate the molecular pathogenesis of glaucoma making it possible to implement effective screening and prevention strategies and to develop novel therapies. The purpose of this proposal is to extend the genetic analysis of two large glaucoma cohorts (the GLAUGEN and NEIGHBOR genomewide association studies) by adding exome data from Illumina HumanExome BeadChip which will make it possible to identify high impact functional genetic defects that contribute to this blinding disease.