NEIGHBORHOOD Consortium for POAG Genetics

原发性开角型青光眼（Primary open-angle glaucoma，POAG）是一种与眼内压（intraocular pressure，IOP）相关的进行性视神经病变 最终导致失明POAG的永久性视野丧失是一种公共健康状况 在世界范围内的意义。原发性开角型青光眼的病因尚不清楚，无法进行一级预防。 眼内压（IOP）升高是一个可改变的风险因素，然而，许多个体存在IOP升高 无视神经疾病，至少33%的POAG病例有进行性视网膜神经节细胞丢失 尽管IOP测量值在正常范围内，这种情况被定义为正常眼压性青光眼（NTG）。 青光眼的抑制性或神经保护性治疗尚不可用，并且对青光眼的治疗知之甚少。 分子事件影响对青光眼性视神经变性的易感性。的总目标 我们的研究是为了阐明POAG的发病机制，以便进行有效的筛查， 预防策略和新疗法的开发。POAG具有显著的遗传性， 全基因组关联研究，包括我们的NEIGHBOOD GWAS，已经确定了30个POAG基因座 由常见的基因组变异所定义。然而，除了常见的变异，复杂的POAG遗传 结构可能还包括罕见的编码变异的贡献，这些变异涉及特定的基因， 疾病致病性，如已发现的其他复杂性状。罕见编码的大规模研究 青光眼人群的变化尚未完成。这一竞争性更新的重点是 全面研究编码变异对POAG以及HTG和NTG亚组的贡献 其主要目标是鉴定新的治疗靶点，特别是那些具有神经保护作用的靶点， 潜力在下一个资助期，我们提出以下具体目标：1）获得高质量的整体 POAG病例和对照的外显子组序列（WES）数据，使用最先进的测序技术和稳健的 变异识别和注释管道; 2）评估罕见编码变异对POAG和NTG的贡献 3）建立基于网络的数据分析、数据共享和交流平台。

Primary open-angle glaucoma (POAG) is an intraocular pressure (IOP) related, progressive optic neuropathy that ultimately leads to blindness. Permanent visual field loss from POAG is a condition of public health significance worldwide. The etiology of POAG is poorly understood and primary prevention is not possible. Elevated intraocular pressure (IOP) is a modifiable risk factor, however, many individuals have IOP elevation without optic nerve disease , and at least 33% of POAG cases have progressive retinal ganglion cell loss despite IOP measurements in the normal range, a condition defined as normal-tension glaucoma (NTG). Preventative or neuro-protective therapies for glaucoma are not yet available and little is known about the molecular events that influence susceptibility to glaucomatous optic nerve degeneration. The overall goal of our research is to elucidate the pathogenesis of POAG allowing for implementation of effective screening and prevention strategies and development of novel therapies. POAG has significant heritability and recent genome-wide association studies, including our NEIGHBORHOOD GWAS, have identified 30 POAG loci defined by common genomic variants. However, in addition to common variants the complex POAG genetic architecture is likely to also include contributions from rare coding variants that implicate specific genes in disease pathogenicity, as has been discovered for other complex traits. Large-scale studies of rare coding variation in glaucoma populations have not yet been done. The focus of this competing renewal is to comprehensively examine the contributions of coding variation to POAG and the HTG and NTG subgroups with a primary goal of identifying novel therapeutic targets and specifically those with neuro-protective potential. For the next funding period we propose the following specific aims: 1) Obtain high quality whole exome sequence (WES) data for POAG cases and controls using state-of-the-art sequencing and robust variant calling and annotation pipelines; 2) Assess contribution of rare coding variants to POAG and to NTG and HTG subgroups; and 3) Build a web-based platform for data analysis, data-sharing and communication.