NEIGHBORHOOD Consortium for POAG Genetics

摘要原发性开角型青光眼是一种与眼压相关的进行性视神经病变。 这最终会导致失明。POAG导致的永久性视野丧失是公共健康的一种状况 在世界范围内具有重要意义。POAG的病因知之甚少，初级预防也是不可能的。 高眼压(IOP)是一个可改变的危险因素，然而，许多人有眼压升高。 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 尽管眼压测量在正常范围内，但这种情况被定义为正常眼压性青光眼(NTG)。 目前还没有针对青光眼的预防性或神经保护性疗法，人们对青光眼的情况知之甚少。 影响青光眼视神经变性易感性的分子事件。的总目标是 我们的研究是为了阐明POAG的发病机制，以便实施有效的筛查和 预防战略和新疗法的开发。POAG具有显著的遗传性和近期 全基因组关联研究，包括我们附近的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，除了常见的变种外，复杂的POAG基因 体系结构可能还包括罕见的编码变体的贡献，这些变体涉及特定的基因 疾病致病性，如已发现的其他复杂性状。稀有编码的大规模研究 青光眼人群中的变异还没有完成。这一竞争性更新的重点是 全面考察编码变异对POAG以及HTG和NTG亚群的贡献 主要目标是确定新的治疗靶点，特别是那些具有神经保护作用的靶点 潜力。对于下一个资金期，我们提出了以下具体目标：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和稳健 变量调用和注释管道；2)评估罕见编码变量对POAG和NTG的贡献 和HTG小组；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.