NEIGHBORHOOD Consortium for POAG Genetics

 描述(申请人提供)：原发性开角型青光眼(POAG)是一种与眼压(IOP)相关的进行性视神经病变，最终导致失明。POAG导致的永久性视野丧失是世界范围内具有公共卫生意义的一种情况。POAG的病因知之甚少，初级预防也是不可能的。目前的治疗方法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，以便实施有效的筛查和预防策略，并开发新的治疗方法。POAG具有显著的遗传性，最近的全基因组关联研究，包括我们的邻居/GLAUGEN荟萃分析，已经确定了POAG的相关基因。然而，为了全面定义POAG复杂的遗传结构，需要具有定义良好的表型的大型数据集。为了达到发现POAG基因所需的样本量，我们成立了邻里联盟(邻居可遗传整体操作数据库)，其中包括3873例患者和33,642名对照的协调基因和表型数据。在之前的资助期间，我们1)为邻里联盟开发了基础设施；2)使用邻里数据进行了分析，包括：POAG和正常血压亚组(NTG)的GWA、基因-表型研究、内表型遗传关联研究、相关基因中罕见编码变体的路径分析和功能评估。这一竞争更新的近期目标是：1)增加新的数据集，提供具有特别相关和感兴趣的临床特征的病例和对照；2)进行基因分析，以确定导致POAG和相关亚组的新基因/基因组区域，并评估基因-基因相互作用和分子途径贡献；3)探索通过最近的GWA发现的新基因的基因-表型关系；以及4)继续支持财团的资源和后勤。此外，这项建议将提供资源，支持研究基因-环境相互作用的研究，以及定义与POAG和NTG相关的疾病机制的分子研究。最终，这些信息将形成新的、理想的神经保护疗法的基础。

 DESCRIPTION (provided by applicant): 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. Current treatments can slow but do not cure this progressive neuropathy. The overall goal of our research is to elucidate the pathogenesis of primary open-angle glaucoma (POAG) making it possible to implement effective screening and prevention strategies and to develop novel therapies. POAG has significant heritability and recent genome-wide association studies, including our NEIGHBOR/GLAUGEN meta-analysis, have identified POAG-related genes. However, to comprehensively define the POAG complex genetic architecture large datasets with well-defined phenotypes are required. To achieve the sample size necessary for POAG gene discovery we formed the NEIGHBORHOOD consortium (NEIGHBOR Heritable Overall Operational Database) that includes harmonized genotype and phenotype data for 3,873 cases and 33,642 controls. During the prior funding period we have 1) developed infrastructure for the NEIGHBORHOOD consortium; 2) conducted analyses using the NEIGHBORHOOD data including: GWAS for POAG and the normal-tension subgroup (NTG), gene-phenotype studies, endophenotype genetic association studies, pathway analyses and functional assessment of rare coding variants in associated genes. The immediate goals of this competing renewal are: 1) Add new datasets that contribute cases and controls with clinical features of particular relevance and interest; 2) perform genetic analyses to identify new genes/genomic regions contributing to POAG and related subgroups and also to assess gene- gene interactions and molecular pathway contributions; 3) Explore gene-phenotype relationships for novel genes discovered through recent GWAS; and 4) continue to support the consortium resources and logistics. Additionally, this proposal will provide resources supporting studies investigating gene-environment interactions and molecular studies defining disease mechanisms relevant to POAG and NTG. Ultimately this information will form the basis of novel, and ideally neuro-protective, therapies.