Candidate Genes for Primary Open Angle Glaucoma

描述(申请人提供)：青光眼是美国导致失明的主要原因之一，对非裔美国人的影响不成比例。这笔赠款的重点是在这一研究不足的人群中寻找POAG易感基因。POAG通过视网膜神经节细胞死亡和视神经退化导致失明，通常伴随眼压升高。这种疾病有很大的遗传成分，但涉及的具体基因尚不清楚。在这笔赠款的第一个资助期，我们通过生成超过800,000个基因表达序列分析(SAGE)标签来研究小梁网络和视网膜中的基因表达。我们推测，在这些组织中表达的基因构成了POAG易感基因的极佳候选基因。我们刚刚完成了142个多重POAG家系的连锁分析，使用了超过5000个单核苷酸多态。对这一筛查的分析发现，在非裔美国人中，3号染色体上有一个新的连锁高峰，其非参数连锁得分大于3.0。它还在2号染色体上发现了第二个非裔美国人连锁高峰，该高峰复制了之前在巴巴多斯人口中发现的一个基因座，Lod得分为3.5。我们现在建议跟踪这两个连锁高峰，以确定引起POAG的易感基因。我们将使用双管齐下的方法来寻找这些基因。首先，我们将使用基因组聚合方法，该方法利用多种类型的数据，包括连锁、关联、表达和生物路径分析。其次，我们将使用传统的关联映射方法来表征这两个区域。POAG易感基因的识别可以为诊断试验提供依据，并有助于更早地发现POAG，并极大地改善数百万患有这种致盲疾病的患者的预后。

DESCRIPTION (provided by applicant): Glaucoma is one of the leading causes of blindness in America, and disproportionately affects African Americans. This grant is focused on finding POAG susceptibility genes in this understudied population. POAG causes blindness through death of the retinal ganglion cells and degeneration of the optic nerve, often accompanied by elevated intraocular pressure. There is a large genetic component to this disease, but the specific genes involved are not yet known. During the first funding period of this grant, we investigated gene expression in the trabecular meshwork and the retina by generating over 800,000 Serial Analysis of Gene Expression (SAGE) tags. We hypothesize that the genes expressed in these tissues constitute excellent candidates for POAG susceptibility genes. We have just completed linkage analysis in 142 multiplex POAG families using over 5,000 single nucleotide polymorphisms. Analysis of this screen identified one novel linkage peak on Chromosome 3 in African Americans with a non-parametric linkage score greater than 3.0. It also identified a second African American linkage peak on chromosome 2 that replicates a previously identified locus in a Barbados population with a lod score of 3.5. We now propose to follow up these two linkage peaks to identify the causative POAG susceptibility genes. We will use a two-pronged attack to find these genes. First we will use a genomic convergence approach that takes advantage of multiple types of data including linkage, association, expression, and biological pathway analysis. Second, we will use a traditional association mapping approach to characterize these two regions. The identification of POAG susceptibility genes could provide the basis for diagnostic tests and lead to earlier detection of POAG and a greatly improved prognosis for the millions of patients affected with this blinding disease.