Candidate Genes for Primary Open Angle Glaucoma

描述（由申请人提供）：青光眼是美国失明的主要原因之一，对非洲裔美国人的影响不成比例。这项资助的重点是在这一未充分研究的人群中发现POAG易感基因。POAG通过视网膜神经节细胞的死亡和视神经的变性导致失明，通常伴有眼内压升高。这种疾病有很大的遗传成分，但涉及的特定基因尚不清楚。在该资助的第一个资助期内，我们通过生成超过80万个基因表达系列分析（SAGE）标签来研究小梁网和视网膜中的基因表达。我们推测这些组织中表达的基因是POAG易感基因的最佳候选基因。我们刚刚使用超过5,000个单核苷酸多态性完成了142个多重POAG家族的连锁分析。对该筛选的分析确定了非裔美国人3号染色体上的一个新的连锁峰，其非参数连锁评分大于3.0。它还确定了2号染色体上的第二个非洲裔美国人连锁峰，该连锁峰复制了先前在巴巴多斯人口中确定的基因座，lod得分为3.5。我们现在建议跟踪这两个连锁峰，以确定病因POAG易感基因。我们将使用双管齐下的攻击来找到这些基因。首先，我们将使用基因组融合方法，该方法利用多种类型的数据，包括连锁，关联，表达和生物途径分析。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易感基因的鉴定可以为诊断测试提供基础，并导致POAG的早期检测和大大改善数百万受这种致盲疾病影响的患者的预后。

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.