Genomic Convergence in Primary Open Angle Glaucoma

描述(申请人提供)：这项建议的基本假设是，可识别的遗传影响在原发性开角型青光眼(POAG)的病理生理学中起着关键作用。此外，我们认为，识别潜在基因的最佳方法是利用多种遗传和基因组研究途径对这种复杂的疾病进行协调攻击，这一过程已被称为基因组收敛。这项建议的主要目的是确定在15号染色体上导致早期成人起病形式POAG的基因(确诊时的平均家庭年龄为45.3岁)。我们通过使用适合于研究复杂遗传性疾病的统计遗传学方法，并利用严格确定的多个POAG家系的大型数据库，在染色体15q11-13上确定了POAG的一个新的遗传位点。使用一种新的表型亚型分析方法(有序子集分析[OSA])，我们已经表明，在生命的第四和第五年，患有早发性POAG的家系的表型子集(大约占完整数据集内的20%)占了15号染色体连锁信息的大部分。我们的初步数据表明，这个新的基因座是一种常见的孟德尔形式的POAG。这一建议的关键要素是应用基因组聚合，或应用基因组研究的多个科学路线，以确定疾病的遗传贡献。这项建议的主要目标有三个：1)通过扩大我们的早发性POAG多基因家系数据集的大小，并结合对这些数据的最新分子和遗传分析，建立早发性POAG家系的关联数据集，从而减少最小候选间隔(MCI)。2)通过在人类POAG组织标本上使用微阵列技术，同时结合现有的SAGE/EST文库，创建一个集中和丰富的候选基因库；以及3)通过对编码区进行测序和使用SNP进行关联分析来分析候选基因。这样，我们将整合我们的家族资源、统计学和分子专业知识来确定POAG的主要基因。这一建议提供了一种强有力的方法来确定POAG的主要原因的基因同一性。确定POAG的分子基础将在寻找这种疾病的新诊断和治疗方法方面提供巨大的好处。

DESCRIPTION (provided by applicant): The underlying hypothesis of this proposal is that identifiable genetic influences play a critical role in the pathophysiology of primary open angle glaucoma (POAG). Furthermore, we believe that the best approach toward identification of the underlying genes is a coordinated attack on this complex disorder utilizing multiple genetic and genomic avenues of investigation, a process that has come to be known as genomic convergence. The major objective of this proposal is to identify the gene that contributes to the development of an early adult onset form of POAG on chromosome 15 (mean family age at diagnosis =45.3 years). We have identified a new genetic locus for POAG on chromosome 15q11-13 through the use of statistical genetic methods suited to the investigation of complex inherited disorders and utilizing a large strictly ascertained database of multiplex POAG families. Using, a novel approach for phenotypic subsetting (ordered subset analysis [OSA]) we have shown that the phenotypic subset of families with an early adult onset form of POAG in the 4th and 5th decades of life (approximately 20% of families within the complete dataset) accounts for the majority of the chromosome 15 linkage information. Our preliminary data suggest that this new locus is a common Mendelian form of POAG. The critical element of this proposal is to apply genomic convergence, or the application of multiple scientific lines of genomic investigation, to determine the genetic contribution of disease. The primary goals of this proposal are threefold: 1) to reduce the minimal candidate interval (MCI) by expanding the size of our early-onset POAG multiplex family dataset and by establishing an association data set of early onset POAG families in conjunction with state of the art molecular and genetic analysis of these data. 2) to create a focused and enriched pool of candidate genes through the use of microarray techniques on human POAG tissue specimens while incorporating the use of existing SAGE/EST libraries; and 3) to analyze candidate genes by sequencing coding regions and conducting association analysis using SNP's. In this manner, we will integrate our family resources, statistical, and molecular expertise to identify the primary genes in POAG. This proposal offers a powerful approach to determine the genetic identity of a major cause of POAG. Determining the molecular underpinnings of POAG will provide enormous benefits in the search for new diagnostic and treatment approaches to this disease.