Genomic Convergence in Primary Open Angle Glaucoma

原发性开角型青光眼的基因组趋同

• 批准号: 7171787
• 负责人: Robert RAND ALLINGHAM
• 金额: $ 65.56万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-12-01 至 2009-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7171787
• 关键词: 15q; Accounting; Adult; Affect; Age; Architecture; Arts; Candidate Disease Gene; Chromosome Mapping; Chromosomes; Chromosomes, Human, Pair 15; Clinical; Code; Complex; Consensus; Data; Data Analyses; Data Set; Databases; Development; Diagnosis; Disease; EST Library; Elements; Environment; Extended Family; Family; Foundations; Functional disorder; Gene Expression; Genes; Genetic; Genetic Identity; Genomics; Genotype; Goals; Haplotypes; Human; Inborn Genetic Diseases; Investigation; Knowledge; Life; Maps; Methods; Microarray Analysis; Molecular; Molecular Genetics; Mutation; Operative Surgical Procedures; Parents; Patients; Play; Primary Open Angle Glaucoma; Process; RNA; Resources; Role; Sampling Errors; Sequence Analysis; Side; Signal Transduction; Single Nucleotide Polymorphism Map; Source; Specimen; Techniques; Testing; Tissue Sample; Tissues; Trabeculectomy; clinical phenotype; density; early onset; genetic analysis; genetic linkage; genetic linkage analysis; insight; molecular pathology; novel diagnostics; novel strategies; proband; programs; size

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.

描述（由申请人提供）：本提案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）的病理生理中起关键作用。此外，我们认为鉴定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疾病进行协调攻击，这一过程已被称为基因组趋同。本提案的主要目的是确定导致15号染色体上早期成人发病形式POAG的基因（诊断时的平均家庭年龄=45.3岁）。我们通过使用适合于复杂遗传疾病调查的统计遗传学方法和利用严格确定的多个POAG家族的大型数据库，在染色体15q11-13上发现了一个新的POAG遗传位点。使用一种新的表型亚群分析方法（有序亚群分析[OSA]），我们已经证明，在生命的第4和第5个十年（在完整数据集中约占20%的家庭）中，成年早期发病形式POAG的家庭的表型亚群占了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POAG的常见孟德尔形式。这一建议的关键要素是应用基因组趋同，或应用基因组研究的多种科学路线，以确定疾病的遗传贡献。本提案的主要目标有三个：1)通过扩大早发性POAG多家族数据集的规模，并通过建立早发性POAG家族的关联数据集，结合这些数据的最新分子和遗传分析，来减少最小候选区间（MCI）。2)结合现有的SAGE/EST文库，通过对人类POAG组织标本使用微阵列技术，建立一个集中和丰富的候选基因库；3)对候选基因进行编码区测序和SNP关联分析。通过这种方式，我们将整合我们的家族资源，统计和分子专业知识来确定POAG的主要基因。这一建议提供了一个强有力的方法来确定POAG的一个主要原因的遗传身份。确定POAG的分子基础将为寻找这种疾病的新诊断和治疗方法提供巨大的好处。