Etiologic Studies of Age-Related Macular Degeneration

描述(由申请人提供)：我们将在已建立和最近确定的遗传基因座以及环境和眼睛决定因素的基础上，纳入本提案中确定的年龄相关性黄斑变性(AMD)的新发现基因座，用于基因-基因、基因-环境和预测性建模分析。我们还建议通过有针对性的测序来评估候选基因/区域中罕见的、潜在的功能变异以及常见的变异的全谱。相关基因的因果变异的发现将提高对AMD发生和发展的潜在机制的理解。对因果变异的了解将导致AMD更准确的定义和分类系统。我们将扩大我们独特的数据库，以实现研究的科学目标，并促进扩大与其他研究人员的合作努力。我们还将进行功能研究，以确定与遗传变异相关的机制。作为这一努力的结果，我们预计将为这种日益增长的失明原因确定更多新的致病遗传途径。这些潜在的发现将带来保护视力的新的治疗和预防措施，并将减轻由于AMD的高级形式而导致的明显视力丧失的负担。 公共卫生相关性：我们将通过识别新的遗传位点，以及行为和可改变因素如何增加或降低遗传易感性，来扩大关于年龄相关性黄斑变性(AMD)遗传结构的知识。发现新的致病和对AMD有强烈影响的遗传标记将导致新的治疗方法。实验研究将确定与新发现的遗传变异相关的机制。

DESCRIPTION (provided by applicant): We will build upon the established and recently identified genetic loci and environmental and ocular determinants, to incorporate newly discovered loci for age-related macular degeneration (AMD) identified in this proposal for gene-gene, gene-environment, and predictive modeling analyses. We also propose to assess the full spectrum of rare, potentially functional variants, as well as common variants in candidate genes/regions by targeted sequencing. The discovery of causal variants in associated genes will improve the understanding of the underlying mechanisms of AMD development and progression. Knowledge of causal variants will lead to more accurate definitions and classification systems for AMD. We will expand our unique databases to accomplish the scientific aims of the study and to facilitate expanded collaborative efforts with other investigators. We will also conduct functional studies to define the mechanisms associated with the genetic variants. As a result of this effort, we anticipate that additional new pathogenic genetic pathways will be identified for this increasing cause of blindness. These potential discoveries will lead to novel therapeutic and preventive measures for preserving vision, and will reduce the burden of marked visual loss due to the advanced forms of AMD. PUBLIC HEALTH RELEVANCE: We will expand knowledge about the genetic architecture of age-related macular degeneration (AMD) by identifying new genetic loci as well as how behaviors and modifiable factors increase or decrease genetic susceptibility. Discovery of new genetic markers which are pathogenic and have a strong influence on AMD will lead to new treatments. Experimental studies will identify the mechanisms related to the newly discovered genetic variants.