Rare Genetic Variation in Macular Degeneration

项目概要/摘要 视网膜相关性黄斑变性（AMD）是一种复杂的疾病， 构成个人风险的因素。补体和其他途径的常见和罕见变异 在疾病的病因学中起很大作用，但大多数这些变体的功能作用不是 知道的补体途径中的罕见变异与常见变异相比对疾病的影响更大。 变异，并能产生明显的生物学效应。需要进一步的研究来揭示 这些罕见的变异及其在这种疾病中的表型表现。该提案的目标是更好地 了解罕见变异的影响，特别是在补体途径中，通过：1）严格的结构 和功能分析，将提供对AMD的病理生理学的分子洞察; 2）基因型- 利用多模态成像对临床可检测的亚表型进行表型评估， 具有和不具有罕见变异的患者之间的差异;以及3）鉴定额外的新的罕见变异， 使用下一代测序，然后将评估其功能和表型 后果这项合作努力将利用一个大型的、特征良好的临床研究队列， 先进的补体分析实验室和世界著名的遗传学设施。功能研究 结合基因型-表型分析和发现新的遗传变异，将扩大对 与AMD相关的病理过程可以揭示影响疾病的高风险亚型 管理，并将提供新的治疗目标。

Project Summary/Abstract Age-related macular degeneration (AMD) is a complex disease with both genetic and environmental components contributing to personal risk. Common and rare variations in the complement and other pathways play a large role in the etiology of the disease, but the functional effects of most of these variants are not known. Rare variants in the complement pathway have stronger impact on the disease compared to common variants and can have clear biologic effects. Further investigation is required to reveal the functional effects of these rare variants and their phenotypic manifestations in this disease. The goals of this proposal are to better understand the impact of rare variants, especially in the complement pathway, through: 1) rigorous structural and functional analyses that will provide molecular insight into the pathophysiology of AMD; 2) genotype- phenotype evaluation of clinically detectible sub-phenotypes utilizing multimodal imaging to pinpoint differences between patients with and without rare variants; and 3) identification of additional novel rare variants using next generation sequencing, which will then be evaluated for their functional and phenotypic consequences. This collaborative effort will leverage a large and well characterized clinical study cohort, a state of the art complement analysis laboratory, and a world renowned genetics facility. Functional studies combined with genotype-phenotype analyses and discovery of novel genetic variants will expand knowledge of the pathological processes related to AMD, may reveal high risk subtypes of the disease that impact disease management, and will provide new targets for therapies.