Etiological Studies of Age-Related Macular Degeneration

项目概要： 虽然有许多与年龄相关性变性（AMD）相关的遗传变异，但一个有意义的研究表明， 一部分缺失的遗传性还有待解释。许多研究都集中在确定共同的 在一般人群中导致这种疾病的变异。该项目的目的之一是发现罕见的，高度 导致家族性AMD的渗透性遗传变异。AMD注册和生物储存库是一个大型的 具有独特特征的队列，包括标准化临床表型数据和纵向 前瞻性数据来自该队列的一些家庭有多名成员患有晚期AMD， 已知的AMD相关的遗传变异解释，并将使用下一代测序技术进行测序。 测序以发现新的变体。在这些家庭中发现的变异与疾病完全分离 将在独立的病例对照队列中评估与AMD的相关性。以发现另外 遗传变异导致遗传力缺失，第二个目的是评估已知和新的遗传变异， 变异体在AMD随时间进展中的作用，特别是每种变异体对AMD启动的影响， 的疾病和过渡到早期，中期和晚期阶段。加深理解 AMD作为一种复杂性状，将评估定量和半定量中间亚表型， 与这些遗传变异的关系。这项研究的结果将填补我们对 AMD的遗传学我们将利用这些发现来开发改进的AMD进展预测模型， 我们的结果可能会导致更准确的诊断和更好的治疗靶点。最终目标是 预防或减缓AMD的进展，并减轻由于这种疾病而导致的视力丧失的负担。

Project Summary: Although there are numerous genetic variants associated with age-related degeneration (AMD), a meaningful fraction of missing heritability has yet to be exlained. Many studies have focused on identifying the common variants contributing to this disease in the general population. One aim of this project is to discover rare, highly penetrant genetic variants contributing to familial forms of AMD. The AMD Registry and Biorepository is a large cohort with unique characteristics that include standardized clinical phenotype data and longitudinal prospective data. Some families from this cohort have multiple members with advanced AMD that cannot be explained by known AMD-associated genetic variants and will be sequenced using next-generation sequencing to discover novel variants. Variants found to perfectly segregate with the disease in these families will be assessed for association with AMD in an independent case-control cohort. To discover additional genetic variants contributing to the missing heritability, a second aim is to assess known and novel genetic variants for their role in progression of AMD over time, particularly the effect each variant has on the initiation of the disease and the transition to early, intermediate, and advanced stages. To further the understanding of AMD as a complex trait, quantitative and semi-quantitative intermediate sub-phenotypes will be assessed for association with these genetic variants. Results from this study will fill gaps in our knowledge about the genetics of AMD. We will use these discoveries to develop improved predictive models for AMD progression, and our results may lead to more accurate diagnoses and better therapeutic targets. The ultimate goal is to prevent or slow the progression of AMD and reduce the burden of visual loss due to this disease.