Etiological Studies of Age-Related Macular Degeneration

项目总结： 尽管有许多与年龄相关退行性变(AMD)相关的遗传变异，但有意义的 丢失的遗传性的一小部分尚未被剔除。许多研究都集中在确定共同的 在普通人群中导致这种疾病的变种。这个项目的目标之一是发现稀有的、高度 导致家族性AMD的渗透性遗传变异。AMD注册和生物库是一个大型 具有独特特征的队列，包括标准化的临床表型数据和纵向 前瞻性数据。这一群体中的一些家族有多个成员患有晚期AMD，这些成员不能 由已知的AMD相关遗传变异解释，并将使用下一代进行测序 测序以发现新的变种。在这些家系中发现的与疾病完美分离的变异 将在一个独立的病例对照队列中评估是否与AMD有关。要发现更多 造成缺失遗传性的基因变异，第二个目标是评估已知和新的基因 随着时间的推移，它们在AMD进展中的作用的变体，特别是每个变体对启动的影响 疾病以及向早、中、晚期的过渡。加深对……的理解 AMD作为一个复杂的性状，数量和半定量的中间亚型将被评估 与这些基因变异有关。这项研究的结果将填补我们对 老年性黄斑变性的遗传学。我们将利用这些发现来开发AMD进展的改进预测模型， 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 预防或延缓AMD的进展，减轻这种疾病造成的视力丧失的负担。

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.