Impact of coding and non-coding variation in progressive supranuclear palsy

进行性核上性麻痹(PSP)是与tau病理相关的最常见的额颞叶变性。虽然在PSP中已经发现了罕见的致病变异、常见的风险因素和最近的罕见风险相关变异，但神经退行性变态和其他额颞叶退行性疾病的相当大比例的遗传性仍未得到解释，这强烈表明更多的遗传风险因素有待发现。在这个应用中，我们建议使用多阶段策略来识别与PSP相关的新的遗传变异。首先，我们将通过神经病理特征的PSP的全基因组测序来检测变异。其次，我们将优先选择病理脑组织样本进行多维筛选，包括转录、蛋白质组学和表观遗传学分析。通过递归应用优先排序算法，将确定最有可能对疾病风险产生高度影响的区域和变种。最后，我们将使用高通量功能筛选来跟踪这些变体。这个项目挖掘了PSP前所未有的病理资源，利用了在私人基金会的支持下创建的病理和遗传基础设施，并提供了改变我们对PSP遗传结构的理解，并向前推进到这种典型的脊椎病的生物学和下游效应，以及这种原型脊椎病的下游影响。

Progressive supranuclear palsy (PSP) is the most common frontotemporal lobar degeneration associated with tau pathology. While rare pathogenic variants, common risk factors, and – more recently – rare risk-associated variants have been identified in PSP, a significant proportion of the heritability for neurodegenerative tauopathies and other frontotemporal lobar degenerations remains unexplained, strongly suggesting that additional genetic risk factors await discovery. In this application, we propose to identify novel genetic variation associated with PSP using a multi-stage strategy. First, we will detect variants through whole-genome sequencing of neuropathologically characterized PSP. Second, we will prioritize pathological brain tissue samples for a multidimensional screen that includes transcriptional, proteomics, and epigenetic assays. Through recursive application of a prioritization algorithm, regions and variants most likely to have a high impact on disease risk will be identified. Finally, we will follow up on these variants using a high-throughput functional screen. This project taps unprecedented pathologic resources of PSP, leverages a pathologic and genetic infrastructure created with support from private foundations, and offers to transform our understanding of the genetic architecture of PSP and to advance towards the biology and downstream effects of this prototypical tauopathy downstream effects of this prototypical tauopathy.