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

摘要 广泛的神经退行性疾病，包括AD和许多ADRD，如PSP、FTLD， 统称为“Tau蛋白病”，因为Tau蛋白是这些疾病的核心特征。此夕h MAPT基因座是额颞叶变性（FTLD）谱系障碍的主要遗传危险因素， 包括进行性核上性麻痹（PSP）。我们的母基金涉及PSP的广泛基因组分析 识别新的致病风险因素并了解其遗传机制。在这里，我们提出一个补充 利用父母补助金中使用的许多相同方法来全面执行遗传和 对100个诱导多能干细胞（IPSC）系的集合进行基因组表征，所述诱导多能干细胞（IPSC）系具有在 微管相关蛋白tau（MAPT）和对照。通过包括男性和女性线的平衡， 对于大多数主要突变的多个品系，包括同基因和未校正的对照，我们将提供 为ADRD研究提供了前所未有的资源。我们将培养和收获所有患者和编辑的同基因IPSC 在严格标准化、高度受控的条件下对细胞系进行下游遗传和基因组分析。 我们将使用多组学方法，包括全基因组测序，批量和单细胞转录 分析和表观遗传学测定，包括全基因组甲基化和单细胞ATAC-seq。通过提供深入的 在这套独特的IPSC系中进行质量控制和分子表型分析， 补充材料将确定生产线的质量和完整性，并能够研究 遗传变异影响会聚ADRD途径。这些线将被存放在NHCDR，和深 基因组和表观遗传表型分析以及遗传数据将与 NINDS工作人员。

Abstract A broad range of neurodegenerative conditions, including AD and many ADRDs, such as PSP, FTLD are collectively known as “tauopathies” because the tau protein is a core feature of these diseases. Further, the MAPT locus is a major genetic risk factor for Frontemporal lobar degeneration (FTLD) spectrum disorders, including Progressive Supranuclear Palsy (PSP). Our parent grant involves extensive genomic analyses in PSP to identify new causal risk factors and understand their genetic mechanisms. Here, we propose a supplement leveraging many of the same approaches used in the parent grant to comprehensively perform genetic and genomic characterization of a collection of 100 Induced Pluripotent Stem Cell (IPSC) lines with mutations in the microtubule-associated protein tau (MAPT) and controls. By including a balance of male and female lines, multiple lines for most of the major mutations, and including isogenic and uncorrected controls, we will provide an unprecedented resource for ADRD research. We will culture and harvest all patient and edited isogenic IPSC lines under rigorously standardized, highly controlled conditions for downstream genetic and genomic analyses. We will use a multi-omics approach involving whole genome sequencing, bulk and single cell transcriptional profiling and epigenetic assays, including genome wide methylation and single cell ATAC-seq. By providing deep quality control and molecular phenotyping in this unique set of IPSC lines, the data production supported by this supplement will define the quality and integrity of the lines and enable the study of the mechanism (s) by which genetic variants influence convergent ADRD pathways. These lines will be deposited at NHCDR, and the deep genomic and epigenetic phenotyping and genetic data will be made publicly available in a coordination with NINDS staff.