Whole genome sequencing consortium on Frontotemporal dementia with underlying TDP-43 pathology

该UG 3/UH 3提案旨在通过建立一个国际测序联盟和一个跨学科的研究团队，鉴定和功能验证具有潜在TDP-43病理学（FTLD-TDP）的额颞叶变性的新基因。FTLD包括影响额叶和颞叶脑区的神经退行性疾病的遗传、临床和病理异质性集合。其诊断可能具有挑战性，并且没有减缓或阻止疾病进展的治疗方法，这突出了FTLD患者巨大的未满足的医疗需求。FTLD占所有痴呆症的10-20%，并且由于其与阿尔茨海默病（AD）相比的早期发病年龄及其对核心人类素质（包括个性，洞察力和言语交流）的巨大影响而具有临床重要性。FTLD-TDP代表了最常见的FTLD病理亚型，并且两个主要基因先前已涉及其遗传病因学，均由我们的研究小组鉴定：颗粒蛋白前体（GRN）突变和9号染色体开放阅读框72（C9 ORF 72）中的重复扩增。然而，尽管取得了这些重大进展，但超过50%的FTLD-TDP患者的病因仍然无法解释，并且FTLD-TDP的许多病理生理学基础尚不清楚。 在本提案的UG 3阶段，我们将从全球30多个研究中心收集病理学证实的FTLD-TDP患者和临床诊断为语义变异型原发性进行性失语症（svPPA）和额颞叶痴呆伴肌萎缩侧索硬化症（FTD/ALS）的患者的生物标本和详细表型数据，这些患者极有可能患有TDP-43病理学（目标2）。将对625名新的FTLD患者进行全基因组测序（WGS），并将其与3000名对照患者的临床可用WGS数据相结合，以组成一个基因复制队列。在目标1a+B中，将通过与其他FTD联合体合作开发的分析管道处理来自复制队列和先前生成的发现队列（500例FTLD-TDP患者和1000例对照）的WGS数据。统计分析随后将提名候选FTLD基因和变体。在本提案的UH 3阶段，我们将使用从FTLD-TDP患者和对照中分离的组织或细胞进行体内整合基因组学、转录组学、蛋白质组学和统计学分析（Aim 3），以及使用整合转录组学、蛋白质组学和高含量成像测定法（Aim 4）使用人诱导多能干细胞模型进行离体分析，对候选FTLD基因进行优先级排序和验证。通过发现新的FTLD-TDP疾病基因，我们将为FTLD-TDP病理生物学提供重要的新见解，促进生物标志物的开发，并为治疗提供新的靶点。

This UG3/UH3 proposal aims to identify and functionally validate novel genes for frontotemporal lobar degeneration with underlying TDP-43 pathology (FTLD-TDP) through the establishment of an international Sequencing Consortium and an interdisciplinary team of investigators. FTLD comprises a genetically, clinically and pathologically heterogeneous collection of neurodegenerative diseases affecting the frontal and temporal brain regions. Its diagnosis can be challenging and no treatments to slow or stop disease progression exist, highlighting the enormous unmet medical need of FTLD patients. FTLD represents 10-20% of all dementias and is clinically important because of its earlier age at onset compared to Alzheimer's disease (AD) and its dramatic impact on core human qualities, including personality, insight and verbal communication. FTLD-TDP represents the most common FTLD pathological subtype and two major genes have previously been implicated in its genetic etiology, both identified by our study team: mutations in progranulin (GRN) and repeat expansions in the chromosome 9 open reading frame 72 (C9ORF72). However, despite these major advances the cause of the disease in more than 50% of FTLD-TDP patient remains unexplained and much of the pathophysiology underlying FTLD-TDP unknown. In the UG3 phase of this proposal, we will collect biospecimens and detailed phenotypic data from patients with pathologically confirmed FTLD-TDP and patients with clinical diagnoses of semantic variant primary progressive aphasia (svPPA) and frontotemporal dementia with amyotrophic lateral sclerosis (FTD/ALS), highly likely to have TDP-43 pathology from more than 30 sites world- wide (Aim 2). Whole genome sequencing (WGS) will be performed on 625 new FTLD patients and combined with publically available WGS data on 3000 controls to comprise a genetic replication cohort. In Aims 1a+b, WGS data from the replication cohort and a previously generated discovery cohort (500 FTLD-TDP patients and 1000 controls) will be processed through an analytical pipeline developed in collaboration with other FTD consortia. Statistical analyses will subsequently nominate candidate FTLD genes and variants. In the UH3 phase of this proposal, we will prioritize and validate candidate FTLD genes using integrative genomic, transcriptomic, proteomic and statistical analyses in vivo using tissues or cells isolated from FTLD-TDP patients and controls (Aim 3) and ex vivo using human induced pluripotent stem cell models using integrative transcriptomic, proteomic, and high- content imaging assays (Aim 4). Through the discovery of novel FTLD-TDP disease genes we will provide important novel insight into FTLD-TDP pathobiology, advance the development of biomarkers and provide novel targets for therapies.