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

这项UG3/UH3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来识别和功能验证额颞叶变性的新基因和潜在的TDP-43病理(FTLD-TDP)。FTLD包括一组遗传、临床和病理上不同的神经退行性疾病，影响额叶和颞叶脑区。它的诊断可能是具有挑战性的，而且没有减缓或阻止疾病进展的治疗方法，这突显了FTLD患者巨大的未得到满足的医疗需求。FTLD占所有痴呆症的10%-20%，具有重要的临床意义，因为与阿尔茨海默病(AD)相比，它的发病年龄更早，而且它对人格、洞察力和语言交流等核心人类素质产生了巨大影响。FTLD-TDP代表最常见的FTLD病理亚型，之前有两个主要基因与其遗传病因有关，我们的研究小组都确定了这两个基因：原颗粒蛋白(GRN)突变和染色体9开放阅读框72(C9ORF72)的重复扩张。然而，尽管取得了这些重大进展，超过50%的FTLD-TDP患者的病因仍不清楚，FTLD-TDP的许多病理生理学基础也尚不清楚。在这项提案的UG3阶段，我们将从经病理证实的FTLD-TDP患者以及临床诊断为语义变异型原发性进行性失语(SvPPA)和伴有肌萎缩侧索硬化症(FTD/ALS)的额颞部痴呆(FTD/ALS)的患者收集生物标本和详细的表型数据，这些患者极有可能来自全球30多个地点的TDP-43病理(目标2)。将对625名新的FTLD患者进行全基因组测序(WGS)，并与3000名对照的公开WGS数据相结合，组成一个基因复制队列。在AIMS 1a+b，来自复制队列和以前生成的发现队列(500名FTLD-TDP患者和1000名对照)的WGS数据将通过与其他FTD联盟合作开发的分析管道进行处理。随后，统计分析将提名候选FTLD基因和变种。在本提案的UH3阶段，我们将使用从FTLD-TDP患者和对照组分离的组织或细胞(目标3)在体内使用整合的基因组、转录、蛋白质组和统计分析来确定和验证候选FTLD基因，并使用整合的转录、蛋白质组和高含量成像分析(目标4)使用体外使用人类诱导的多能干细胞模型(目标4)。通过FTLD-TDP疾病新基因的发现，将为FTLD-TDP的病理生物学研究提供重要的新视角，推动生物标志物的发展，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.