Genetics

项目摘要--遗传学核心(核心F) 孟德尔式的突变，常见的风险因素，以及-最近-罕见的风险相关变异 在神经退行性疾病中被发现。然而，阿尔茨海默病的相当大一部分遗传性 (AD)和额颞叶痴呆(FTD)仍未得到解释，这表明额外的遗传风险因素 等待确认身份。这个PPG Genetics核心在过去的൭൫年里一直支持PPG调查人员由൬) 收集和存储来自整个PPG队列的dna和rna样本；൭)为已知的 痴呆的致病原因和风险相关变异，使用传统和下一代 测序方法；൮)通过以下方式有助于发现新基因和新的风险相关变异 数据生成和基于病例的筛选，使用遗传和基因组方法；以及൯)建立 促进数据共享、存储和挖掘的信息学平台，包括访问专用计算 和存储资源。在此续订申请中，我们建议利用此基础架构和专业知识来 扩大PPG可用的遗传和基因组分析组合。在扩大角色的背景下，我们 建议将主要核心活动从加州大学洛杉矶分校(GeschWind)转移到加州大学旧金山分校(横山)。我们将继续 样本收集和银行，并将扩大我们的测序和基因分型工作，以包括整个外显子组 用于基因筛选的测序，用于种群图谱的全基因组SNP阵列，用于疾病的片段分析- 导致三核苷酸重复扩增，以及支持൭项目的转录组学：分子生物标记物。是这样的 数据将与正在进行的临床、影像、生物标记物和神经病理学研究相结合 PPG促进了我们对神经退行性疾病遗传结构的理解。给定 遗传信息的基本性质在FTD的病因学和病理生理学中，这个核心服务于所有 该计划中的项目，并链接到其他PPG核心。

PROJECT SUMMARY—Genetics Core (Core F) Mendelian mutations, common risk factors, and – more recently – rare risk-associated variants have been identified in neurodegenerative diseases. Yet, a significant proportion of the heritability for Alzheimer's disease (AD) and frontotemporal dementia (FTD) remains unexplained, suggesting that additional genetic risk factors await identification. This PPG Genetics Core has supported PPG investigators over the past ൭൫ years by ൬) collecting and storing DNA and RNA samples from the entire PPG cohort; ൭) providing genetic testing for known pathogenic causes of dementia and risk-associated variants, using both traditional and next-generation sequencing methods; ൮) contributing to the discovery of novel genes and novel risk-associated variants through data generation and case-based screening, using genetic and genomic approaches; and ൯) establishing an informatics platform to facilitate data sharing, storage, and mining, including access to dedicated computational and storage resources. In this renewal application, we propose to leverage this infrastructure and expertise to expand the portfolio of genetic and genomics assays available to the PPG. In the context of expanding roles, we propose to transition primary core activities from UCLA (Geschwind) to UCSF (Yokoyama). We will continue sample collection and banking and will expand our sequencing and genotyping efforts to include whole exome sequencing for gene screening, genome-wide SNP arrays for population mapping, fragment analysis for disease- causing trinucleotide repeat expansions, and transcriptomics in support of Project ൭: Molecular Biomarkers. Such data will be integrated with the clinical, imaging, biomarker, and neuropathological studies being conducted within the PPG to advance our understanding of the genetic architecture of neurodegenerative disease. Given the fundamental nature of genetic information in the etiology and pathophysiology of FTD, this core serves all the projects in this program and is linked to the other PPG cores.