Development and application of new tools to identify repeat expansions in human diseases

开发和应用新工具来识别人类疾病的重复扩展

• 批准号: 10729985
• 负责人: Graham Scott Erwin
• 金额: $ 11.86万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10729985
• 关键词: Alzheimer' s Disease; Alzheimer' s disease related dementia; Award; Behavioral; C9ORF72; DNA Sequence; Data; Data Set; Development; Disease; Disease Progression; Frequencies; Frontotemporal Dementia; Funding; Genetic; Genotype; Human Genome; Memory Loss; National Institute on Aging; Personality; Public Health; Research; Services; Tandem Repeat Sequences; United States National Institutes of Health; Variant; cohort; data sharing; genetic risk factor; genetic variant; genome sequencing; human disease; nervous system disorder; new therapeutic target; novel therapeutics; targeted treatment; tool; whole genome

Frontotemporal dementia (FTD) is a devastating neurological disease that is characterized by behavioral and personality changes, as well as memory loss as the disease progresses. In familial FTD, the major genetic cause is a tandem repeat (TR) expansion in C9orf72, demonstrating that TR expansions can lead to Alzheimer’s Disease Related Dementia (ADRD). Despite the importance of TRs to FTD, the frequency and function of TR variants associated with Alzheimer’s Disease (AD) is unknown. We hypothesize that variations in TR DNA sequences are associated with AD. We have recently deployed new tools to genotype hundreds of thousands of TRs in the human genome with high accuracy and precision. Therefore, our overall objective is to identify TR variations from whole-genome sequencing data in AD and control cohorts. This supplement award will provide a new angle to analyze thousands of NIH-funded, publicly-available AD datasets released through the National Institute on Aging Genetics of Alzheimer’s Disease (NIAGADS) Data Sharing Service. Furthermore, annotating TR variants associated with AD will determine whether some of these genetic variants are functionally implicated in disease. These results will illuminate our understanding of genetic risk factors in AD and set the stage for a new class of precision-targeted therapeutics.

额颞性痴呆(FTD)是一种毁灭性的神经疾病， 以行为和个性变化为特征，以及记忆丧失为疾病 进步了。在家族性FTD中，主要的遗传原因是串联重复序列(Tr)在 C9ORF72，证明TR的扩张可以导致阿尔茨海默病相关痴呆 (ADRD)。尽管TRs对FTD很重要，但TR变异体的频率和功能 与阿尔茨海默病(AD)相关的疾病尚不清楚。 我们假设TRDNA序列的变异与AD有关。我们有 最近部署了新的工具来对人类基因组中的数十万个Trs进行基因分型 具有很高的准确度和精密度。因此，我们的总体目标是识别tr变异。 来自AD和对照队列的全基因组测序数据。本补充奖将于 为分析数千个由NIH资助、公开提供的AD数据集提供了一个新的角度 由国家阿尔茨海默病衰老遗传学研究所(NIAGADS)发布 数据共享服务。此外，注释与AD相关联的TR变体将确定 这些基因变异中的一些是否在功能上与疾病有关。这些结果将 阐明我们对阿尔茨海默病遗传风险因素的理解，并为新一代阿尔茨海默病 精准靶向疗法。