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

额颞叶痴呆（FTD）是一种毁灭性的神经系统疾病， 其特征是行为和性格的变化，以及记忆力的丧失， 进步。在家族性FTD中，主要的遗传原因是一个串联重复序列（TR）扩增， C9orf72，证明TR扩增可导致阿尔茨海默病相关痴呆 （ADRD）.尽管TR对FTD很重要，但TR变体的频率和功能 与阿尔茨海默病（AD）相关的疾病是未知的。 我们推测TR DNA序列的变异与AD相关。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TR进行基因分型 具有高精度和精确度。因此，我们的总体目标是识别TR变化 AD和对照组的全基因组测序数据。该补充奖将 提供了一个新的角度来分析数千个NIH资助的、公开可用的AD数据集 国家老年痴呆症遗传学研究所（NIAGADS） 数据共享服务。此外，注释与AD相关的TR变体将确定 这些基因变异是否在功能上与疾病有关。这些结果将 阐明了我们对AD遗传风险因素的理解，并为一类新的 精准靶向治疗

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.