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

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.