PROJECT SUMMARY: CORE C: GENOMICS AND TRANSCRIPTOMICS The primary objective of Core C is to support the genomics and transcriptomics needs of the U54 FTD Center without Walls. Utilizing pre-existing whole genome sequencing data from 721 patients with neu- rodegenerative disease and healthy older adult controls, this Core will provide foundational information regarding variation in tau metabolism pathway genes that will be directly interrogated by the Center through its Projects. Additional gene candidates nominated by the Center will be screened by Core C for relevance to human neurodegenerative disease. In parallel, this Core will generate a `tau polygenic risk score' (TPRS) that will be used to stratify samples at high versus low genetic risk for tau-mediated neu- rodegeneration. These samples will be studied by Project 2 to elucidate the cellular processes by which tau is dysregulated in patients with varying degrees of genetic risk for tau-mediated neurodegeneration. Core C will also support the bioinformatics and statistical needs of the Projects throughout the study period, including analysis of bulk and single-nucleus transcriptomics data generated by Project 2. All of this data will be integrated into an informational database, the `Tau Metabolism and Variant database' (TMVdb), in collaboration with administrative Core A. The TMVdb will be regularly updated and both it and the data used to generate it will be made available to the research community through an analytical workbench interface. All of the Core's proposed activities will contribute to the Center's primary goal of understanding how human genetic variation contributes to tau metabolism and homeostasis and will be critical to its success.