Impact of coding and non-coding variation in progressive supranuclear palsy

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Abstract A broad range of neurodegenerative conditions, including AD and many ADRDs, such as PSP, FTLD are collectively known as “tauopathies” because the tau protein is a core feature of these diseases. Further, the MAPT locus is a major genetic risk factor for Frontemporal lobar degeneration (FTLD) spectrum disorders, including Progressive Supranuclear Palsy (PSP). Our parent grant involves extensive genomic analyses in PSP to identify new causal risk factors and understand their genetic mechanisms. Here, we propose a supplement leveraging many of the same approaches used in the parent grant to comprehensively perform genetic and genomic characterization of a collection of 100 Induced Pluripotent Stem Cell (IPSC) lines with mutations in the microtubule-associated protein tau (MAPT) and controls. By including a balance of male and female lines, multiple lines for most of the major mutations, and including isogenic and uncorrected controls, we will provide an unprecedented resource for ADRD research. We will culture and harvest all patient and edited isogenic IPSC lines under rigorously standardized, highly controlled conditions for downstream genetic and genomic analyses. We will use a multi-omics approach involving whole genome sequencing, bulk and single cell transcriptional profiling and epigenetic assays, including genome wide methylation and single cell ATAC-seq. By providing deep quality control and molecular phenotyping in this unique set of IPSC lines, the data production supported by this supplement will define the quality and integrity of the lines and enable the study of the mechanism (s) by which genetic variants influence convergent ADRD pathways. These lines will be deposited at NHCDR, and the deep genomic and epigenetic phenotyping and genetic data will be made publicly available in a coordination with NINDS staff.