Integrated Cell-type Specific Biological Annotation of Genomic Variants in Alzheimer Disease

University Of Washington, Seattle WA

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Abstract

Alzheimer disease (AD) is a complex phenotype likely influenced by the combinatorial impact of many genetic elements. While environmental factors and age certainly contribute to phenotypic expression, we hypothesize that the underlying biological process of AD is driven by the burden of genetic variants influencing risk. It is therefore critical to understand the biological implication of AD risk alleles if we hope to realize the goal of more precise and effective AD therapeutics. We are leveraging our interdisciplinary Alzheimer Disease (AD) research programs at the University of Washington and partners in the Seattle area to create a cell-type specific systems biology program in AD. The cellular heterogeneity of human brain confounds interpretation of transcriptomic and epigenomic data from bulk tissue. We have developed an iterative process to functionally annotate the known AD GWAS SNPs in a cell type specific unbiased manner with transcriptomic and epigenomic network analysis of single cell CNS neural tissue. Through innovative combinatorial ATAC-seq methods to map the open chromatin profile from isolated single cells in human brain we will generate chromatin accessibility and transcriptomic profiles from single cells isolated from autopsy fresh brain. In parallel we are deriving iPSC differentiated neuronal and microglial lines generated from the same cohort of sporadic AD. Through development of these datasets and identifying shared and distinct features, we can begin to identify not only the epigenomic and transcriptomic impact of GWAS variants, but that of aging and stem cell reprogramming. We hypothesize that non-coding variants confer AD risk through cellular pathways which can be assessed in vitro. We will pilot this approach to assess the impact of GWAS variants on cellular phenotypes well established as relevant to AD pathogenesis. GWAS AD SNPs and novel genomic variants will tested for association with a subset of AD relevant in vitro cell biology phenotypes in iPSC derived neurons and microglia and transdifferentiated neurons. Through our integrated molecular and cell biology phenotyping we aim to identify candidate pathways by which non-coding variants may confer AD risk, and identify novel pathways associated with AD pathogenesis for further in vitro study.