Session Description

The CureAlz CIRCUITS consortium seeks to uncover the circuitry of AD across the disease spectrum at single-cell resolution, across brain regions, genetic backgrounds, and cellular states, and to study the impact of common, rare, and somatic variants on transcriptional and epigenomic states, using systematic profiling, and systematic perturbations. The resulting resources, shared widely across the broader community, will enable deep new insights on AD at an unprecedented scale, resolution, and scope.  The labs making up the CIRCUITS consortium are collaboratively studying the spatiotemporal progression of AD across individuals and across brain regions using single-cell transcriptomics (scRNA-seq) and single-cell epigenomics (scATAC-seq); assessing the impact of ApoE genotype and other strong-effect variants on gene expression at single- cell resolution; profiling diverse classes of microglia, including inflammatory and synaptic microglia, and their gene expression and epigenomic changes in the context of AD; investigating somatic mutations in AD and their convergence on common pathways with common and rare inherited variants; and systematically perturbing hundreds of predicted driver enhancers, target genes, and upstream master regulators, and using highly-multiplexed expression-based reporters. CIRCUITS is building on the compelling but challenging findings from genome-wide association studies (GWAS) and whole-genome sequencing (WGS).  The vast majority of genetic variants in loci associated via GWAS in AD are noncoding and even lack any protein-altering variants, hindering mechanistic dissection.  WGS are still underpowered for yielding statistically significant results after multiple hypothesis testing due to small cohort sizes and the tens of millions of rare variants implicated. New methods for interpreting the results of GWAS and WGS studies by focusing on biologically meaningful variants, which requires a much deeper understanding of the non-coding genome, are clearly needed.  The CIRCUITS collaboration is addressing these challenges through combined computational and experimental efforts bringing together genetics, epigenomics, regulatory genomics, regulatory networks, functional modelling, comparative genomics, systematic perturbations, genome editing, and cellular phenotyping. The combination of these techniques has enabled the mapping of the circuitry of non- coding variants, and specifically to identify: (1) the cell types through which genetic variants act; (2) the target genes whose expression they affect; (3) the causal nucleotides in a given genetic locus; (4) the upstream regulators whose binding is disrupted; (5) the cellular consequences; and (6) the organismal consequences of non-coding associations.