High throughput identification of genetic regulators of microglial inflammatory processes in Alzheimer's disease

Greater than a hundred genetic risk factors for Alzheimer’s disease (AD) have been identified by genome-wide association studies (GWAS), many of which are primarily expressed in microglia. However, the pathogenic role for most of them remains unclear. We sought to assess at scale how AD GWAS hits influence human microglial inflammatory responses. Thus, we conducted CRISPR inhibition (CRISPRi) screens of 119 AD GWAS hits in hiPSC-derived microglia (iMGLs), with reactive oxygen species (ROS) produced in response to the viral mimic poly(I:C) as a readout. Top hits that either decreased or increased ROS in response to poly(I:C) when knocked down were then interrogated in CROP-seq experiments, where CRISPRi was combined with single cell RNA-sequencing (scRNA-seq). These analyses identified 9 unique microglial clusters, including a poly(I:C)-driven inflammatory cluster (2). Emerging evidence s…