Functional characterization of Alzheimer´s disease genetic variants in microglia

Alzheimer's disease (AD) is an age-related neurodegenerative progressive disorder affecting 10% of people over 65. Less than 5% of patients have known causal genetic mutations while the exact cause of AD for the majority of patients, especially the late onset form, is unknown. Large scale epigenomic studies revealed that disease associated SNPs are highly enriched in cell-type-specific cis-regulatory elements. In AD, SNPs are more significantly enriched in the regulatory regions of myeloid lineages rather than the neuronal cells. However, how AD SNPs affect microglia enhancers, and more interestingly differentially affect state-specific enhancers such as activated upon stimulation, e.g. viral infection, remain largely unexplored. In this study we identified cis-regulatory elements in both resting and IFN-beta stimulated microglia and further functionally characterized how regulatory SNPs lead to immune response dysregulation in the pathogenesis of AD. Overall design: We pooled iPSC derived microglia, monocyte derived dendritic cells, monocyte derived macrophages, and fresh monocytes without or with treatment of IFNß (100U/mL) for 6 hours in scRNA-seq. Each of these 4 cell types/ 2 conditions were labeled with individual hashtag (HashTAG001-008), pooled and loaded to 2 lanes of 10X Chromium. Sequencing data from each lane was processed separately and then aggregated using the Cell Ranger.