New polygenic risk score for Alzheimer’s disease impacts states and functions in iPSC‐derived microglia.

Abstract

AbstractBackgroundRecent genetics studies for Alzheimer’s disease have identified multiple risk variants affecting amyloid processing, immune response, lipid transport, and endocytosis, among others 1. More than half the risk genes associated with late‐onset AD are selectively expressed in microglia and peripheral myeloid cells. Yet, we know little about the underlying biology or how myeloid cells contribute to AD pathogenesis.MethodTo gain insights into the broad impact of genetics on microglia, we selected 50 cell lines from the CIRM biobank with variable APOE genotypes and polygenic risk scores (PRS). Building on our in vitro platform that recapitulates microglia states in vitro 2, we used villages 3, or pooled culture, to differentiate these lines into microglia and assessed key microglia functions, transcriptional profiles, and response to various perturbations.ResultCell villages allow us to compare phenotypes across lines with little technical variability robustly. Our data determined functional phenotypes that were altered by PRS and others that were affected by APOE genotypes. Moreover, quantitative trait locus (QTL) analysis identified new variants affecting phagocytosis, proliferation, and response to lipids. Finally, single‐cell RNA sequencing of our village pinpointed key microglia pathways altered between high and low PRS individuals.ConclusionCell village allows for the characterization of up to hundreds of cell lines while minimizing technical variability allowing us to identify phenotypes dysregulated across various genetic backgrounds. Our data pinpointed the impact of a novel Alzheimer’s disease PRS on microglia states and functions and identified new variants affecting microglia functions.1. Sims, R., Hill, M. & Williams, J. Nat Neurosci 23, 311‐322 (2020). 2. Dolan, M.‐J. et al. Biorxiv 2022.05.02.490100 (2022) https://doi.org/10.1101/2022.05.02.490100. 3. Wells, M. F. et al. Biorxiv 2021.11.08.467815 (2021) https://doi.org/10.1101/2021.11.08.467815.