Integrated QTL mapping and CRISPR screening in pooled iPSC-derived microglia reveals genetic drivers of neurodegenerative risk

Mounting evidence implicates microglia in neurodegeneration, but linking disease-associated genetic variants to target genes and cellular phenotypes is hindered by the inaccessibility of these cells. We differentiated 261 human iPSC lines into microglia-like cells (iMGL) in pools with phenotypic (differentiation, phagocytosis and migration) and single-cell transcriptomic readouts. Burden analysis of deleterious variants detected 36 genes influencing microglial phenotypes. Expression quantitative trait locus (eQTL) analysis found 7,121 eGenes, and 79 colocalizations across four neurodegenerative disease GWAS, half of which had limited prior evidence of causality. Integration of eQTL and phenotypic associations highlighted the role of disease-relevant variants including LRRK2 and TREM2 acting via microglial phagocytosis. A coupled CRISPR screen identified a role of TREM2 in phagocytosis and highlighted the importance of cellular state in directionality of phenotype. By contextualizing variant effects within disease-relevant microglial states, we provide a comprehensive framework for interpreting the function of risk loci in neurodegenerative disorders.