Genetic Dependency of Alzheimer’s Disease-associated Genes Across Cells and Tissue Types
Abstract Background Multiple genes with genetic variants or expression changes associated with Alzheimer’s disease (AD) have been identified. Altering their expression and activity levels serve as potential therapeutic strategies, yet the cellular implications of such alterations remain largely unknown. Methods Cellular dependencies of 105 AD-associated genes, previously identified by genome-wide association studies (GWAS) and gene expression network studies, were evaluated in over 700 cell lines with CRISPR knockout/RNAi knockdown screen data. Expression-driven dependencies were examined within multiple tissue lineages. ResultsMultiple genes showed widespread cell dependencies across tissue lineages, suggesting their inhibition may yield off-target effects. SPI1, MEF2C, GAB2, and ABCC11 were identified as genes of interest since their genetic knockouts specifically affected high-expressing cells of the hematopoietic and lymphoid lineage related to microglia. Other genes exhibiting expression-driven dependencies include ACTG1 in autonomic ganglia and GLS in central nervous system lineages. Conclusions Analyses of genetic screen data identified AD-associated genes whose knockout or knockdown selectively affected cell lines of relevant tissue lineages, prioritizing targets for potential AD treatments.