Abstract
Effective treatments targeting disease etiology are urgently needed for Alzheimer’s disease (AD). Although candidate AD genes have been identified and altering their levels may serve as therapeutic strategies, the consequence of such alterations remain largely unknown. Herein, we analyzed CRISPR knockout/RNAi knockdown screen data for over 700 cell lines and evaluated cellular dependencies of 104 AD-associated genes previously identified by genome-wide association studies (GWAS) and gene expression network studies. Multiple genes showed widespread cell dependencies across tissue lineages, suggesting their inhibition may yield off-target effects. Meanwhile, several genes including SPI1, MEF2C, GAB2, ABCC11, ATCG1 were identified as genes of interest since their genetic knockouts specifically affected high-expressing cells whose tissue lineages are relevant to cell types found in AD. Overall, 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.
Highlights
Effective treatments targeting disease etiology are urgently needed for Alzheimer’s disease (AD)
Genome wide associated studies (GWAS) that identified genes implicated in AD were downloaded from Kunkle et al and Jansen et al.8,9. 42 unique genes from these two sources were compiled, and APP, PSEN1, and PSEN2 were added to the AD risk gene list13. 60 key AD network hub genes associated with AD were downloaded from Zhang et al.[10]
To examine the genetic dependency of AD-associated genes across tissues, we identified the proportion of cell lines within each tissue type showing significant negative dependency scores (< − 0.5), as lower scores indicate that a gene is required for cell survival and proliferation
Summary
Effective treatments targeting disease etiology are urgently needed for Alzheimer’s disease (AD). We analyzed CRISPR knockout/RNAi knockdown screen data for over 700 cell lines and evaluated cellular dependencies of 104 AD-associated genes previously identified by genome-wide association studies (GWAS) and gene expression network studies. 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. AD medications consist of cholinesterase inhibitors (donepezil, galantamine, and rivastigmine), NMDA receptor uncompetitive antagonist memantine, or a combination of both (donepezil)[2] These medications only address symptoms and are helpful for a limited timespan in improving patients’ cognitive abilities. TYROBP was identified as a pivotal regulator of the phagocytotic pathway[10], cross-validating with immunity-implicated genes found by GWAS
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