Genetic Dependency of Alzheimer’s Disease-Associated Genes across Cells and Tissue Types

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.

Single Cell transcriptional analysis ofex vivomodels of cortical and hippocampal development identifies unique longitudinal trends

“…Next we curated and investigated the gene expression patterns and cell specificity of 94 genes associated with genetic epilepsy (compiled and curated from [59, 60]), 227 Autism Spectrum Disorder (ASD) genes (SFARI Category 1 and SPARK genes[61, 62, 86, 87]), 32 schizophrenia genes [63, 88], 16 dystonia genes [64, 65], 84 genes associated with Alzheimer’s Disease [66], 55 Parkinson’s disease genes from the Gene4PD database [67], 57 Obesity genes [89], and 87 Coronary Artery Disease (CAD) genes [90, 91] (Table S9).…”

“…The extent and specifics of the dynamic temporal gene expression in these postnatal cultures over network development is not well characterized, and is crucial for experimental design when using these cultures, or deciding which model to use. This is of increased importance when looking at genes that are known to be causal for, or associated with, neurological disorders [59][60][61][62][63][64][65][66][67].…”