A Multimodal Genomic Analysis Framework Identifies Transposable Element (TE) Activation in Alzheimer's Disease. (20th December 2022) - Feng, Yayan
Abstract: Background: Transposable elements (TEs), known colloquially as "jumping genes" or "viral elements", constitute approximately 45% of the human genome. Recent evidences showed that TEs are activated in AD by age‐associated epigenetic alterations or retroviral infection; yet, mechanisms of AD‐risk TE activation remain elusive. Method: We investigated TE activation underlying AD pathobiology and therapeutic discovery using three large RNA‐sequencing datasets from the AD knowledge portal: (1) 284 AD patients and 150 healthy controls from Mount Sinai Brain Bank (MSBB), (2) 161 AD patients and 195 healthy controls from Mayo Clinic (Mayo), and (3) 106 AD patients and 44 healthy controls from Religious Orders Study or the Rush Memory and Aging Project (ROSMAP). We developed a multi‐modal genomic analysis framework that leverages TE differential expression, genome‐wide association study (GWAS), and X‐quantitative trait loci (X‐QTLs). Result: We identified 6, 13, and 4 differentially expressed TEs (i.e., L1MC4, HERVK22‐int, and HERV1_LTRa) across MSBB, Mayo, and ROSMAP cohorts, respectively, at the family level. We further identified 442, 857, and 806 differentially expressed TEs (i.e., L1ME2) at locus levels across MSBB, Mayo, and ROSMAP cohorts, including 18, 5, and 2 locus‐based TEs in Mayo cohorts that specifically activated in neurons, microglia, and endothelial cells, respectively. Using integrative analysis of differentially expressed TEs with AD GWAS loci, and X‐QTLs, we identified the likely AD‐risk genes (including CEACAM19, CR1, and TOMM40, and cg04406254) involved in TE activation of AD. Using a drug repurposing approach, we showed that valacyclovir (an approved antiviral drug) was significantly associated with reduced incidence of AD in two large patient databases: (a) Hazard ratio (HR) = 0.55 (p < 0.001) in MarketScan with 7.32 individuals; and (b) HR = 0.72 (p < 0.001) in Optum with 5.62 million older individuals (> 65 years old). In addition, valacyclovir alters LINE‐1 expression in AD patient‐induced pluripotent stem cells (iPSC)‐derived neurons, supporting mechanistically potential beneficial effect of suppressing TE activation in AD. Conclusion: This study characterized the genome regulatory control of AD‐risk TE activation and established the likely causal relationship between TE activation and AD pathobiology. The TE‐targeted therapeutic approaches (i.e., valacyclovir) will require randomized controlled trials.