Identifying risk genes and therapeutics for Alzheimer’s disease through integration multi‐omics and drug‐perturbation signatures

Abstract

AbstractBackgroundAlzheimer’s disease (AD) is a severe and irreversible neurodegenerative disease with no effective treatments currently availableMethodTo better understand AD mechanisms and identify therapeutics, we collected AD GWAS loci from the largest meta‐analysis and incorporated multiple lines of genomic evidence, including human brain chromatin interaction map in microglia, brain cell‐type specific expression and gene‐gene interaction network, to infer high‐confidence risk genes (HRGs) at each GWAS locus. We then used the HRGs and network propagation to construct a genetic perturbation signature of AD, and queried a database of drug‐induced transcriptomic signatures (LINCS 1000) to evaluate compounds that are able to reverse the genetic perturbation signature.ResultThis resulted in 72 HRGs, which were further validated in multiple independent datasets of human microglia expression quantitative trait loci (eQTLs) and splicing quantitative trait loci (sQTLs), protein quantitative trait loci (pQTLs) in human brain, cerebrospinal fluid (CSF) and plasma, and genes of protein targets in brain and CSF associated with asymptomatic AD. Pathway analysis implicates the involvement of endocytosis and amyloid pathways, and highlights cellular compartments such as gamma‐secretase complex, NF‐kappaB complex, neurofibrillary tangle and endosome. Query of the genetic perturbation signature of AD against LINCS 1000 revealed several drugs that can reverse the genetic perturbation signature.ConclusionIn conclusion, by incorporating multiple lines of evidence and resources, our study offers new insights into the pathological processes underlying AD and potential therapeutic drugs.