Integrative Network-Based Analysis Reveals Gene Networks and Novel Drug Repositioning Candidates for Alzheimer Disease

Abstract

Background and ObjectivesTo integrate genome-wide association study data with tissue-specific gene expression information to identify coexpression networks, biological pathways, and drug repositioning candidates for Alzheimer disease.MethodsWe integrated genome-wide association summary statistics for Alzheimer disease with tissue-specific gene coexpression networks from brain tissue samples in the Genotype-Tissue Expression study. We identified gene coexpression networks enriched with genetic signals for Alzheimer disease and characterized the associated networks using biological pathway analysis. The disease-implicated modules were subsequently used as a molecular substrate for a computational drug repositioning analysis, in which we (1) imputed genetically regulated gene expression within Alzheimer disease implicated modules; (2) integrated the imputed gene expression levels with drug-gene signatures from the connectivity map to identify compounds that normalize dysregulated gene expression underlying Alzheimer disease; and (3) prioritized drug compounds and mechanisms of action based on the extent to which they normalize dysregulated expression signatures.ResultsGenetic factors for Alzheimer disease are enriched in brain gene coexpression networks involved in the immune response. Computational drug repositioning analyses of expression changes within the disease-associated networks retrieved known Alzheimer disease drugs (e.g., memantine) as well as biologically meaningful drug categories (e.g., glutamate receptor antagonists).DiscussionOur results improve the biological interpretation of genetic data for Alzheimer disease and provide a list of potential antidementia drug repositioning candidates for which the efficacy should be investigated in functional validation studies.