PAGER

PAGER integrates GWAS and gene expression data to prioritize drug repositioning candidates by identifying dysregulated gene co-expression modules and their pathway-level targets in polygenic diseases such as Parkinson's disease.

Key Features:

• Integration of Genomic Data: Integrates genome-wide association studies (GWAS) with gene expression data to identify genetic variants and upstream perturbations affecting disease-associated pathways.
• Gene Co-expression Network Analysis: Applies weighted gene correlation network analysis (WGCNA) to identify co-expression modules in brain regions including the frontal gyrus, lateral substantia, and medial substantia, reporting a Brown module (449 genes) and a Turquoise module (905 genes).
• Functional Pathway Enrichment: Performs enrichment analyses on modules to annotate pathways such as cellular respiration, intracellular transport, energy-coupled proton transport against electrochemical gradients, microtubule-based movement (Brown module), and M-phase cell cycle regulation (Turquoise module).
• Drug-Target Interaction Analysis: Queries drug–protein regulatory relationship databases (DMAP) to evaluate candidate drugs and computes a Drug Effect Sum Score (DESS) from known drug-target activity profiles.
• Drug Repositioning Potential: Ranks drugs by DESS to identify both previously reported Parkinson's disease candidates and novel repositioning opportunities.

Scientific Applications:

• Systems Pharmacology: Prioritizes pathway- and module-level targets rather than single genes to address the complexity of polygenic disease mechanisms.
• Drug Repositioning: Enables ranking and selection of candidate therapeutics for repositioning by aggregating drug effects across disease-associated gene modules.
• Integrative Genomics: Links GWAS-derived genetic susceptibility to dysregulated gene expression modules using gene expression microarray data to generate therapeutic hypotheses.

Methodology:

Integrates GWAS and gene expression microarray data; uses WGCNA to define co-expression modules; conducts pathway enrichment on modules; queries DMAP for drug–protein regulatory relationships and computes DESS to score and rank drugs.