Gene, cell type, and drug prioritization analysis suggest genetic basis for the utility of diuretics in treating Alzheimer disease

Abstract

Summary: We introduce a user-friendly tool for risk gene, cell type, and drug prioritization for complex traits: GCDPipe. It uses gene-level GWAS-derived data and gene expression data to train a model for the identification of disease risk genes and relevant cell types. Gene prioritization information is then coupled with known drug target data to search for applicable drug agents based on their estimated functional effects on the identified risk genes. We illustrate the utility of our approach in different settings: identification of the cell types, implicated in disease pathogenesis, was tested in inflammatory bowel disease (IBD) and Alzheimer disease (AD); gene target and drug prioritization was tested in IBD and schizophrenia. The analysis of phenotypes with known disease-affected cell types and/or existing drug candidates shows that GCDPipe is an effective tool to unify genetic risk factors with cellular context and known drug targets. Next, analysis of the AD data with GCDPipe suggested that gene targets of diuretics, as an Anatomical Therapeutic Chemical drug subgroup, are significantly enriched among the genes prioritized by GCDPipe, indicating their possible effect on the course of the disease.

Keywords

• Gene prioritization
• GWAS
• Machine learning
• GCDPipe