Precision drug repurposing via convergent eQTL-based molecules and pathway targeting independent disease-associated polymorphisms

摘要

Repurposing existing drugs for new therapeutic indications can improve success rates and streamline development. Use of large-scale biomedical data repositories, including eQTL regulatory relationships and genome-wide disease risk associations, offers opportunities to propose novel indications for drugs targeting common or convergent molecular candidates associated to two or more diseases. This proposed novel computational approach scales across 262 complex diseases, building a multi-partite hierarchical network integrating (i) GWAS-derived SNP-to-disease associations, (ii) eQTL-derived SNP-to-eGene associations incorporating both cis- and trans-relationships from 19 tissues, (iii) protein target-to-drug, and (iv) drug-to-disease indications with (iv) Gene Ontology-based information theoretic semantic (ITS) similarity calculated between protein target functions. Our hypothesis is that if two diseases are associated to a common or functionally similar eGene - and a drug targeting that eGene/protein in one disease exists - the second disease becomes a potential repurposing indication. To explore this, all possible pairs of independently segregating GWAS-derived SNPs were generated, and a statistical network of similarity within each SNP-SNP pair was calculated according to scale-free overrepresentation of convergent biological processes activity in regulated eGenes (ITSeGENE-eGENE) and scale-free overrepresentation of common eGene targets between the two SNPs (ITSsnp-snp). Significance of ITSsnp-snp was conservatively estimated using empirical scale-free permutation resampling keeping the node-degree constant for each molecule in each permutation. We identified 26 new drug repurposing indication candidates spanning 89 GWAS diseases, including a potential repurposing of the calcium-channel blocker Verapamil from coronary disease to gout. Predictions from our approach are compared to known drug indications using DrugBank as a gold standard (odds ratio=13.1, p-value=2.49