Mapping drug biology to disease genetics to discover drug impacts on the human phenome

Abstract

Unintended effects of medications on diverse diseases are widespread, resulting in not only harmful drug side effects, but also beneficial drug repurposing. This implies that drugs can unexpectedly influence disease networks. Then, discovering how biological effects of drugs relate to disease biology can both provide insight into the biological basis for latent drug effects, and can help predict new effects. Rich data now comprehensively profile both drug impacts on biological processes, and known drug associations with human phenotypes. At the same time, systematic phenome-wide genetic studies have linked each common phenotype with putative disease driver genes. Here, we develop Draphnet, a supervised linear model that integrates in vitro data on 429 drugs and gene associations of nearly 200 common phenotypes to learn a network connecting these molecular signals to explain drug effects on disease. The approach uses the -omics level similarity among drugs, and among phenotypes, to extrapolate impacts of drug on disease. Our predicted drug-phenotype relationships outperform a baseline predictive model. But more importantly, by projecting each drug to the space of its influence on disease driver genes, we propose the biological mechanism of unexpected effects of drugs on disease phenotypes. We show that drugs sharing downstream predicted biological effects share known biology (i.e., gene targets), supporting the potential of our method to provide insights into the biology of unexpected drug effects on disease. Using Draphnet to map a drugs known molecular effects to their downstream effect on the disease genome, we put forward disease genes impacted by drug targets, and we suggest new grouping of drugs based on shared effects on the disease genome. Our approach has multiple applications, including predicting drug uses and learning about drug biology, with potential implications for personalized medicine. Author summaryMedications can impact a number of cellular processes, resulting in both their intended treatment of a health condition, and also unintended harmful or beneficial effects on other diseases. We aim to understand and predict these drug effects by learning the network connecting the biological processes altered by drugs to the genes driving disease. Our model, called Draphnet, can predict drug side effects and indications, but beyond prediction we show that it is also able to learn a drugs expected effect on the disease genome. Using Draphnet to summarize the biological impact of each drug, we put forward the disease genes impacted by drugs or drug targets. For instance, both anti-inflammatories and some PPAR-agonists share downstream effect on the cholesterol ester transfer protein (CETP), a gene previously experimentally supported as an effector of fenofibrate. Our approach provides a biological basis for drug repurposing, potentially accelerating clinical advances.