Network and pathway expansion of genetic disease associations identifies successful drug targets

Abstract

It is widely accepted that genetic evidence of disease association acts as a sound basis for the selection of drug targets for complex common diseases and that propagation of genetic evidence through gene or protein interaction networks can accurately infer novel disease associations at genes for which no direct genetic evidence can be observed. However, an empirical test of the utility of combining these beliefs for drug discovery has been lacking. In this study, we examine genetic associations arising from an analysis of 648 UK Biobank GWAS and evaluate whether targets identified as proxies of direct genetic hits are enriched for successful drug targets, as measured by historical clinical trial data. We find that protein networks formed from specific functional linkages such as protein complexes and ligand-receptor pairs are suitable for even naive guilt-by-association network propagation approaches. In addition, more sophisticated approaches applied to global protein-protein interaction networks and pathway databases, also successfully retrieve targets enriched for clinically successful drug targets. We conclude that network propagation of genetic evidence should be used for drug target identification.