A pleiotropic–epistatic entangelement model of drug response

•Drug response involves multifaceted features, mediated by genes.•Each feature is pleiotropically linked with another.•We frame a pleiotropic–epistatic entanglement model for drug response.•This model provides a generic tool to chart pharmacogenetic architecture. Because drug response is multifactorial, graph models are uniquely powerful for comprehending its genetic architecture. We deconstruct drug response into many different and interdependent sub-traits, with each sub-trait controlled by multiple genes that act and interact in a complicated manner. The outcome of drug response is the consequence of multileveled intertwined interactions between pleiotropic effects and epistatic effects. Here, we propose a general statistical physics framework to chart the 3D geometric network that codes how epistasis pleiotropically influences a complete set of sub-traits to shape body–drug interactions. This model can dissect the topological architecture of epistatically induced pleiotropic networks (EiPN) and pleiotropically influenced epistatic networks (PiEN). We analyze and interpret the practical implications of the pleiotropic–epistatic entanglement model for pharmacogenomic studies.