Pharmacogenomic network analysis of the gene-drug interaction landscape underlying drug disposition

In recent decades the identification of pharmacogenomic gene-drug associations has evolved tremendously. Despite this progress, a major fraction of the heritable inter-individual variability remains elusive. Higher-dimensional phenomena, such as gene-gene-drug interactions, in which variability in multiple genes synergizes to precipitate an observable phenotype have been suggested to account at least for part of this missing heritability. However, the identification of such intricate relationships remains difficult partly because of analytical challenges associated with the complexity explosion of the problem. To facilitate the identification of such combinatorial pharmacogenetic associations, we here propose a network analysis strategy. Specifically, we analyzed the landscape of drug metabolizing enzymes and transporters for 100 top selling drugs as well as all compounds with pharmacogenetic germline labels or dosing guidelines. Based on this data, we calculated the posterior probabilities that gene i is involved in metabolism, transport or toxicity of a given drug under the condition that another gene j is involved for all pharmacogene pairs (i, j). Interestingly, these analyses revealed significant patterns between individual genes and across pharmacogene families that provide insights into metabolic interactions. To visualize the gene-drug interaction landscape, we use multidimensional scaling to collapse this similarity matrix into a two-dimensional network. We suggest that Euclidian distance between nodes can inform about the likelihood of epistatic interactions and thus might provide a useful tool to reduce the search space and facilitate the identification of combinatorial pharmacogenomic associations.