Integrative genomics strategies to elucidate the complexity of drug response

Abstract

Pharmacogenomic investigation from both genome-wide association studies and experiments focused on candidate loci involved in drug mechanism and metabolism has yielded a substantial and increasing list of robust genetic effects on drug therapy in humans. At the same time, reasonably comprehensive molecular data such as gene expression, proteomic and metabolomic data are now available for collections of hundreds to thousands of individuals. If these data are structured in a statistically robust and computationally tractable way, such as a network model, they can aid in the analysis of new pharmacogenomics studies by suggesting novel hypotheses for the regulation of genes involved in drug metabolism and response. Similarly, hypotheses taken from these same models can direct genome-wide association studies by focusing the genome-wide association studies analysis on a number of specific hypotheses informed by the relationships customarily seen between a gene’s expression or protein activity and genetic variation at a particular locus. Network models based on other sorts of systematic biological data such as cell-based surveys of drug effect on gene expression and mining of literature and electronic medical records for associations between clinical and molecular phenotypes also promise similar utility. Although surely primitive in comparison with what will be developed, these model-based approaches to leveraging the increasing volume of data generated in the course of patient care and medical research nevertheless suggest a huge opportunity to improve our understanding of biological systems involved in pharmacogenomics and apply them to questions of medical relevance.