A systems biology approach to drug discovery

Common human diseases like obesity and diabetes are driven by complex networks of genes and any number of environmental factors. To understand this complexity in hopes of identifying targets and developing drugs against disease, a systematic approach is required to elucidate the genetic and environmental factors and interactions among and between these factors, and to establish how these factors induce changes in gene networks that in turn lead to disease. The explosion of large-scale, high-throughput technologies in the biological sciences has enabled researchers to take a more systems biology approach to study complex traits like disease. Genotyping of hundreds of thousands of DNA markers and profiling tens of thousands of molecular phenotypes simultaneously in thousands of individuals is now possible, and this scale of data is making it possible for the first time to reconstruct whole gene networks associated with disease. In the following sections, we review different approaches for integrating genetic expression and clinical data to infer causal relationships among gene expression traits and between expression and disease traits. We further review methods to integrate these data in a more comprehensive manner to identify common pathways shared by the causal factors driving disease, including the reconstruction of association and probabilistic causal networks. Particular attention is paid to integrating diverse information to refine these types of networks so that they are more predictive. To highlight these different approaches in practice, we step through an example on how Insig2 was identified as a causal factor for plasma cholesterol levels in mice.