A systems biology approach to genetic studies of complex diseases.

Revealing mechanisms underlying complex diseases poses great challenges to biologists. The traditional linkage and linkage disequilibrium analysis that have been successful in the identification of genes responsible for Mendelian traits, however, have not led to similar success in discovering genes influencing the development of complex diseases. Emerging functional genomic and proteomic ('omic') resources and technologies provide great opportunities to develop new methods for systematic identification of genes underlying complex diseases. In this report, we propose a systems biology approach, which integrates omic data, to find genes responsible for complex diseases. This approach consists of five steps: (1) generate a set of candidate genes using gene-gene interaction data sets; (2) reconstruct a genetic network with the set of candidate genes from gene expression data; (3) identify differentially regulated genes between normal and abnormal samples in the network; (4) validate regulatory relationship between the genes in the network by perturbing the network using RNAi and monitoring the response using RT-PCR; and (5) genotype the differentially regulated genes and test their association with the diseases by direct association studies. To prove the concept in principle, the proposed approach is applied to genetic studies of the autoimmune disease scleroderma or systemic sclerosis.