gene networks underlie disease?

The Scientist | "It is an important discovery," said Constantin Polychronakos, an endocrinologist at the McGill University Health Center who was not involved in the study. "Instead of looking at individual genes and trying to make sense out of it, they were looking at whole networks of genes."

Many common diseases have an exceedingly complex genetic architecture, with a multitude of genes interacting with each other and the environment to result in disease. Genome-wide association (GWA) studies, however, a widely-used method for unraveling the genetic underpinnings of disease, focus on the incredibly small portion of the DNA -- the less than 1 percent of the genome that varies among individuals. This approach identifies genetic variants that seem to be associated with particular diseases, but these variants often play only a minor role in the development of disease, and their physiological effects remain largely unknown.

"You have a relationship between a genetic variant and the associated disease, but you don't really know what it's doing," explained Norbert Hubner, a geneticist at Max Delbrück Center for Molecular Medicine (MDC) in Berlin and one of the authors of the paper.

Hubner and his colleagues examined seven different rat tissues for individual variations in the expression levels of various transcription factors. Then, using a predictive statistical approach, they could identify which gene variants likely led to those differences in transcription factor expression.

They identified one particular transcription factor that they decided to investigate further. Interferon regulatory factor 7 (IRF7) was active in the majority of the rat tissues studied and is known to be a key regulator of inflammatory processes. It seemed to be the central player of a network of more than 300 genes involved in inflammatory processes and which appeared to be active in macrophages -- immune cells known to be critical participants in inflammation and the development of autoimmune disorders -- as as well as their precursors, monocytes. The team thus dubbed this network IRF7-driven inflammatory network, or IDIN for short.

To determine whether a similar network was operating in human monocytes, the researchers used previously collected data on gene expression and GWA studies in humans to identify an analogous network.

"We found the same network in both human populations [we looked at]," said coauthor Enrico Petretto, a computational biologist at Imperial College London. "There was very significant overlap between rats and humans." Notably, many of the human genes were known factors in type 1 diabetes (T1D).