Metabolic Network Finds Disease Links

By building an extensive computer network of molecular relationships, researchers have been able to uncover links to diseases they never before suspected.

The genes that cause many diseases have been discovered. However, subtle shifts in the complex network of molecular interactions in the body can also cause disease. Some diseases, such as diabetes and obesity, or Gaucher disease and Parkinson’s disease, tend to affect people at the same time and are considered risk factors for each other, showing how extensive and interconnected this molecular network is. That’s why researchers have broadened the way they look at disease over the past few years, moving beyond single genes to consider multiple genes or proteins at the same time.

A research team led by Dr. Albert-László Barabási at Northeastern University, Dr. Nicholas A. Christakis at Harvard Medical School and Dr. Zoltan N. Oltvai at University of Pittsburgh set out to look at the relationships among metabolism-related diseases. They chose metabolic diseases because high-quality molecular interaction maps already exist for human cell metabolism, and earlier attempts at linking these diseases based on shared genes proved disappointing. The task was daunting: The cell’s metabolism involves thousands of molecules in a complicated network of biochemical reactions.

The researchers, funded by several NIH Institutes, pulled together information from 2 databases of known metabolic reactions and the molecules involved in them. They then related these to known gene–disease links from another database. Two diseases were considered connected if the products of their associated genes were involved in metabolic reactions with a common molecule.

In the July 22, 2008, issue of Proceedings of the National Academy of Sciences, the scientists reported that over 300 of the 1,437 disorders from the gene–disease database are related to at least one metabolic reaction. On average, a disease is connected in the metabolic disease network to about 5 other diseases. Most diseases have links to only a few others, but some appear as “hubs,” with links to many others. Hypertension, for example, has links to 27 other diseases.

To see whether the links in the metabolic disease network could predict which diseases occur together, the researchers analyzed the Medicare records of over 13 million elderly patients in the United States. They had a total of over 32 million hospital visits over the period 1990–1993. The scientists found that 31% of the diseases whose reactions are coupled in the network showed a statistically significant tendency to occur together—3 times more than the average for all diseases.

These results demonstrate how taking a broader approach to disease can give scientists a deeper understanding of the complex molecular shifts behind disease. The metabolic disease network uncovered a total of 193 pairs of diseases that are metabolically linked and tend to occur together. The network can expand as researchers identify more disease–gene associations and help uncover the metabolic origins of other diseases.

—by Harrison Wein, Ph.D.