Earlier this year, Aravinda Chakravarti, Ph.D., a professor in the Johns Hopkins University School of Medicine’s McKusick-Nathans Institute of Genetic Medicine, and colleagues reported the results of a new genomewide association study of Hirschsprung’s disease. One of their findings was a variant in a gene called Ret that had not been previously associated with the disease. The protein Ret codes for and interacts with proteins that guide developing nerve cells in the human gut as they grow toward their final targets. 

For the new study reported at the meeting, Chatterjee and others in Chakravarti’s laboratory zoomed in on the regulatory DNA surrounding the Ret gene. “Hirschsprung’s is a very well-studied genetic disease, yet the variants found in genes can’t account for all cases we see,” Chatterjee explains. “That’s why we thought the regulatory areas surrounding important genes might be part of the explanation.”

The research group compared the genetic markers of more than 350 people with Hirschsprung’s disease and more than 700 healthy controls to find single-letter changes in DNA near Ret that appeared to be associated with the disease. In the lab, they studied how those genetic variations affected DNA’s ability to bind proteins that lead to gene expression. They also genetically modified mice to have similar changes to see what the effects would be. Chatterjee is expected to report that the team identified three common variants that, in combination, raise the odds of having Hirschsprung’s disease by fourfold compared with people with none of the variants. One in every 5,000 babies is born with Hirschsprung’s disease, a disorder marked by bowel obstruction that can be fatal if not treated surgically. The disease arises early in development, when nerves that should control the colon fail to grow properly. Those nerves are part of the enteric nervous system, which is separate from the central nervous system that enables our brains to sense the world.

The genetic causes of Hirschsprung’s disease are complex, making it an interesting case study for researchers like Chakravarti. His research group took on the condition in 1990, and in 2002, performed the first-ever genomewide association study to identify common gene variants linked to the disease.

Chatterjee notes that the results of genomewide association studies of many complex diseases have, as with Hirschsprung’s, failed to paint a complete picture of the genetic causes of those conditions. This study adds to evidence that homing in on regulatory regions surrounding genes that are known to be important in those diseases could be an important next step, he says.

Aravinda Chakravarti is supported by the National Institute of Child Health and Human Development (grant number HD28088).

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