Genetic studies in humans, zebrafish, and mice have revealed how two different types of genetic variations team up to cause a rare condition called Hirschsprung's disease. The findings add to an increasingly clear picture of how flaws in early nerve development lead to poor colon function, which must often be surgically corrected. The study also provides a window into normal nerve development and the genes that direct it. The results appear in the April 2, 2015 issue of the American Journal of Human Genetics. Approximately one in every 5,000 babies is born with Hirschsprung's disease, which causes bowel obstruction and can be fatal if not treated. 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 Aravinda Chakravarti (photo), Ph.D., a Professor in the Johns Hopkins University School of Medicine's McKusick-Nathans Institute of Genetic Medicine, Director of the Center for Complex Genomics, and the 2008 President of the American Society of Human Genetics (ASHG). His research group took on the condition in 1990, and in 2002, it performed the first-ever genome-wide association study (GWAS) to identify common variants linked to the disease. But while Dr. Chakravarti's and other groups have identified several genetic variants associated with Hirschsprung's, those variants do not explain most cases of the disease. So Dr. Chakravarti and colleagues conducted a new GWAS of the disease, comparing the genetic markers of more than 650 people with Hirschsprung's disease, their parents, and healthy controls.
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