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Hirschsprung's Disease Genetic Analysis Reveals Mix of Common, Rare Risk Variants

NEW YORK (GenomeWeb) – Genetic factors that contribute to a highly heritable developmental condition called Hirschsprung's disease include a complex suite of risk variants, ranging from common polymorphisms in non-coding elements to rarer coding variants and copy number variants (CNVs), according to new research from investigators at Johns Hopkins University, the University of Washington, the Broad Institute, and New York University.

"In our study, we found that the risk of the complex phenotype that is Hirschsprung's disease stemmed from a combination of variants in numerous genes and different classes of genetic variants: non-coding variants, single-nucleotide variants, and copy number variants, and both rare and common variants," senior and corresponding author Aravinda Chakravarti, director of the NYU School of Medicine's Center for Human Genetics and Genomics, and his colleagues wrote.

Chakravarti and his colleagues used array-based genotyping and exome sequencing to search for variants associated with Hirschsprung's disease, comparing 190 individuals with the enteric nervous system disease to 627 unaffected controls. The analysis, published online today in the New England Journal of Medicine, not only highlighted the gene pathways and functional groups that were recurrently impacted in Hirschsprung's disease patients, but also pointed to the longer-term possibility of developing risk scores for better classifying disease cases.

"Our primary goal was to enable genetic stratification of patients in order to determine how genetic susceptibility manifests in clinical disease and its penetrance," the authors wrote. "Such genetic stratification could be used to determine whether post-surgical outcome — for example, continued bowel dysfunction and enterocolitis, which is reported in 30 to 50 [percent] of patients — is related to genotype."

Hirschsprung's disease is marked by unusual bowel features and gastrointestinal problems such as enterocolitis or fecal incontinence, the team explained, often appearing in combination with other symptoms in a manner that may reflect specific syndromes. But despite prominent heritability, the condition has been linked to many different low- and high-penetrance risk variants that have been incompletely characterized.

With that in mind, the researchers focused on 190 Hirschsprung's disease cases and 627 unaffected controls, including 404 participants in the 1000 Genomes Project 223 so-called "pseudo-controls" — parental chromosomes that were not transmitted to the affected children.

Comparing these cases and controls led them to four non-coding elements that contained common variants in more than 48 percent of Hirschsprung's disease cases, but just 17.1 percent of controls.

But rarer variants differed in prevalence between individuals with or without the disease as well: Nearly 35 percent of cases carried rare coding variants in two dozen genes from enteric neural-crest fate pathways compared to 5 percent of controls. Some of those genes had been implicated in Hirschsprung's disease previously, though several were newly associated with the condition.

Likewise, the team's analyses of CNVs indicated that large, relatively high-risk CNVs turned up in more than 11 percent of the Hirschsprung's disease patients, but just 0.2 percent of unaffected controls.

One gene was particularly prone to structural or regulatory changes in individuals with Hirschsprung's disease, the team reported. More than 72 percent of the patients had alterations in the receptor tyrosine kinase-coding gene RET, while those types of changes were found in fewer than half of the unaffected controls. 

"[M]ost of the risk of Hirschsprung's disease arose from a common widespread genetic susceptibility, on top of which rare coding and rare copy number variants exacerbated the risk," the authors explained. "Despite this molecular diversity, the implicated genes clustered, on the basis of their known function, into gene regulatory networks … a model that may be relevant to the understanding of other complex disorders."

In a related editorial in NEJM, Allan Goldstein, a pediatric surgery researcher at Massachusetts General Hospital, and Nancy Cox, a genetic medicine researcher at Vanderbilt University Medical Center, called the study "a reminder of the critical lessons learned and insights gained through discovering the complexity behind what once appeared to be simple."

"[F]rom a fundamental biology perspective, this study reveals new genes and regulatory elements with roles in the development of the enteric nervous system, a remarkably well-orchestrated process that builds a complex, intrinsic nervous system in the gut (also known as 'the second brain')," Goldstein and Cox wrote.