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Ashkenazi Jewish Genes Linked to Crohn's

Human intestine, illustration.

As part of their study, investigators compiled a catalog of genetic variants in this population that alter the sequences of all known genes. This approach is known as whole exome sequencing.

"This data resource is a genetic treasure trove that will help the research community around the world study genetic diseases," said Dermot McGovern, MD, PhD, FRCP(Lon), director of Translational Medicine in the Cedars-Sinai F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute. "It has the potential to help clinicians screen and identify patients with increased risk for Crohn’s disease. It also provides a catalogue of other heritable diseases that are found at higher frequencies in the Ashkenazi Jewish population."

McGovern was co-senior author of the multi-institution research study, published in the journal PLOS Genetics, which examined the genetics of 18,745 individuals, including 5,685 Ashkenazi Jewish people. The study focused on Crohn’s disease, an autoimmune inflammatory disease of the intestinal tract, as well as several rare diseases found at higher rates among Ashkenazi Jews.

With ancestry in northern European Jewish groups, Ashkenazi Jews are two to four times as likely to suffer from Crohn's disease as non-Jewish peoples of European and African-American descent, according to a 2012 study published in PLOS Genetics.

Dermot McGovern, MD, PhD, FRCP(Lon)

For the new study, investigators scoured the exomes in their sample population of Ashkenazi Jews, looking for associations and links with Crohn’s disease. They found 10 variations of the NOD2 and LRRK2 exomes that are associated with increased risk for Crohn’s and are more likely to occur among Ashkenazi Jews.

The study suggested there may be subtle differences in the underlying mechanisms that predispose to Crohn’s disease in this population compared with non-Jewish populations—a finding that may have important implications as more precise or personalized approaches to managing Crohn’s disease become possible, McGovern said.

In addition, the study found substantially higher frequencies of exome variations associated with other diseases that develop more frequently among Ashkenazi Jews, including Gaucher, Canavan and Tay-Sachs diseases.

These enriched genetic risk factors of the Ashkenazim appear to originate in a history of migrations, catastrophic reductions in population and then repopulation from a small number of surviving founder families over many centuries, explained McGovern, a professor of Medicine. The effect was to concentrate the genetic variations in a comparatively small population.

"The goal of our study was to quantify the known elevated risk of this genetically unique group for certain heritable diseases and to aid in the future screening and treatment for Crohn's and other rare diseases," McGovern said. "We now have a comprehensive understanding of the exome of the Ashkenazi Jewish population—in effect, an imprint left by history on their genetic architecture."

Stephan R. Targan, MD, director of the F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute and professor of Medicine, and research scientist Talin Haritunians, PhD, at Cedars-Sinai were among the study's co-authors. In addition to McGovern, the other co-corresponding authors were associated with the Broad Institute of MIT and Harvard in Cambridge, Massachusetts; Stanford University in Stanford, California; the Icahn School of Medicine at Mount Sinai in New York; Massachusetts General Hospital in Boston; and the University of Helsinki in Helsinki.

Funding: Research reported in this article was supported in part by The Leona M. & Harry B. Helmsley Charitable Trust and the National Institutes of Health under award number 5 U54 HG003067-13.

The IRB numbers for human subjects in research referenced in this article are 3358 and 28224.