Study of Ashkenazi Origins Will Improve Personalized Medicine

Ten million Ashkenazi Jews learned this week that they are all 30th cousins, after a study led by Columbia Engineering’s Itsik Pe’er determined that modern-day Ashkenazi Jews are descended from 350 ancestors living in medieval Europe.

The data answer longstanding questions about the population’s history, but the study’s main goal is medical.

For Ashkenazi Jews, the data amplify the power of personalized genomics in the clinic, says Lorraine Clark, PhD, one of the study’s co-authors and associate professor of pathology & cell biology and co-director of the Personalized Genomic Medicine Laboratory at CUMC. About half of the study’s participants had participated in a prior study of Parkinson’s genes conducted by Dr. Clark.

“The fantastic thing about this study is that it provides a genomics reference panel for the Ashkenazi Jewish population for the first time,” says Dr. Clark.

A reference panel—a collection of genomes from healthy people—is necessary when clinicians examine a patient’s genome for clues to the illness. Geneticists compare the patient’s genome with those in the panel to see which of the patient's variants are benign and which are potentially pathogenic. Knowing the genetic cause of a patient’s disease can, in some cases, guide physicians to the most effective treatment for that patient.

“If the variant isn’t in the reference panel, it may be pathogenic,” Dr. Clark says. But because the Ashkenazi genome differs from the general European genome, “looking into a largely European reference panel can lead to false alarms. The benign variants of the Ashkenazi population are not represented in the European panel, so what the physician thinks is causing disease may just be a benign variant.”

The new Ashkenazi reference panel is more powerful at filtering out the benign variants and eliminates about 70 percent of these false alarms.

Not all genes and gene variants that cause disease are known, and the new data will help researchers find variants associated with such complex diseases as schizophrenia, Parkinson’s, diabetes, and cancer.

“The Ashkenazi Jewish population has already been a powerful resource in the search for genes,” says Dr. Clark, who first identified the Parkinson’s gene glucocerebrosidase in an Ashkenazi population. That gene has since been confirmed as a Parkinson’s risk factor in several other ethnic groups.

Such genes, though discovered in Ashkenazi Jewish populations, are expected to be linked to disease in other populations, as well as to aid the search for new treatments for everyone.

“What’s unique about the Ashkenazi genome data is we can now identify those missing variants that contribute to common diseases,” Dr. Clark says. “We can’t do that in the general U.S. population, because we can’t see what’s noise and what’s associated with the disease. In the Ashkenazi Jewish genomes, there is less variation from person to person, and it’s easier to spot the genes that increase disease risk.”

The genomes of other isolated populations, such as Icelanders and the Amish, are also combed for genes linked to disease, but the large size of the Ashkenazi population—combined with the homogeneity of their genomes—eases the search.

The study was conducted by the Ashkenazi Genome Consortium (Dr. Clark is a founding co-member) and published online Sept. 9 in Nature Communications.