Stanford research points to chance as cause of genetic diseases in Ashkenazi Jews

STANFORD, Calif. - A population of Jewish people known as the Ashkenazi Jews have an unusually high risk of several genetic diseases, and up until now, no one has understood why. Was it random chance that made mutations so common or did evolution play a role in keeping mutations around?

The answer to this question, said researchers at Stanford University Medical Center, appears to be chance. Their findings appear in the March online issue of the American Journal of Human Genetics and in the journal's April print edition.

Some disease mutations unusually common in Ashkenazi Jews, who make up 90 percent of the American Jewish population, include Tay-Sachs disease and some forms of breast cancer, high cholesterol and hemophilia. Four of these disorders, including Tay-Sachs disease, are in a class of diseases called lysosomal storage diseases. People with these disorders lack enzymes that break down toxins into harmless compounds. Instead, the toxins are stored in cellular compartments called lysosomes, where they can build up to high levels and eventually damage the cell.

'It's been known for a long time that Ashkenazi Jews have a high risk of these lysosomal storage diseases,' said Neil Risch, PhD, professor of genetics, statistics, and health research and policy at the School of Medicine and one of the senior authors on the study. 'The majority opinion has been that there must be some selective advantage for those mutations.'

Researchers had suspected that lysosomal storage diseases may be similar to sickle cell anemia, in which people who carry two mutated copies of the gene have a disease, but those who inherit one copy of the mutation are protected against malaria. Those people - called carriers - are more likely to be healthy, have more children and pass their mutation on to future generations.

If carriers of lysosomal storage mutations were protected against other diseases, then those mutations should be more common in Ashkenazi Jewish populations than mutations that cause diseases unrelated to lysosomal storage. Risch and his colleagues analyzed DNA sequences from Ashkenazi Jewish people and compared how common mutations were in lysosomal storage disease genes vs. other disease genes.

The researchers found that mutations in lysosomal storage disease genes are no more common than mutations that cause other inherited diseases in the Ashkenazi Jewish population. This suggests that carriers for lysosomal storage mutations had no benefit over their peers. Instead, Risch said, these mutations were probably present in the Jews who coalesced into the Ashkenazi Jewish population 900 years ago.

'The mutations that persisted represent whatever the people who had the most children happened to be carrying,' Risch said. It just happened that those who founded the Ashkenazi Jewish population had disease mutations and passed them along to their children. Because Ashkenazi Jews tend to marry within their own population, those mutations remained common.

Risch also looked at the regional distribution of mutations in Ashkenazi Jews, and the age of those mutations. He found three points in time when mutations entered the population. One mutation has been in the Jewish population for 120 generations - around the time that the Jewish people formed a distinct population in the Middle East. This mutation causes a type of hemophilia called Factor 11 deficiency type II.

The majority of the mutations - including all of the mutations in lysosomal storage genes - entered the population when the Ashkenazi Jews formed a coherent group about 50 generations ago. The final mutations cropped up in the Lithuanian Ashkenazi Jews about 12 generations ago.

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