Study of Ashkenazi Jewish Population Reveals New Schizophrenia Mutation

Researchers at The Feinstein Institutes for Medical Research, in collaboration with Columbia University, have identified a gene mutation that could result in schizophrenia, a chronic brain disorder that affects nearly one percent of the world’s population. The findings, published in today in Neuron, could lead to novel treatment strategies.

The research team, led by Todd Lencz, PhD, with Itsik Pe’er, PhD, Tom Maniatis, PhD, and Erin Flaherty, PhD, of Columbia University, carried out an innovative genetic study identifying a single letter change in the DNA code in a gene called PCDHA3 that is associated with schizophrenia. The affected gene makes a type of protein called a protocadherin, which generates a cell surface “barcode” required for neurons to recognize, and communicate with, other neurons. They found that the PCDHA3 variant blocks this normal protocadherin function. 

Past research has shown that genes play an important role in the disorder, but it has proven difficult to isolate individual genes that contribute substantial effects. These results indicate that further investigation into restoring communication between neurons could be a critical step in developing novel treatment options for schizophrenia.

The discovery was made possible by the special genetic characteristics of the samples studied by Dr. Lencz’s team; patients with schizophrenia and healthy volunteers drawn from the Ashkenazi Jewish population. The Ashkenazi Jewish population represents an important population for study based on its unique history. Just a few hundred individuals who migrated to Eastern Europe less than 1,000 years ago are the ancestors of nearly 10 million Ashkenazi Jews today. This lineage, combined with a tradition of marriage within the community, has resulted in a more uniform genetic background in which to identify disease-related variants.

“In addition to our primary findings regarding PCDHA3 and related genes, we were able– due to the unique characteristics of the Ashkenazi population – to replicate several prior findings in schizophrenia despite relatively small sample sizes,” said Dr. Lencz, professor in the Institute of Behavioral Science at the Feinstein Institutes. “In our study, we demonstrated this population represents a smart, cost-effective strategy for identifying disease-related genes. Our findings allow us to zero in on a novel aspect of brain development and function in our quest to develop new treatments for schizophrenia.” 

Schizophrenia, characterized by delusions, hallucinations and disorganized thoughts and behavior is one of the leading causes for disability in the United States. Schizophrenia usually requires lifelong treatment, including medication and psychosocial therapy. 

“Dr. Lencz’s research into the role of genetics in schizophrenia offers a major advance,” said Kevin J. Tracey, MD president and CEO of the Feinstein Institutes. “This work may open new avenues to developing therapeutics, which are sorely needed.”

Reference: 

Lencz, T., Yu, J., Khan, R. R., Flaherty, E., Carmi, S., Lam, M., Ben-Avraham, D., Barzilai, N., Bressman, S., Darvasi, A., Cho, J. H., Clark, L. N., Gümüş, Z. H., Vijai, J., Klein, R. J., Lipkin, S., Offit, K., Ostrer, H., Ozelius, L. J., … Pe’er, I. (2021). Novel ultra-rare exonic variants identified in a founder population implicate cadherins in schizophrenia. Neuron, 0(0). https://doi.org/10.1016/j.neuron.2021.03.004

This article has been republished from materials provided by Feinstein Institutes for Medical Research. Note: material may have been edited for length and content. For further information, please contact the cited source.