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A new gene has been found that increases the risk of schizophrenia in Ashkenazim

The research continues the discoveries of the late Prof. Ariel Darbasi who searched for the genetic link to schizophrenia as well as researching other serious genetic diseases common among the Ashkenazi Jews, who at a certain period numbered only a few hundred families and after that, the genetic defects of these families spread throughout the population

schizophrenia. Illustration: depositphotos.com
schizophrenia. Illustration: depositphotos.com

The late Prof. Ariel Derbsi, who served, among other things, as the head of the department of genetics at the Hebrew University, and then as the head of the major for life sciences and biology, was one of the well-known researchers in the field of genetics who passed away recently. Until the day of his death (September 28.9.18, 2002), he was looking for the genetic link to schizophrenia in the genetics department at the university. In XNUMX he reported A research team led by Bo discovered a gene called COMT which is one of the causes of the disease, and suggested basing the gene mapping for schizophrenia on the Ashkenazi population. In 2013, a joint team with him and American researchers found a gene that indicates an increased risk of mental disorders among Ashkenazi Jews. the research, whose findings were published in Nature Communications, revealed that mutations in the NDST3 gene region in Ashkenazi Jews up 40% their risk of having schizophrenia, schizoaffective disorder, or manic-depressive disorders. The studies were carried out on large samples.

a year later, A significant study was published in the journal Nature, in which it was reported that 108 genes were found to be involved in the development of schizophrenia, of which 83 genes were not revealed before. The study included a rare international research collaboration in its scope, in which hundreds of researchers from around the world took part, including 140 thousand participants, and is considered one of the most comprehensive studies done to date in the field of mental illness. Approximately 37 DNA samples from schizophrenia patients were compared with DNA samples from 113,075 people who do not have the disease, a large sample that allowed researchers to discover another significant part of the genetic basis of schizophrenia. "We hope for similar discoveries in the future," said Prof. Darbasi in an interview at the end of 2013.

During the last few years, until the year of Prof. Darbasi's death, several other works in the field were published. However, even after his death, Prof. Darbasi's research continues to receive exposure, creating excitement in the world of science. In a new study in which Prof. Darbasi took part, which was published recently, in which Prof. Shai Karmi from the School of Public Health at the Hebrew University also participated, another gene was found that may indicate an increased risk of mental disorders among Ashkenazi Jews (a genetically very homogeneous population). According to the study, the findings of which were published in the prestigious journal Neuron, it appears that a variant in the PCDHA3 gene in Ashkenazi Jews significantly increases their risk of suffering from the disorder of schizophrenia. The mutation in the gene damages the function of the protein, and can interfere with the creation of normal neuronal networks.

pcdha3 protein: The p.asn559ser variant causes mismatching of the pcdha3 protein and disrupts homophilic aggregation in vitro. Courtesy of the Hebrew University
pcdha3 protein: The p.asn559ser variant causes mismatching of the pcdha3 protein and disrupts homophilic aggregation in vitro. Courtesy of the Hebrew University

During the study, the genomes of 786 people with schizophrenia and 463 people who served as a control group - a group of healthy people - were sequenced. The study showed that a mutation in the PCDHA3 gene appeared in five patients but not in the healthy group. Also, the study found 141 genes that had mutations in at least three patients, and were not observed at all in healthy people, with the expectation that at least some of them will be discovered in the future to be related to the disease. The main finding is that a significant part of these genes belongs to a gene family called 'cadherins' - proteins that are found on the cell membrane and are responsible for the attachment of cells to one another, therefore they have a role in creating tissue structure, including in the brain. "The mutation we identified is of low frequency, so it is difficult to accurately estimate the relative risk of carriers of developing schizophrenia. On the other hand, findings from laboratory experiments on cell lines strengthen the argument that this is a real risk factor," Dr. Karmi explains this week.

The researchers focused on particularly rare variants found after sequencing the genome. It was found that among the patients, all of them Ashkenazi Jews, there were more cases of very rare genetic changes, especially those expected to affect the sequence of the encoded proteins. In addition, despite the relatively small sample in this study, the researchers were able to reproduce associations between certain genes and schizophrenia, previously only found in much larger samples. "In addition to our main findings regarding PCDHA3 and genes related to it, we were able - due to the unique characteristics of the Ashkenazi population - to go back and verify a number of previous findings we discovered about schizophrenia despite the relatively small size of the sample", described researcher Prof. Todd Lentz, one of the leaders of the study.

The study further substantiates the claim that there is an advantage to adopting the Ashkenazi Jewish population as a model for identifying and locating rare genetic changes associated with diseases. Prof. Shai Karmi explains: "The genetic similarity we see between each pair of Ashkenazi Jews indicates that about 20-30 generations ago, the size of this population was very small, genetically equal to only a few hundred. We showed in the article we edited that if one of those Ashkenazi 'founders' had a mutation that increases the risk of schizophrenia, the mutation had a relatively high chance of surviving to this day, despite the severe disease it may cause. Therefore, the chance of discovering such a mutation in the study conducted on Ashkenazim also increases, despite the relatively small sample."

The prevalence of schizophrenia in the general population is 0.3-0.7%, with the prevalence in males being slightly higher, but there are differences in the time of its onset and its characteristics. The patients are characterized by delusions, hear voices or see sights that do not exist, often lose social interest in their immediate environment, and suffer from cognitive decline. The accepted assumption attributes 80% of the origin of the disease to genetic predisposition alongside environmental factors. It is now clear to experts in the field that this is the effect of many genetic factors involved in the development and functioning of the brain. Therefore, it is difficult to locate the specific genes associated with it. Prof. Derbsi himself devoted many years to the development of the methods and the mapping of the genes related to schizophrenia, but his important work was interrupted by enmity.

"This article fulfills the vision of the late Prof. Ariel Darbasi, who promoted the use of the Ashkenazi population with its unique genetic characteristics, as a tool to identify genes for complex diseases," explains Prof. Shagib Shipman, his student and colleague in the Department of Genetics at the Hebrew University. "The ability to identify a certain gene for schizophrenia and the understanding of its mechanism of action can lead us to find targets that will be used to create new drugs to treat schizophrenia."

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