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Filtering the genetic information of schizophrenia

It is known that schizophrenia has a significant genetic component. But when looking for certain genes that cause the disease, a difficulty is encountered. The disease is affected by many genes, but the effect of each gene by itself is small

Prof. Eitan Domani and Dr. Livi Herzberg. Genetic spelling errors. Photo: Weizmann Institute
Prof. Eitan Domani and Dr. Livi Herzberg. Genetic misspellings. Photo: Weizmann Institute

It is known that schizophrenia has a significant genetic component. But when looking for certain genes that cause the disease, one encounters a difficulty: indeed, one can find hundreds of genes associated with the development of schizophrenia, but each of them individually increases the chance of the disease only negligibly. hall, New findings - which emerged thanks to a collaboration between scientists from the Weizmann Institute of Science and their colleagues from the "Shalvat" mental health center, and the Aiken School of Medicine in "Mount Sinai", New York - may point to a way out of this complication.

Disease-encoding genes are usually identified as part of genome research. The identification is carried out by comparing genetic segments of thousands of subjects - sick and healthy - and searching for small differences, one "sign" that appears in each subject in one of two versions. If, for example, one variant appears more frequently in schizophrenia patients, compared to the rest of the population, one can start to ask whether the same difference is related to the disease. But, when there are hundreds of possible candidates, the data starts to look like "noise", as it is difficult to determine with certainty whether this or that difference is indeed a mistake in the "word", or whether it is an alternative spelling. In fact, many of the replaced letters in the genome of schizophrenia patients appear in "non-coding" regions - that is, in segments of the genome that do not contain instructions for making proteins, but are responsible, for example, for regulating protein levels. This fact burdens the research, since it is difficult to identify the function of these segments under laboratory conditions. Dr. Libby Herzberg - who received a qualified degree under the guidance of Prof. Eitan Domani from the Department of Physics of Complex Systems at the Weizmann Institute of Science, after which she studied for a PhD and at the same time completed her medical studies, and now specializes in psychiatry in "Shalvata" - she decided to face these difficulties.

schizophrenia. Illustration: shutterstock
schizophrenia. Illustration: shutterstock

Dr. Herzberg and Prof. Domani, in collaboration with Prof. Vahram Harutonian from "Mount Sinai", studied the genetic basis of mental illnesses. In Prof. Harotonian's laboratory there is a database, collected from a large number of brains donated to research, including brains of schizophrenic patients. The scientists measured the levels of messenger RNA produced by the various genes, and combined this data with the genetic information - to understand how the "spelling errors", which were found to be related to schizophrenia, affect the functioning of a wide variety of brain cells. By cross-referencing messenger RNA level data from Prof. Harutonian's database with the list of genes related to schizophrenia identified as part of the genome research, the scientists were able to create a filter, through which they could identify the genetic segments where the slight spelling errors are associated with the disease, and were also uniquely expressed in the brain.

After filtering, the scientists analyzed the reduced list of genes. Methods developed by Prof. Dumani over the years - and with the help of which the actions of several genes are examined together (instead of testing each gene separately) - have proven themselves: out of the many genes that came up in the genetic research, the scientists identified 19 genes, whose messenger RNA levels behave in a manner Similar in schizophrenia patients. This finding implies the existence of cooperation between those 19 genes.

But what exactly does this group of genes do - after all, they can behave and act in hundreds of ways, thereby influencing in thousands of ways? To answer this question, a further analysis of the data was conducted, from which it emerged that the group of genes identified by the scientists is related to the functioning of the cells' calcium channels. Nerve cells rely on these channels, located in their membranes, to regulate the absorption of calcium ions - a mechanism that stimulates the cells to action. Cross-checking the results of the tests with data from the field of genome research, and with databases regarding protein behavior, confirmed their findings.

"These findings strengthen the concept that calcium regulation plays a central role in schizophrenia," says Dr. Herzberg. "The genetic interrelationships we uncovered may indicate targets to which it will be possible to target drugs effectively." Prof. Domani adds: "In the next step we will try to understand exactly how the regulation of calcium signals goes wrong
During the course of the disease, and to answer this question, further research is needed." The scientists hope that these findings and insights will help in the future to develop advanced tools for diagnosing and treating schizophrenia patients.

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