A gene increases the risk of schizophrenia in Ashkenazi Jews but can help identification of patients from other backgrounds

So have I been allotted months of futility; Nights of misery have been apportioned to me.




(the israel bible)

July 9, 2021

5 min read

Hebrew University courtesy photo of the late Prof. Ariel Darvasi

Prof. Ariel Darvasi – an esteemed Hebrew University of Jerusalem (HUJI) geneticist who died suddenly at the age of 56 three years ago – was a leading researcher who reached the conclusion there is an advantage to adopting the Ashkenazi Jewish population as a model for identifying and detecting rare genetic changes associated with disease.

The reason is that over many hundreds of years, Jews of Ashkenazi origin lived together and almost always married partners of the same origin, so it is a very genetically homogeneous population.

Darvasi, who was head HUJI’s genetics department and later served as head of the life sciences and biology department, was one of the most recently recognized researchers in genetics. In 2002, a research team he led discovered a gene called COMT that was one of the causes of schizophrenia and suggested basing the mapping of schizophrenia genes on the Ashkenazi population. 

In the prestigious journal Nature Communications, he revealed that mutations in the NDST3 gene region in Ashkenazi Jews increase their risk of developing schizophrenia, schizoaffective disorder (manic-depression or bipolar disorder) by 40%, and the studies were performed on large samples. 

A year later, a significant study was published in the journal Nature in which it was reported that 108 genes involved in the development of schizophrenia were found, of which 83 genes were not previously known. The study included a rare international research collaboration in which hundreds of researchers from around the world took part and encompassed 140,000 participants. Even today, it is considered one of the most comprehensive studies done to date in the field of mental illness. 

Some 37,000 DNA samples from schizophrenia patients were compared to DNA samples from 113,075 mentally healthy people – 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,” Darvasi said in an interview in late 2013. 

He was born in Chile and at the age of 10, he and his family moved to Israel and settled in Jerusalem. He obtained his bachelor of science degree in biology and computer science in 1988 and his master of science degree and his doctorate in genetics from  HUJI. Subsequently, he conducted post-doctoral research at The University of Paris.

As a young scientist, he won the Landau Prize, one of Israel’s highest honors for sciences. He published over 100 scientific articles.

In recent years, until the year of his death, a number of additional works in the field have been published. But even after he was gone, Darvasi’s research continues to gain exposure, creating excitement in the world of science. In newly published research in which Darvasi participated in which Prof. Shai Carmi from HUJI’s School of Public Health also participated, another gene was found that could indicate an increased risk of mental disorders among Ashkenazi Jews. The study, published in the prestigious journal Neuron under the title “Novel ultra-rare exonic variants identified in a founder population implicate cadherins in schizophrenia,” shows that a variant of the PCDHA3 gene in Ashkenazi Jews significantly increases their risk of developing schizophrenia.

During the study, the genome of 786 people with schizophrenia and 463 people who served as a control group – a healthy group of people – underwent gene sequencing. The study showed that a mutation in the PCDHA3 gene appeared in five patients but not in the healthy group. The study also 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 would be discovered in the future to be linked to the disease. 

The main finding is that a significant portion of these genes belongs to a family of genes called “cadherins” – proteins that are located on the cell’s membrane and are responsible for linking cells to each other and therefore have a role in creating tissue structure, including in the brain. 

“The mutation we identified is rare, so it is difficult to estimate exactly what the relative risk of carriers of schizophrenia is. On the other hand, findings from laboratory experiments in cell lines reinforce the notion that this is a real risk factor,” Carmi declared.

The researchers focused on particularly rare variants. It was found that among the patients – all Ashkenazi Jews – there were more cases of very rare genetic changes and especially those that were expected to affect the sequence of the encoded proteins. In addition, despite the relatively small sample in this study, the researchers were able to reconstruct links between certain genes and schizophrenia that were previously found only in much larger samples. “In addition to our main findings regarding PCDHA3 and related genes, we were able, due to the unique characteristics of the Ashkenazi population, to re-verify a number of previous findings on schizophrenia despite the relatively small size of the sample,” said researcher Prof. Todd Lenz of Hofstra University in New York. 

The study further substantiates the claim that there is an advantage to adopting the Ashkenazi Jewish population as a model for identifying and detecting rare genetic changes associated with disease in people of different origins around the world. “The genetic similarity we see between every pair of Ashkenazi Jews indicates that about 20 to 30 generations ago, the size of this population was very small, genetically equivalent to only a few hundred. We showed in our article that if one of those Ashkenazi ‘founders’ had a mutation that increased the risk of schizophrenia,” said Carmi, “the mutation had a relatively high chance of surviving to this day, despite the serious illness it could cause. Therefore, the chance of discovering such a mutation in a study conducted in Ashkenazi Jews also increased, despite the relatively small sample.” 

The prevalence of schizophrenia in the general population is 0.3 to 0.7%, with the prevalence in males being slightly higher, but there are differences in the time of onset and its characteristics. Patients are characterized by delusions, hearing voices or seeing images that do not exist. They also often lose social interest in their immediate environment and suffer from cognitive decline. The accepted assumption attributes 80% of the source of the disease to a genetic predisposition alongside environmental factors. It is now clear to experts in the field that this is due to the influence of very many genetic factors involved in the development and function of the brain. Thus, it is difficult to locate the specific genes associated with it. Darvasi himself spent many years developing the methods and mapping of the genes associated with schizophrenia but his important work was interrupted by his passing. 

“This article fulfills the vision of the late Prof. Ariel Darvasi who promoted the use of the Ashkenazi population with its unique genetic characteristics, as a tool for identifying genes for complex diseases,” stated Prof. Sagiv Shipman of HUJI’s Institute of Life Sciences and the Center for Autism, who was Darvasi’s student and colleague. “The ability to identify a particular gene for schizophrenia and an understanding of its mechanism of action can lead us to find targets that will be used to create new drugs for the treatment of schizophrenia.”

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