Identification of risk genes for schizophrenia–gene variants provide new clues to biological causes of mental illness

The problem lies with the synapses: Until now, the genetic causes of schizophrenia were largely unknown, but now two research teams have identified ten rare risk genes and 287 other genes with less effect. These findings highlight the biological mechanisms underlying schizophrenia and provide new starting points for treatment of previously incurable mental illness, scientists report in Nature.

About 20 million people worldwide suffer from schizophrenia. typical of this mental illness hallucinationsParanoia, disorders of self-consciousness and self-awareness. Although these symptoms can be relieved with psychiatric medications, schizophrenia cannot be cured – also because its biological causes are not clear. There are many indications that the disease has a strong genetic component, with 60 to 80 percent of it being hereditary. But only so far Some dangerous genetic variants and determine its effects.

“Mental disorders have so far been a black box – we know very little about disease mechanisms,” explains Targinder Singh of the Broad Institute at MIT and Harvard University.

Look for clues in the genome

Two studies of the genome now provide important insights. Because they show which genetic variants increase the risk of schizophrenia, which genes lie in and how strong the effect is. Importantly, together, both studies shed light on the molecular mechanisms that get out of control in schizophrenia. “The results obtained in a global collaboration represent an important advance in our understanding of the causes of schizophrenia,” comments Joshua Gordon, director of the US National Institutes of Mental Health (NIMH).

To this end, the first team led by Vasily Trubetskoy of Charité – Universitätsmedizin Berlin conducted a genome-wide comparison study with more than 76,700 schizophrenics and 243,600 control subjects. The researchers looked for genetic variants in the form of altered individual DNA bases, which occurred significantly more often in the people tested who were sick — and thus represent potential risk genes for schizophrenia.

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287 mutations in 120 genes

In fact, the researchers found what they were looking for: They identified 287 different types of genes in about 120 genes that occur most frequently in patients with schizophrenia. “This represents a significant increase in the number of loci associated with schizophrenia,” Trubetskoy and colleagues wrote. Each of these mutations increases the risk of disease by only a small percentage, and is therefore very small. However, these genetic variants are very common in those affected.

More detailed analyzes revealed that the mutations are mainly concentrated in genes that are active in neurons of the nervous system and that control basic processes there, including synapses – switching points in the brain where electrical nerve signals are passed via chemical messages. However, at the same time, these genetic variants are distributed almost throughout the brain. “This indicates that abnormal neural function in schizophrenia is limited to a few brain structures,” the researchers say.

Ten very high risk genes

A second study by Singh and his collaboration with SCHEMA provides deeper insights. Instead of comparing the entire genome, they just compared the protein-coding genes of 24,200 people with schizophrenia and more than 97,000 healthy controls. They specifically looked for rare but very dangerous genetic mutations that produce defective or abbreviated proteins. As a result, these proteins can only perform their function to a limited extent or not at all.

The result: The team identified changes in ten genes in patients with schizophrenia that significantly increase the risk of developing the disease. “Usually the chance of a person developing schizophrenia in their lifetime is less than 1 percent,” says co-author Benjamin Neal of Massachusetts General Hospital. “But if you have one of these rare mutations, the risk increases to 10, 20 or even 50 percent.”

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clamp malfunctions

The 10 new risk genes provide additional clues to any abnormality that leads to schizophrenia. Two of these genes, GRIN2A and GRIA3, are closely related to the structure and function of synapses. The two genes control the docking point of transmitter glutamate, which has long been suspected to be involved in the brain hyperexcitability of patients with schizophrenia.

The GRIN2A gene is also more active in the young brain. This may explain why schizophrenia usually appears at this age. Other genes influence transcriptional regulation or play a role in recycling unused proteins into neurons. “Identifying these 10 genes is a huge advance in schizophrenia research because each of them now provides a strong starting point for biological research,” says Neal.

Two approaches, gene matching

In addition, the results of the two studies overlap somewhat: some of the genetic variants discovered by Trubetskoy and his team are also present in the 10 risk genes discovered by the second research group. “In fact, we were hoping to find some overlap between common and rare risk variants,” says Neal. “The fact that we have now found this strengthens the assumption that schizophrenia is closely related to the function of synapses.”

At the same time, these results also confirm the suspicion that genetic variants with strong and weak effects can certainly start from the same genes and biological mechanisms – and in extreme cases accumulate.

Hope for better treatments

It has not been clarified exactly what all risk genes and genetic variants do in the brain, and how they promote the onset of schizophrenia. According to the scientists, the new findings open valuable starting points for further deciphering the biological basis of schizophrenia – and thus possibly finding better treatments for the disease.

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“Realistically, it will take us a few years to translate these findings into concrete biomarkers and treatments that can improve the lives of sufferers,” says Stephen Heymann of the Broad Institute. “But it is very motivating that we now see a clearer path to get there.” (Nature, 2022; doi: 10.1038/s41586-022-04434-5; doi: 10.1038/s41586-022-04556-w)

Source: Broad Institute of MIT and Harvard, Cardiff University

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