A large international study revealed the keys to the genetic origin of schizophrenia

Schizophrenia is a serious mental disorder that affects 24 million people worldwide. That is, one in 300 people will live with this ailment throughout their lives. The drama of this disease goes beyond its own associated consequences - it has a two to three times greater probability of premature death -, since research has for years been a kind of black box that prevented progress in its treatment.

Now, two studies published by the scientific journal Nature, achieved a milestone in this field, as they discovered specific genes that are involved in the development of the disease. On the one hand, an international scientific team, with participation from 45 countries, associated this disorder with a failure in synapse communication (the union between neurons).

According to the authors, this is the largest genetic study in history of this psychiatric disorder, in which analyzed the DNA of 76,755 people with schizophrenia and 243,649 without it to better understand the genes and biological processes that support this disorder - the analysis included more than 7,000 people of African-American or Latino descent.

The study by the Psychiatric Genomics Consortium (PGC), led by Cardiff University, in the United Kingdom, and with Spanish participation, discovered a much larger number of genetic links with schizophrenia, in 287 different regions (loci) of the genome.

The team stated that this global study sheds “the strongest light” on the genetic basis of schizophrenia. “Previous research had shown associations between schizophrenia and many anonymous DNA sequences, but it has rarely been possible to link findings to specific genes,” researcher Michael O'Donovan, from Cardiff University, explained in a statement.

Not only did the present study greatly increase the number of these associations, but it was now possible to “link many of them to specific genes, a necessary step in what remains a difficult path towards understanding the causes of this disorder and the identification of new treatments”.

Specifically, the team found a “substantial increase” in the number of genomic regions associated with schizophrenia and within these regions identified 120 genes likely to contribute to the disorder. Although there are a large number of genetic variants involved in schizophrenia, the study showed that they concentrate on genes that are expressed in neurons, pointing to these cells as the most important site of pathology.

The results also suggest that the abnormal functioning of neurons in schizophrenia affects many areas of the brain, which could explain its various symptoms, which may include hallucinations, delusions, and trouble thinking clearly.

The work “clearly reveals that the origin of this disease lies in alterations in the development of the nervous system, something that was not known until now,” said the Spanish University of Granada, which is participating in the study: the work opens the door to new drugs that modulate the neurotransmitter called glutamate.

In another study also published in Nature, prepared by the SCHEMA Consortium (Schizophrenia Exome Meta-Analysis) and scientists from the Broad Institute from MIT and Harvard, in the United States, extremely rare genetic mutations were identified that alter proteins in 10 genes and that significantly increase the risk of developing schizophrenia.

With a sample of 24,248 people with schizophrenia and 97,322 without it, the group of researchers identified that those with schizophrenia had an “ultra-rare” variation in 10 specific genes, which increased the risk of a person developing schizophrenia. These variants, which they have called PTV (Protein Truncanting variants), prevent cells from producing their complete protein. In addition, they pointed to a relationship between the disease and 22 other damaged genes.

It is these malfunctions in the genes that cause the synapse to malfunction, something that, in 2016, researchers also from the Broad, Harvard and Boston Children's Hospital had already identified. However, in their case, they focused on a single gene, C4, which would cause excessive “pruning” of the synapse, triggering the risk of schizophrenia.

The new study focuses, among others, on the GRIN2A and GRIA3 genes, which are responsible for coding parts of the glutamate receptor, a neurotransmitter that is present in 90% of brain synapses and acts as a mediator of sensory, motor, cognitive, emotional information, as well as the formation of memory and its recovery.

Glutamate had already been identified as potentially implicated in the development of schizophrenia (also in other neurodegenerative diseases, such as Alzheimer's), but there is now solid genetic proof of this. In addition, GRIN2A activity peaks in the brain during adolescence, the stage at which people usually have the first symptoms.

Taken together, these papers highlight an emerging view of schizophrenia as a failure in communication at the synapse (the union between neurons) and illustrate how different types of genetic variation affecting the same genes can influence the risk of different genes psychiatric and neurodevelopmental disorders.

Professor James Walters, director of the MRC Center for Neuropsychiatric Genetics and Genomics at Cardiff University, stated: “We hope that the results of this study and those accompanying it will serve to advance the understanding of the disorder and facilitate the development of radically new treatments.”

As Benjamin Neale, one of the authors responsible for the SCHEMA study, points out, both projects converge into similar groups of genes and biological mechanisms, which patents that there is “a relationship between synaptic biology and the risk of schizophrenia”. “Our hope was that we would end up with a certain amount of overlap in the stories,” says the researcher.

Knowing the mechanisms of schizophrenia, science is one step closer to achieving a treatment that manages to curb the progression of the disease, although there is still more progress in its mechanisms.

With information from EFE

KEEP READING: