World study finds genetic factors that explain the cause of schizophrenia

The explanation of the cause of schizophrenia has made a great advance. Based on an unprecedented worldwide study, researchers analyzed thousands of samples of human genomes and observed 120 genetic variations that may be directly associated with psychiatric illness. A large part of these variations, according to estimates, can represent up to 24% for the development of the disorder.

The research was published in the prestigious journal Nature and was carried out by the PGC (Psychiatric Genomics Consortium). The investigation involved thousands of researchers around the world. In Brazil, a group of psychiatrists and biomedical doctors from Unifesp (Federal University of São Paulo) took part in the study.

Due to its global nature, the research had the unprecedented feat of compiling the largest number of global samples of human genomes for analysis aimed at schizophrenia. In total, more than 300,000 of these samples made up the experimental group (which has the disease) and the control group (which does not have this diagnosis).

Most of the study focused on the analysis of common variants, those that are normal to occur in the population and, therefore, are not considered mutations.

“These common variants differ by a single DNA base, which is made up of four bases — adenine, thymine, guanine and cytosine. These bases are interspersed throughout the genetic sequence, but at specific points in our genome these locations can vary from person to person. So, while in that same position I have an adenine, someone may have guanine. That’s what makes them different”, says Sintia Belangero, professor in the morphology and genetics department at Unifesp and one of the main researchers at the article.

This type of analysis focused on common variants consists mainly of associating them with some trait that the researchers want to investigate — in this case, it was schizophrenia —, comparing the control and experimental groups that make up the study.

“You take a scan of the genome, considering millions or thousands of variants, and associate one by one of these variants with the phenotype”, explains Belangero.

From there, it was possible to observe the regions of the genome involved with the disease. The study found, in total, 287 of these regions for schizophrenia.

After that, the researchers carried out further analyzes in these regions in order to identify which genes would really be associated with the origin of the disease, in order to further specify the factors related to the disorder. “Regions are like neighborhoods, and the genes are the streets”, exemplifies the researcher.

One of the methodologies used for this part of the research is called Mendelian randomization, in which a fine mapping is made that allows both observing the regions and “inferring causality, that is, which of the genes has a causal relationship with the disease”.

With techniques like these, the researchers were able to identify the 120 genes that really have a strong association with schizophrenia and that can explain up to 24% of its etiology (cause of a disease).

“On average, 80% of the cause of schizophrenia is attributed to genetics. A strong contributor is these common variants that were investigated in the study and, through calculations, it was estimated that they comprise up to 24% of this total. 80%”, says the teacher.

The tools used by the study also made it possible to identify that the 120 genes act mainly in neurons, which are important cells in the brain. This finding, according to Belangero, further highlights the relationship between genes and schizophrenia as they are expressed primarily in brain cells and may reinforce the association with psychiatric illness.

However, in addition to the common variants, a part of the study also investigated the issue of those considered rare variants, that is, which are mutations.

In this case, it was necessary to perform DNA sequencing of the genomes, a method different from the association method performed for the common alterations.

It was through this analysis that the scientists found another interesting point: the mutations associated with schizophrenia were similar to those seen in autism.

“These genes that we found in this article have already been described as involved with autism, making this another indication that schizophrenia has a genetic share with this other disease”, says Belangero.

The findings made by the research, in addition to being an important advance in understanding the causes of schizophrenia, could be useful in the future for medical practice. Currently, says Belangero, there are no medical tests to support diagnoses of psychiatric illnesses, making it “very important to understand more and more of the etiology [desses distúrbios] so that one day we can get closer to a more accurate diagnosis”.

Another point is that investigations to understand the cause of a disease can help advance the so-called personalized medicine in which the treatment is changeable depending on the condition of each patient.

“Although schizophrenia is treatable, it does not work for everyone. So, if we know a person’s genetics well, it is possible to develop individualized and personalized treatments”, adds the professor.

It’s not all just genetics

The genetic factor is the most important to explain the cause of schizophrenia, but not only. “Schizophrenia is a complex disease, that is, it has genetic and environmental factors involved”, says Belangero. It is precisely for this reason that it is not possible to state that the findings made in the study are the only factors for someone to develop schizophrenia.

Environmental aspects, for example, involve several types, such as the development of the person during childhood, the urban context in which he lives and, mainly, the excessive use of marijuana.

Even though they are important for understanding another side of the cause of the disease, Belangero points out that they remain secondary. “Environmental factors for schizophrenia are important, but we know that the biggest contribution is genetics”, he concludes.