An article published in the magazine Nature and in the preparation of which scientists from Unicamp participated, presented the most complete study on the genetic architecture of epilepsies, a field that studies how the genetic bases of an organism's observable characteristics are distributed. With the collaboration of more than 350 authors from all continents, the research carried out a joint and multiethnic analysis of genetic data from almost 30 thousand patients with epilepsy – in addition to 50 thousand control patients – obtained from the bases of different groups that already worked with the topic and sought to answer questions such as how many and what are the places in the genome that are predisposed to the disease, in addition to knowing whether there are aspects in common between the different types of the disease.
Unicamp, the only institution in Latin America to participate in the study, did so through the Brazilian Institute of Neuroscience and Neurotechnology (Brainn), a multidisciplinary center focused on studying neurological diseases – especially epilepsy and strokes ( AVC) – and which is funded by the São Paulo State Research Support Foundation (Fapesp). To this end, Cepid Brainn, a Research, Innovation and Dissemination Center (Cepid), carries out investigations at different levels, such as in the areas of imaging exams, patient rehabilitation and genetics, with the aim of producing knowledge, training human resources and developing technology applied to improving the population’s quality of life.
According to Brainn researcher Íscia Lopes Cendes, one of the authors of the article, carrying out such a comprehensive analysis of the genetic architecture of epilepsy was only possible due to the extraordinary number of participants from different parts of the world, a fact quite relevant since the genetic constitution of individuals can differ according to their geographical origin. “Many of the previous studies regarding various diseases were carried out predominantly in European populations. This is the first time we have had a study, especially in the case of epilepsy, with such diverse populations,” she claims.
Unicamp contributed to the research with data generated by studies developed within Cepid-Brainn, as well as with expertise technique for carrying out statistical analyzes in the area of bioinformatics and for the analysis of genomic data, a specialty of Professor Cendes' laboratory. In addition, members of the institute participated in monthly meetings held by the International League Against Epilepsy (Ilae) – the first author of the study –, an entity formed in 2014 to discuss strategies for preparing the research, including corrections to direction, quality control mechanisms and even the writing of the article itself.
The research found that the genetic architecture of epilepsies is very complex, identifying 26 points in the genome that present robust statistical significance for predisposition to generalized epilepsy, a type of epilepsy that affects both sides of the brain. With this data in hand, the authors came up with a list of candidate genes to guide future studies on the disease, in addition to analyzing possible compounds with the potential to be used as medication to correct the gene expression signature, modified in patients with epilepsy.
Cendes recalls that this is a disease that affects between 1% and 2% of the world's population, of which a third do not respond adequately to currently available medications. “So this is a very interesting strategy because they came up with a list that can potentially be tested in different models and eventually in clinical studies because many of these compounds have already been approved for human use in the case of other diseases. This shortens the path to testing alternatives to the usual treatment of epilepsy, especially generalized epilepsies, for which there is no specific focus on where to perform surgery,” he explains.
On the other hand, the researchers did not find statistically relevant points in the genetic analysis for focal epilepsies – which originate on only one side of the brain. Even so, points were identified that suggest the possibility of a genetic location, which points to the need to continue studies on the topic. This is a line that Cendes has developed in his laboratory, with studies on mesial temporal lobe epilepsy, a type of focal epilepsy in which almost two-thirds of patients are highly refractory to drug treatment.
Although it does not have as many participants as the study recently published in Nature, the line that the researcher has been developing turns out to be very well characterized from a phenotypic point of view. The professor explains that a small variation in clinical presentation is something positive because it allows groups to be concentrated in order to facilitate the finding of relevant results. “These are different strategies. In one you study as many people as possible, what was done in this work Nature, and in another you refine the phenotype to see if you find something in a specific subgroup. So, we have been working a lot with this second strategy, that of refining the phenotype, which would be a continuation of this study that has just been published”, concludes the professor.