World’s largest epilepsy study reveals ‘genetic architecture’ and points to new therapies

More than 29 thousand patients were analyzed and 26 areas of the genome associated with the disorder were identified; Brazil was the only Latin American representative through the Brazilian Institute of Neuroscience and Neurotechnology of the State University of Campinas.

By Luciana Constantino  |  Agência FAPESP – Considered the largest genetic study of epilepsy in the world, a study published in the journal Nature Genetics reveals specific alterations in DNA that signal a greater risk of the brain disorder. Identifying these alterations will improve diagnosis and advance the possibility of new treatments for the disease.

The researchers identified 26 different areas (loci) of the genome that are linked to epilepsy, with 29 genes thought to play an important role in the disorder. Of these genes, 17 were associated with epilepsy for the first time; ten are linked to the development of the disease when mutated or altered (known as monogenic epilepsy genes) and the other seven are known to already have approved drugs that focus on treating autism spectrum disorders.

Analysis of the subtypes revealed significantly different “genetic architectures” mainly between two subtypes of epilepsy – focal and generalized – and common variations in DNA can explain between 39.6% and 90% of the genetic risk for the latter type.

Coordinated by a consortium of the International League Against Epilepsy (ILAE) involving more than 350 scientists, the study compared data from 29,944 people with the disease to those of 52,538 control subjects. It included epilepsy cases of European (92%), African (3%) and Asian (5%) descent.

Brazil was the only Latin American representative through the Brazilian Institute of Neuroscience and Neurotechnology (BRAINN), a FAPESP Research, Innovation and Dissemination Center (RIDC) based at the State University of Campinas (UNICAMP).

“We at BRAINN were involved in all stages of the work, from the detailed characterization of the patients from a clinical, imaging and neurophysiological point of view – which we’re very good at – to planning the analyses, suggesting how they could be carried out and then checking the results. We were also actively involved in writing the article, which was submitted to the journal over a year ago. Many international studies exclude patients from Brazil because we have such great genomic diversity. However this study did a meta-analysis, which allows us to combine populations with different genomic structures. For the future, we want to expand this diversity even more,” Iscia Teresinha Lopes-Cendes, a professor at UNICAMP’s School of Medical Sciences and co-author of the BRAINN article, told Agência FAPESP.

There are an estimated 2 million Brazilians with epilepsy, at least 25% of whom are uncontrolled, according to the Ministry of Health. Worldwide, the World Health Organization (WHO) estimates that 50 million people are affected by the disorder, a third of whom are resistant to the treatments available on the market.

A highly hereditary neurological disease with no cure, epilepsy causes seizures, up to 40 or 50 a day in the most severe cases, leading to loss of consciousness and falls. Uncontrolled seizures not only disrupt the patient’s daily routine but also pose a serious risk of sudden and premature death.

Treatment involves a combination of medications, which are not always effective. Most medications reduce the activity of neurons across the board, which controls seizures, but they have side effects. An alternative is surgery to remove the part of the brain affected by the malformation.

Now, the researchers are proposing some medications that are normally used for other conditions, but act on the epilepsy risk genes identified in the study.

Knowledge over time

Recognizing the complexity of the genetic and environmental factors related to epilepsy, the consortium was formed in 2010 to collaborate on investigating large datasets at an international level.

“This is an important milestone for the ILAE Consortium on Complex Epilepsies and shows what can be achieved when scientists collaborate openly and share data from around the world,” said the league’s president, Professor Helen Cross, in a press release.

To arrive at the results suggesting different genetic architectures between focal and generalized forms of epilepsy, genetic data were combined with databases of phenotypic information, expanding the sample to more than 51,600 patients and 1 million “controls.” This discovery of the different genetic framework for the different types of epilepsy provides clues to understanding the various syndromes.

In their work, the scientists point out that the proteins that carry electrical impulses through the gaps between the brain’s neurons are part of the risk for generalized forms of epilepsy. In this sense, they emphasize the importance of accurately characterizing or classifying specific epileptic syndromes (syndromic phenotyping) in order to better understand the genetic basis of the disease.

An advocate of studies with so-called “pure data,” Lopes-Cendes says that she is now working specifically on mesial temporal lobe epilepsy (MTLE) with hippocampal atrophy. “We’ve been continuously generating data for specific research on the topic. I’d argue that in certain studies, mixing information from different types of epilepsy can ’dilute’ the data and not highlight results that might appear if the group of patients studied was more homogeneous. I think a balance is needed,” she adds.

In early 2023, the researcher and her group published another article that deepened our understanding of MTLE, considered the most common and refractory to pharmacological treatment, by evaluating, for the first time, the profile of messenger RNA (mRNA, a molecule that contains the information for the production of proteins) from surgical tissue obtained from patients.

Because of her work in genetics, Lopes-Cendes was recently invited by the WHO to join the new Technical Advisory Group on Genomics (TAG-G), which is responsible for contributing to the process of accelerating access to genomic knowledge and technologies, especially in low- and middle-income countries. The group consists of 15 scientists from different countries.

The article “GWAS meta-analysis of over 29,000 people with epilepsy identifies 26 risk loci and subtype-specific genetic architecture” can be read at: www.nature.com/articles/s41588-023-01485-w.