Specific alterations in human DNA have been shown to raise the likelihood of getting epilepsy, according to the biggest genetic study of its type, which was managed by the International League Against Epilepsy and involved researchers from FutureNeuro at RCSI University of Medicine and Health Sciences.
The study, which was published on August 31st, 2023 in Nature Genetics, makes significant advancements in the understanding of how epilepsy arises and could assist in the creation of novel therapies for the condition.
There are several varieties of epilepsy, a common brain disease believed to have a hereditary component and can run in families. In this study, researchers compared the DNA of 52,500 individuals without epilepsy to several groups of almost 30,000 individuals with epilepsy. The variations revealed regions in the human DNA that could have a role in the emergence of epilepsy.
The scientists discovered 26 unique regions in human DNA that seem to be connected to epilepsy. This number included 19 unique to a type of epilepsy known as “genetic generalized epilepsy” (GGE). Additionally, they were able to identify 29 genes inside these DNA areas that are likely causing epilepsy.
The researchers discovered that when ‘focal’ and ‘generalized’ epilepsies were compared with one another, the genetic pattern was very different. The findings also revealed that part of the risk for generalized types of epilepsy is accounted for by proteins that transmit electrical impulses through the spaces between neurons in the human brain.
Gaining a better understanding of the genetic underpinnings of epilepsy is key to developing new therapeutic options and consequently a better quality of life for the over 50 million people globally living with epilepsy.”
Gianpiero Cavalleri, Professor, Human Genetics, RCSI School of Pharmacy and Biomolecular Science
He added, “The discoveries we report on here could only be achieved through international collaboration, on a global scale. We are proud of how the global community of scientists working to better understand the genetics of the epilepsies have pooled resources and collaborated effectively, for the benefit of people impacted the condition.”
The researchers also demonstrated that several epileptic drugs in use today function by focusing on the same epilepsy risk genes identified in this study. However, the researchers were able to suggest a few suitable substitute medications based on their findings.
As they are often used for other disorders, they will need to be clinically evaluated before being used to treat epilepsy, but they are known to target some of the other epilepsy risk genes discovered.
This identification of epilepsy associated genetic changes will allow us to improve diagnosis and classification of different epilepsy subtypes. This in turn, will guide clinicians in selecting the most beneficial treatment strategies, minimizing seizures.”
Colin Doherty, Study Co-Author and Clinical Investigator, SFI FutureNeuro Centre
Doherty is also a consultant neurologist at St James’s Hospital.
The study was conducted by more than 150 researchers from Europe, Australia, Asia, South America, and North America. They collaborated as a part of the Consortium on Complex Epilepsies of the International League Against Epilepsy (ILAE).
Researchers established the ILAE Consortium in 2010 after realizing that the complexity of the genetic and environmental variables that underlie epilepsy will necessitate study across enormous datasets and, as a result, unprecedented global collaboration.
Cavalleri added, “Undertaking such a comprehensive study is a remarkable achievement that RCSI and Futureneuro are proud to have played a leading role in. The challenge now is to translate the findings of this research to improve the lives of people with epilepsy.”
Professor Samuel Berkovic from University of Melbourne stated, “With this study, we have bookmarked parts of our genome that should be the major focus of future epilepsy research. It will form the basis for further work looking at the molecular pathways involved in seizure generation, neuronal dysfunction and altered brain activity.”
Professor Helen Cross, President of the International League Against Epilepsy, further stated, “This is a major milestone for the ILAE Consortium on Complex Epilepsies, demonstrating what can be achieved when scientists openly collaborate and share data from across the world. The outputs are wide-reaching and applicable to epilepsy patients globally.”
International League Against Epilepsy Consortium on Complex Epilepsies (2023). GWAS meta-analysis of over 29,000 people with epilepsy identifies 26 risk loci and subtype-specific genetic architecture. Nature Genetics. doi.org/10.1038/s41588-023-01485-w