Advances in Epilepsy’s Genetic Makeup

By Lauren Arcuri

While it is now understood that epilepsy has a substantial genetic component, little is known about the specific genes responsible for the most common forms of the condition. To find new epilepsy genes, the largest study of its kind was undertaken by 150 researchers. The study, published in Nature Communications in December 2018, provides important clues about the complex genetic makeup of epilepsy and could lead to novel treatments. 

The International League Against Epilepsy (ILAE) Consortium on Complex Epilepsies compared the DNA of more than 15,000 people with epilepsy to the DNA of about 30,000 people without epilepsy. The results revealed 16 risk loci, or places in the genome where genetic changes are associated with epilepsy. Eleven of these had not previously been associated with the disease. 

Many people in the general population actually have these risk loci (also known as genetic variants), says Sam Berkovic, M.D., one of the co-authors of the study and laureate professor in the Department of Medicine at the University of Melbourne, Australia, but they are present in higher numbers in people with epilepsy. 

However, rather than “causing” epilepsy, each variant only slightly increases the risk of developing the disease. So if an individual has a lot of these variants, that raises their risk significantly, Berkovic says. That’s why geneticists are starting to use polygenic risk scores, in which combinations of genetic variants are considered together to estimate a person’s risk of developing various disorders. This study could help researchers develop a similar risk score for epilepsy, which would aid in diagnosis. 

“The hope is that the genes we identify will point to pathways in the brain that lead to epilepsy,” says Berkovic. “Once we identify those pathways, therapeutic interventions that target them can be developed.”

The Epilepsy Genetics Initiative (EGI), created by Citizens United for Research in Epilepsy (CURE), is also using genetic data to find individualized treatments for epilepsy. These researchers have created a centralized database that 
holds the exome sequence data of individuals with epilepsy. This data is analyzed and reanalyzed to find mutations that make a major contribution to a person’s epilepsy. 

“A lot more people with epilepsy are getting their genome sequenced,” says Erin Heinzen, Ph.D., a researcher in CURE, co-author of the Nature Communications study, and assistant professor at Columbia University’s Institute for Genomic Medicine. “But often the results are negative—there’s nothing there pointing to the cause of the disorder. The EGI was formed to pull that data into a research setting so that we can keep studying it. Three months from now, a new gene might be discovered that helps us pinpoint the cause of that person’s epilepsy.”

Originally printed in EpilepsyAdvocate, Spring 2019