Researchers have discovered new genetic links to different types of epilepsy. The study, the largest and most diverse yet of the genetic factors that increase the risk for epilepsy, has also revealed new potential targets for treatment.

More than 200 researchers from the Epi25 Collaborative analyzed data from 54,000 participants — nearly double that of previous studies, according to the Broad Institute.

Epilepsy is one of the most common neurological disorders, and while scientists have long recognized that genetics plays a role in the development of the disorder, they haven’t been able to identify all the specific genes involved.

According to the Epilepsy Foundation, epilepsy is a brain disorder that causes recurring, unprovoked seizures. Doctors may diagnose epilepsy if a patient has two unprovoked seizures or one unprovoked seizure with a high risk of more. Seizures may relate to a brain injury or a family trait, but often the cause is completely unknown.

However, the new study, published in Nature Neuroscience, may have uncovered clues to the causes of the disorder. Researchers used a method called exome sequencing to uncover shared and distinct ultra-rare genetic risk across several epilepsy subtypes.  An exome is the part of a genome that contains the instructions for making proteins and is made up of all the exons in a genome.

The researchers, led by Benjamin Neale, co-director of the Stanley Center for Psychiatric Research at the Broad Institute, unraveled complicated genetic codes that predisposed individuals to epilepsy. The Epi25 group has been gathering information from patients with various types of epilepsy since 2014. These include both severe and milder forms of the disorder called genetic generalized epilepsy and non-acquired focal epilepsy (NAFE).

To identify the genes that contributed to these subtypes of epilepsy, scientists looked for “ultra-rare” variants, or URVs, in the exomes of the participants. These mutations occur less than once in 10,000 individuals and if they are found more often in people with epilepsy, they may play a key role in increasing the risk of the disease.   

The researchers uncovered genes that code for the receptors of the neurotransmitter GABAA and play a crucial role in increasing epilepsy risk among all subtypes. They also found that patients with NAFE shared a strong signal for the gene DEPDC5, says the Broad Institute. This gene is responsible for encoding part of a protein complex called GATOR1 that is important for brain function. When the other genes that encode GATOR1 were identified, the signal amplified suggesting that GATOR1 is likely involved in the mechanism that causes NAFE.

The researchers say that their findings may improve genetic testing for those with epilepsy and unravel underlying pathways that lead to disease and ultimately targeted treatment.

“These genetic insights provide data-driven starting points for unraveling the biology of the epilepsies,” said Neale, “which in turn should help spur future, subtype-tailored advances in diagnosis and treatment.”