Largest-Ever Genetic Study on Epilepsy Uncovers Potential Therapeutic Paths

One of the largest and most diverse studies to date on genetic factors related to epilepsy has revealed potential new treatment targets.

Researchers from the Broad Institute of MIT and Harvard found that the genetic factors identified were associated with how neurons communicate and fire, suggesting ways that future treatments could be tailored to patients’ genomes.

The study is published in Nature Neuroscience.

Probing links between genetics and epilepsy

Approximately 50 million people worldwide have epilepsy, making it one of the most common neurological conditions. It is a seizure disorder, causing sudden burst of electrical activity in the brain that lead to seizures or fits.

Genetics play a major role in determining epilepsy risk, but so far researchers haven’t been able to identify all the specific genetic contributions, mostly focusing on one or a few genes at a time.

In the new study, the researchers used whole-exome sequencing to investigate every protein-coding gene. Over 54,000 participants took part in the study, led by researchers Benjamin Neale, co-director of the Stanley Center for Psychiatric Research at the Broad Institute, and Samuel Berkovic, a professor of medicine at the University of Melbourne.

“For a complex and heterogeneous disorder like epilepsy, we really wanted to survey as comprehensive a sample as possible across a wide range of genetic variation,” said Siwei Chen, the lead author of the study and postdoctoral researcher in Neale’s lab.

Searching for ultra-rare variants

The new work came from a group of over 200 researchers called the Epi25 Collaborative. Epi25 collects information from patients with various types of epilepsy, from severe types known as developmental and epileptic encephalopathies to milder types like genetic generalized epilepsy.

The study focused on “ultra-rare” gene variants (URVs) found less than once per 10,000 participants, as these could be more likely to play a role in the condition if found more often in people with epilepsy or with a specific type of epilepsy.

Identifying the ultra-rare variants required analyzing DNA from across the globe with diverse genetic ancestries. In total, around 21,000 patients with epilepsy and 33,000 controls were analyzed.

The researchers found links between disease risk and genes involved in passing signals between neurons. Genes playing a major role in epilepsy risk across subtypes were those coding for ion channels, including receptors for the neurotransmitter GABA_A. While this trend was present for all subtypes, the specific variants contributing to mutations in ion channel proteins varied when looking at each subtype individually.

Next, the researchers combined data from genes with similar functions or that encode parts of the same protein complex. This allowed for an improved ability to focus on specific cellular pathways.

For example, patients with a subtype called non-acquired focal epilepsy (NAFE) showed a strong signal for the gene DEPDC5, which encodes a part of a protein complex called GATOR1, critical to brain cell function. This signal became even stronger after combining it with the two genes that encode the rest of the GATOR1 complex, indicating that it may be highly involved in a mechanism that contributes to NAFE.

The road to precision treatments

These findings could one day help to tailor treatment strategies based on a patient’s genetics, or group patients based on the biological effects of specific variants. The researchers say the findings could also improve genetic testing for epilepsy and clarify how genetic variation leads to disease.

"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."

Reference: Chen S, Abou-Khalil BW, Afawi Z, et al. Exome sequencing of 20,979 individuals with epilepsy reveals shared and distinct ultra-rare genetic risk across disorder subtypes. Nat Neurosci. 2024:1-16. doi: 10.1038/s41593-024-01747-8

This article is a rework of a press release issued by the Broad Institute. Material has been edited for length and content.