Largest-ever epilepsy genetic study uncovers possible therapeutic targets

The largest and most diverse study to date of the genetic drivers of epilepsy has revealed new potential targets for treatment, both common and unique to different epilepsy subtypes. The findings highlight factors involved in how neurons communicate and fire, suggesting potential targets for new therapies. In the future, the findings could also help doctors tailor treatments to a patient’s genome.

Epilepsy is one of the most common neurological disorders. Scientists have long known that genetics play a major role in epilepsy risk, but identifying all specific genetic contributions has proven difficult, and previous studies have focused on one or a few genes at a time. . Epilepsy also has several subtypes, and although a group called developmental encephalopathies is linked to several genes, other forms of the disease are less well understood.

The study, published in Natural neurosciencecomes from the Epi25 Collaborative, a group of more than 200 researchers from around the world working to uncover the genetic basis of epilepsy. It builds on previous work by the group using ever-larger cohorts of participants, which now number more than 54,000 people, nearly double previous studies.

The researchers, led by Benjamin Neale, co-director of the Stanley Center for Psychiatric Research at the Broad Institute of MIT and Harvard and core faculty member of the Analytical and Translational Genetics Unit at Massachusetts General Hospital; and Samuel Berkovic, professor of medicine at the University of Melbourne, used an approach called whole exome sequencing to examine every gene in the protein-coding region of the genome.

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

Ultra-rare variants

Since 2014, Epi25 has collected information from patients with several types of epilepsy, including a group of severe epilepsies called developmental and epileptic encephalopathies, as well as more common, milder forms called generalized genetic epilepsy and non-focal epilepsy. acquired (NAFE).

To find genes that contribute heavily to these subtypes, the authors searched participants’ exomes for “ultra-rare” variants, or URVs, mutations found less than once per 10,000 participants. If these variants are more common in people with epilepsy than in those who don’t, or in one type of epilepsy rather than another, they are more likely to play a role in the disease.

Because VURs are so rare and scientists wanted to understand many types of epilepsy, researchers analyzed the DNA of people around the world with a range of different genetic ancestry to find significant signals. The 54,000 study participants included approximately 21,000 epilepsy patients and 33,000 controls.

The exomes revealed links between disease risk and several genes involved in transmitting signals across synapses between neurons. In particular, genes encoding ion channel protein complexes, such as receptors for the neurotransmitter GABA_Aplay a major role in the risk of epilepsy across all subtypes. Although this trend was present for all subtypes, the specific variants contributing to ion channel protein mutations varied when examining each subtype individually.

To improve their ability to focus on specific cellular pathways, researchers grouped data from genes with similar functions or encoding parts of the same protein complex. For example, data from patients with NAFE showed a strong signal for the DEPDC5 gene, which encodes part of a protein complex called GATOR1 that is essential for brain cell function. Combining it in their analysis with the two genes that encode the rest of the GATOR1 complex, the signal became even stronger, indicating that GATOR1 may be strongly involved in a mechanism contributing to NAFE.

In the future, the findings could help doctors tailor treatment strategies based on a patient’s genotype or stratify patients based on the biological effects of specific variants. The researchers say the findings could also improve genetic testing for epilepsy and provide a clearer picture of how genetic variation leads to the disease.

“These genetic insights provide data-driven starting points for elucidating the biology of epilepsies,” said Neale, “which should in turn help drive future advances in diagnosis and treatment, tailored to sub-diagnosis. types.”

Study summary data is available through the Epi25 WES Browser, an interactive browser hosted by the Broad Institute, allowing clinicians to easily search for variants observed in their patients and facilitate clinical and translational efforts in follow-up studies.