New genetic links have been found by the largest whole-exome sequencing study of epilepsy to date that examined 54,000 human exomes, about 21,000 were patients with epilepsy and 33,000 controls.
They found that genes encoding ion channels showed strong association with multiple epilepsy subtypes, including epileptic encephalopathies and generalized and focal epilepsies. Most of the study’s other discoveries are subtype specific, highlighting distinct genetic contributions to different epilepsies.
“These genetic insights provide data-driven starting points for unraveling the biology of the epilepsies, which in turn should help spur future, subtype-tailored advances in diagnosis and treatment,” said co-lead author, Benjamin Neale, PhD, co-director of the Stanley Center for Psychiatric Research at the Broad Institute of MIT and Harvard.
The study was published in Nature Neuroscience, the research involved the Epi25 Collaborative, and was led by Neale and Samuel Berkovic, MD, Laureate Professor in the department of medicine at the University of Melbourne and director of the Epilepsy Research Center at Austin Health in Australia.
The Epi25 Collaborative is a group of over 200 researchers 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, now nearly double than previous studies.
The findings of this study point to effects in how neurons communicate, suggesting potential targets for new therapies.
The researchers write, “Top candidate genes are enriched for roles in synaptic transmission and neuronal excitability, particularly postnatally and in the neocortex. We also identify shared rare variant risk between epilepsy and other neurodevelopmental disorders. Our data can be accessed via an interactive browser, hopefully facilitating diagnostic efforts and accelerating the development of follow-up studies.”
Epilepsy is one of the most common neurological disorders. Scientists have long known that genetics play a major role in risk of the condition, but pinpointing specific genetic contributions has been slow. Epilepsy also has several subtypes. The developmental encephalopathies have been connected to several genes, but other forms of the disease are less well understood.
Epi25 has collected information from patients with multiple types of epilepsy since 2014, including a severe group that includes developmental and epileptic encephalopathies, as well as the more common and milder genetic generalized epilepsy and non-acquired focal epilepsy (NAFE).
To find genes that strongly contribute to subtypes, the researchers searched the participants’ exomes for “ultra-rare” variants, or URVs—mutations found less than once per 10,000 participants. If these variants are found more often in people with epilepsy than in those without, or in one type of epilepsy than another, they are more likely to play a role in disease.
The researchers analyzed every gene in the protein-coding region of the genome from people across the world with a range of different genetic ancestries. The study’s 54,000 participants included about 21,000 patients with epilepsy and 33,000 controls.
The exomes revealed connections between disease risk and several genes involved in the transmission of signals across the synapses between neurons. In particular, genes coding for ion channel protein complexes, such as receptors for the neurotransmitter GABA, play a major role in epilepsy risk across subtypes.
Summary-level data from the study are available via the Epi25 WES Browser, an interactive browser hosted by the Broad Institute, allowing clinicians to look up variants seen in their patients and facilitating follow-up studies.
