The largest study of its kind has identified individual genes, gene sets, and gene variants that increase risk of developing epilepsy – vital discoveries to improve diagnosis and treatment for one of the most common neurological conditions .
A collaboration between 40 research groups around the world has released its collected data in an interactive web portal for further analysis. Understanding more about the genes linked to the condition can now allow more targeted investigation of the different mechanisms at play.
This is useful as epilepsy can vary greatly between people: in terms of its causes, its severity, and the way it manifests, making the condition difficult to study.
"Epilepsy has a prevalence of 4-10 per 1,000 individuals worldwide," write the researchers in their published paper.
"The role of genetic contributions to epilepsy has been long recognized, yet delineating the full range of genetic effects on the epilepsies remains a core challenge."
The team focused on the exomes in DNA molecules, the parts of our genetic code that directly encode the sequences of amino acids making up proteins. Variations in these exomes play a significant role in influencing disease risk in general, making them suitable for exploring potential links in epilepsy.
Through a process of whole-exome sequencing (WES) – carefully scanning the pieces of DNA most likely to be linked to disease – they compared the genes of 20,979 people with epilepsy to those of 33,444 people without the disorder.
The researchers looked for ultra-rare variants, or URVs: small changes in the coding of a gene that affect its production. If URVs are only present in people with epilepsy, it suggests they play a part in making us more vulnerable to it.
That led the team to seven specific genes, three gene sets (combinations of genes), and four specific variations inside genes – all biological clues in the mysterious case of how epilepsy gets established.
These variants occur in genes closely associated with neuron signaling, and with helping to keep the electrical pathways in the brain humming along at a healthy rate. It makes sense that disruption in these areas might lead to the seizures and other symptoms that come with epilepsy.
Comparing their results to other large-scale WES studies, the team also found strong evidence that rare variants that increase risk of epilepsy overlap with some that increase risk of other neurodevelopmental disorders.
Now the research can continue: looking into techniques through which these genes could be manipulated through treatments, and potentially preventing the brain's wiring from being disrupted in ways that cause epilepsy.
"The ongoing sequencing and genotyping efforts, together with the ever-increasing scale of genetic association studies, will continue to expand and refine understanding… ," write the researchers, "and hopefully enable a move toward more targeted treatment approaches."
The research has been published in Nature Neuroscience.