An international research team led by Cleveland Clinic has developed the first polygenic risk score that can distinguish on a cohort level between patients with epilepsy and controls, as well as between patients with generalized and focal epilepsies. The team’s findings, published in Brain, come from the largest study of epilepsy genetics to date and hold promise for improved diagnosis and treatment of epilepsy.
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Typically, physicians diagnose epilepsy after more than one unprovoked seizure. Development of the polygenic risk score could facilitate earlier, more accurate diagnosis and allow physicians to better pinpoint the epilepsy type at seizure onset, thus allowing earlier and more effective therapeutic interventions.
“Distinguishing between focal and generalized epilepsy has been difficult, particularly during the early stages of epilepsy development, but making an accurate diagnosis is of critical importance, given some differences in therapies and prognosis,” says study co-author Imad Najm, MD, Director of Cleveland Clinic’s Epilepsy Center. “This risk score helps us solve a long-standing clinical problem. Validation of these results will aid clinical decision-making in patients with suspected epilepsy.”
Genetic variants in epilepsy
Rare genetic de novo variants in any of dozens of genes can cause rare neurological disorders that present with seizures, including severe early-onset forms of epilepsy. In addition, large deletions can increase the risk for epilepsy with mild cognitive problems up to sevenfold. Both types of variants have clear impact on clinical practice.
In contrast, such variants are absent for common epilepsy, and therefore genetic testing has not been indicated in the setting of common epilepsy.
While genome-wide association studies (GWAS) have identified several common genetic variants for epilepsy, it is challenging to quantify an individual’s genetic risk based on these variants due to small or modest effect sizes. In contrast, the polygenic risk score — a single, quantitative representation of the effect sizes of thousands of variants — could demonstrate predictive ability.
For many other medical conditions, including myocardial infarction, diabetes, breast cancer and neuropsychiatric disorders, recent research studies have shown that polygenic risk scores are predictive and could prove helpful in clinical settings. The new study in Brain was the first to examine these scores in the context of epilepsy. Genetic data were drawn from Cleveland Clinic’s Epilepsy Center, the Epi25 Collaborative (the largest epilepsy research network in the world) and additional sites around the world.
Largest study of epilepsy genetics to date
Principal investigator Dennis Lal, PhD, a researcher in Cleveland Clinic’s Genomic Medicine Institute and Epilepsy Center, and collaborators combined all known common genetic variants identified from several large GWAS cohorts — two independent, one clinically ascertained and three biobanks — to calculate the individual polygenic risk for epilepsy for more than 8,000 people with epilepsy and 622,000 population controls.
Once generalized and focal polygenic risk scores were derived, individual scores were assessed in controls versus people with epilepsy, as well as in people with generalized versus focal epilepsy. The researchers used a variety of statistical methods to test the ability of the polygenic risk score to identify significant differences among cohorts and to account for diagnostic methodology and ethnicity.
Study results allowed the team to identify cohorts that bore a significantly higher genetic predisposition to epilepsy. Results also showed that people with generalized epilepsy carry a significantly greater number of common genetic risk variants than people with focal epilepsy.
“The potential for clinical implications here should not be understated,” says Dr. Lal, who led the work along with first author Costin Leu, PhD, a computational biologist in Cleveland Clinic’s Genomic Medicine Institute. “The fact that we can now identify people at high risk for epilepsy — and even start to distinguish between the two main types of epilepsy — based on genetic scores is really exciting. These landmark results set the stage for an entirely new direction of epilepsy research.”
Toward inclusion in clinical practice
The researchers hope to one day replicate these results in a prospective setting. They also note that the available cohorts had a strong Eurocentric bias, which they say underscores the need for greater population diversity in future GWAS studies.
“While additional research is necessary, we believe these findings will lay the groundwork to one day use genetic risk assessments in the clinic to diagnose common epilepsies and guide precision treatment earlier in the disease process,” concludes Dr. Najm.