A Cleveland Clinic-led initiative has come up with a new risk scoring system for epileptic or seizure disorders of genetic origin. The researchers summed up the risks for a very large number of genes weakly implicated in some common forms of epilepsy, to create a polygenic risk score.
When applied to a large group of similar individuals, the score distinguished correctly between epileptic and healthy people, and also between epileptics with generalized and focal epilepsy victims. This could help develop personalized approaches to diagnosing and treating epilepsy. The study, published in the journal Brain, is the single largest piece of research on the genes involved in epilepsy so far. It is also the largest study ever to look at epilepsy on the basis of human genetic samples.
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About 1 in a hundred Americans suffers from epilepsy. When an individual develops a first seizure episode, it is a matter of high priority to know whether this is the beginning of a seizure disorder. Epilepsy is diagnosed when two or more seizures occur without provocation. In 94% of patients, the epilepsy is either generalized or focal.
In generalized epilepsy, both hemispheres of the brain are involved. In focal epilepsy, however, only one hemisphere is implicated in the abnormal electrical activity. However, this type of prediction is hard to make. This is why the current genetic risk scoring could be of great use in helping doctors to identify the patients who need to be put on medications to prevent the development of epilepsy in the future. Early intervention may be extremely useful in these cases.
Genes and epilepsy – is there a connection?
Epilepsy can be a disorder by itself or may be part of a brain disorder that presents with seizures. In about 40% of patients with the latter condition, a single rare mutation is to blame for the brain disorder in each case. These various conditions are now under the spotlight, with personalized therapies being developed to correct the dysfunctional genes.
On the other hand, in the more common forms of epilepsy that stand alone, genetic screening of large cohorts of patients using genome-wide association studies (GWAS) have been carried out in the hope of finding genes that help predict the individual’s risk of epilepsy. However, this is based on finding one variant that is commonly found – which leaves out other possible variants. Again, the small effect size found with these variants means that the possible value of the association found between a given gene variant and the risk of the epilepsy is low. These factors make it almost impossible to tell if any given patient with a history of a seizure will develop epilepsy or not. In other words, no specific genes have been pinpointed as being responsible for the common forms of epilepsy so far, making it more difficult to predict or manage these conditions.
Creating a polygenic risk score for epilepsy
The current study therefore combined all common gene variants (numbering thousands) identified from multiple large populations studied using GWAS in previous research. The total came to over 12,000 people who had epilepsy, and 24,000 non-epileptics. They analyzed and quantified the risk of each of these variants to come up with their polygenic epilepsy scores. The low value for each association of a given gene with the risk for epilepsy was thus magnified by being combined with thousands of other associations. The combination of effect sizes for this very large number of common variants provided a useful prognostic score for genetic epilepsy. These were validated in over 8,000 more people with epilepsy and 622,000 others who did not have this condition.
Similarly calculated scores have been found to be useful in predicting the outcome and in making an accurate diagnosis in many other conditions such as myocardial infarction, diabetes and breast cancer. Thus this study has pioneered in applying this established concept to epilepsy, and has confirmed the predictive value of the polygenic score even in patients who are already receiving standard medical management.
Researcher Imad Majm says, “While additional research is necessary, we believe these findings will lay the groundwork for one day using genetic risk assessments in the clinic to diagnose common epilepsies and guide precision treatment earlier in the disease process.” Agreeing to this, co-researcher Dennis Lal says, “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.”
Costin Leu, Remi Stevelink, Alexander W Smith, Slavina B Goleva, Masahiro Kanai, Lisa Ferguson, Ciaran Campbell, Yoichiro Kamatani, Yukinori Okada, Sanjay M Sisodiya, Gianpiero L Cavalleri, Bobby P C Koeleman, Holger Lerche, Lara Jehi, Lea K Davis, Imad M Najm, Aarno Palotie, Mark J Daly, Robyn M Busch, Epi25 Consortium, Dennis Lal, Polygenic burden in focal and generalized epilepsies, Brain, https://doi.org/10.1093/brain/awz292, https://academic.oup.com/brain/advance-article/doi/10.1093/brain/awz292/5585821?searchresult=1