Polygenic risk scores shed light on familial epilepsy burden

Key takeaways:

• Researchers said common risk variants help explain why epilepsy occurs in some family members and not others.
• The study has implications for genetic counseling and disease prognosis.

In families with genetic epilepsy and febrile seizures, relatives who showed higher polygenic risk scores were more likely to have an epilepsy diagnosis along with a more severe phenotype, according to new research.

“Genetic modifiers have long been proposed to at least partially explain phenotypic heterogeneity of monogenic diseases,” Karen L. Oliver, MS, research fellow at the Epilepsy Research Centre in the department of medicine at the University of Melbourne in Australia, and colleagues wrote in eBio Medicine. “Therefore, modifiers are important to detect, not just for disease prognosis, but because they may reveal novel therapeutic avenues.”

Oliver and colleagues sought to investigate whether common polygenic risk for epilepsy could explain the infiltration and expression of rare pathogenic variants of the condition found to be common within families.

Their study included 304 individuals within 58 clinically heterogeneous families from the University of Melbourne’s Epilepsy Genetics program as well as the Epi4K Consortium who demonstrated genetic epilepsy with febrile seizures plus (GEFS+). Also included in the dataset were five individuals with the GEFS+ phenotype with the common SCN1B pathogenic variant found in a distant relative with connections to nine other GEFS+ families.

Relatives were grouped as either unaffected or affected with epilepsy, then further graded according to phenotype severity and given a number as an indicator from 1 to 5: no seizures, febrile seizures only, febrile seizures plus, generalised/focal epilepsy, or developmental and epileptic encephalopathy. Individuals with a score of 1 or 2 were considered unaffected and those with a score of 3, 4 or 5 were considered affected.

Epilepsy polygenic risk scores (PRS) were subsequently tested for association with epilepsy phenotype, where mean PRS differences among families were compared between concordant vs. discordant pairings to ascertain phenotype severity.

According to the results, a higher polygenic risk for epilepsy was associated with an epilepsy diagnosis (OR = 1.39; 95% CI, 1.08-1.8), and relatives with a more severe phenotype had a mean pairwise PRS difference of +0.19 higher than relatives with a milder phenotype.

Data further showed that these differences increased with greater phenotype discordance between relatives.

“Interpretation of rare pathogenic variants in the context of polygenic background promises to provide and additional level of stratification for epilepsy risk in patients and their relatives,” Oliver and colleagues wrote.