Polygenic burden in focal and generalized epilepsies

Area of Science:

• Genetics
• Neurology
• Epilepsy Research

Background:

• Rare genetic variants are known causes of epilepsy, particularly severe pediatric forms.
• The role of common genetic risk burden in epilepsy phenotypes and its clinical utility remain largely undetermined.

Purpose of the Study:

• To quantify common genetic risk burden in generalized and focal epilepsy using polygenic risk scores (PRS).
• To investigate the potential clinical applications of PRS in epilepsy patient classification and research.

Main Methods:

• Utilized PRS derived from genome-wide association studies in European-ancestry populations.
• Analyzed PRS in multiple independent cohorts of patients with generalized epilepsy (GE-PRS) and focal epilepsy (FE-PRS), along with population controls.
• Included non-Finnish European, Finnish-ancestry, and Japanese-ancestry cohorts for replication and cross-ancestry analysis.

Main Results:

• Significantly higher GE-PRS observed in European-ancestry patients with generalized epilepsy compared to focal epilepsy and population controls across multiple cohorts.
• FE-PRS were significantly elevated in European-ancestry patients with focal epilepsy compared to controls in specific cohorts.
• European ancestry-derived PRS did not predict epilepsy types in Japanese-ancestry individuals.
• Enrichment of generalized epilepsy patients in the top 0.5% of GE-PRS was significant.

Conclusions:

• Common genetic variant risk for epilepsy, especially generalized epilepsy, is significantly enriched in patient cohorts compared to controls.
• Polygenic risk scores show promise for complementing existing biomarkers in epilepsy.
• Future increases in sample size and PRS accuracy may enhance PRS utility for patient classification, comorbidity research, and targeted treatments.