Investigating the role of polygenic risk in the severity of focal epilepsy
Abstract number :
2.066
Submission category :
12. Genetics / 12A. Human Studies
Year :
2025
Submission ID :
494
Source :
www.aesnet.org
Presentation date :
12/7/2025 12:00:00 AM
Published date :
Authors :
Presenting Author: Marisha Dhakal, BA – Northwestern
Hyun Yong Koh, MD, PhD – Baylor College of Medicine
Muhammed Cagri Bayraktutan, MD – Boston Children's Hospital
William Leung, MBBS – Massachusetts General Hospital
nivedita Jha, MBBS – Massachusetts General Hospital
Christopher McGraw, MD, PhD – Northwestern
Rationale: Epilepsy is a highly prevalent condition affecting over 50 million people globally. In focal epilepsy, wide variance has been observed in seizure frequency and the response to anti-seizure medication, which cannot fully be explained by known risk factors. The role of genetic factors in this clinical variation has not yet been assessed.
Methods: We performed a retrospective study of adult individuals with focal epilepsy seen at Mass General Brigham (MGB) Epilepsy clinics (N=606), from whom SNP genotyping was available through the MGB BioBank and clinical data were available by chart review. In this preliminary analysis (N=256), we compared clinical characteristics of individuals with or without history of refractory epilepsy (N=151, and 105, respectively), followed by subgroup analysis of individuals with ongoing seizures (N=74) versus those who later became well-controlled (seizure frequency < 1 per year; N=76). To assess whether the burden of common risk variants in each individual contributes to epilepsy severity and medication refractoriness, polygenic risk scores will be calculated from the ILAE GWAS summary statistics using PLINK v1.9.
Results: Our preliminary analysis of individuals with history of refractory versus non-refractory epilepsy showed significant effects of lower mean age at onset (P=4.47x10-9), prolonged duration (10+ years) of uncontrolled seizures (P= 4.54x10-12, OR (odds ratio)= 8.96), EEG with focal epileptiform discharges (P= 1.9x10-2, OR= 1.93), presence of focal onset with impaired awareness seizures (P=9.03x10-4, OR=2.36), hippocampal sclerosis (P=4.3x10-2, OR=3.18), and presence of psychiatric comorbidities (P= 4.41x10-3, OR= 2.18). Protective factors included short interval (< 1 year) before seizure control (P=2.78x10-8, OR=0.21), and history of ischemic stroke (P=3.89x10-2, OR=0.11). Our subgroup analysis of the refractory epilepsy cohort comparing those with uncontrolled seizures versus those whose seizures became well-controlled showed increase risk with prolonged duration of uncontrolled seizures (P=4.08x10-6; OR=6.24) and use of 3+ ASMs (P=7.66x10-3, OR=2.89), and showed reduced risk with short duration of uncontrolled seizures (P=3.06x10-5; OR=0.04). There was no significant association with prior epilepsy procedures (resection, ablation, neuromodulation; 62.2% vs 67.1%, P=0.527), resection (31.1% vs 30.3%, P=0.914), MRI findings, or EEG findings.
Conclusions: Our study corroborates several previously reported risk factors for refractory epilepsy, particularly duration of uncontrolled seizures, while highlighting the limitations of known factors to account for differences in seizure frequency among patients with refractory epilepsy. These findings set the stage for Phase 2 of our analysis to complete phenotyping of the remaining patients (N=350) and assess the contribution of common epilepsy risk variants to differences in outcome.
Funding: This research is not funded.
Genetics