Authors :
Presenting Author: Chethan Rao, DO, MS – University of Maryland
Karlijn Meeks, PhD, MSc – University of Maryland
Rationale:
Genome-Wide Association Studies (GWAS) have identified a growing number of single-nucleotide polymorphisms (SNPs) associated with epilepsies. Understanding the genetic architecture of epilepsies provides opportunities for identifying individuals at risk, such as through Polygenic Risk Scores (PRS). However, several studies have shown that prediction accuracy of PRS is poor among ancestral groups underrepresented in GWAS. In addition, children with epilepsy from ancestries historically underrepresented in genomics research have higher rates of variants of uncertain significance (VUS), which has implications for diagnosis, management, and prognostication. Therefore, we aimed to gain insight into the representation of diverse individuals in GWAS for epilepsy.Methods:
We retrieved all published GWAS on epilepsy, including genetic/idiopathic generalized epilepsy (childhood absence epilepsy and juvenile myoclonic epilepsy, among others) and focal epilepsy (self-limited epilepsy with centrotemporal spikes and focal epilepsy with hippocampal sclerosis, among others) from the GWAS Catalog (08/2024). Cohorts were screened for sample overlap and de-duplicated accordingly. We characterized studies in terms of ancestries per the 1000 Genomes Project ancestry categories (African, Native American, East Asian, South Asian, and European). Results:
A total of 3,574,909 participants (293,725 cases and 3,281,184 controls) were included across the 68 epilepsy GWAS. In total, 71.5% of participants were of European ancestry, 14.3% East Asian, 0.5% African, 13.7% ancestry not reported, and 0% South Asian or Native American. Among cases, a mere 8% of participants were non-European (6.4% East Asian, 1.5% African). Across all GWAS studies, 98 unique SNPs with genome-wide significant p-value of < 5x10-8 were identified. Though studies with exclusively European ancestry participants made up 66% of all studies, these studies contributed only 21% of significant SNPs identified. Whereas mixed-ancestry studies (2 or more ancestries), comprising 16% of studies, contributed 58% of significant SNPs identified.
Conclusions:
The vast majority of epilepsy GWAS participants are of European ancestry. While East Asian and African ancestry populations are severely underrepresented, representation of South Asian and Native American ancestries is completely lacking. Moreover, our finding that mixed ancestry studies more often identified significant SNPs demonstrates the benefit of including participants of diverse ancestries for discovery. Conversely, the continued lack of diversity in epilepsy GWAS would likely exacerbate existing health disparities in epilepsy.Funding:
None to disclose.