Increased Polygenic Burden Drives Concordance for Epilepsy in Monozygotic Twins
Abstract number :
2.037
Submission category :
12. Genetics / 12A. Human Studies
Year :
2024
Submission ID :
747
Source :
www.aesnet.org
Presentation date :
12/8/2024 12:00:00 AM
Published date :
Authors :
Presenting Author: Yew Li Dang, MB BCh BAO, FRACP – University of Melbourne
Karen Oliver, PhD – University of Melbourne
Kate Esnault, BSc – The University of Melbourne
Piero Perucca, MD PhD – Univeristy of Melbourne
Samuel Berkovic, MD, FRS – University of Melbourne
Rationale: The risk of epilepsy, in the presence of putative genetic or acquired causes, may be modified by the genetic background that is now measurable by polygenic risk scores (PRSs). We tested this hypothesis by measuring PRSs for epilepsy in monozygotic (MZ) twins. We hypothesized that a higher epilepsy PRS in concordant MZ twins would portend a higher risk of epilepsy thus ensuring both twins are affected. In contrast, MZ twins discordant for epilepsy would have a lower epilepsy PRS, closer to that in the general population, which may explain why only one twin is affected.
Methods: 142 MZ twins (69 concordant, 73 discordant) were recruited from the Epilepsy Research Centre. Single nucleotide polymorphism (SNP) genotyping was performed for one of the twins in each pair. Factors affecting concordance for epilepsy in MZ twins were compared using Fisher’s exact test, with Bonferroni adjustments applied for multiple comparisons (padj). We generated epilepsy PRSs for the twins and 3128 European ancestry-matched population controls using PRSice-2, with a p-value threshold of 0.5 for SNP inclusion. SNP weights for PRSs were derived from the 2018 epilepsy genome-wide association study (GWAS). Statistical analyses were performed using logistic regression in R, adjusting for sex, principal components of ancestry and phenotype groups where relevant.
Results: Cohort characteristics are shown in Table 1. Clinically, there were significantly more concordant MZ twins with genetic generalized epilepsies (padj=0.014) compared to other epilepsy phenotypes. All lesion-positive MZ pairs were discordant (padj=0.007).
Relative to population controls (mean PRS 0), concordant MZ twins had significantly higher epilepsy PRSs (mean PRS 0.42, p=0.001) (Figure 1), whereas discordant MZ twins were not significantly different (mean PRS 0.18, p=0.16). Although the mean epilepsy PRS in concordant MZ twins was nominally higher than that in the discordant twins, this difference was not significant (mean 0.42 vs 0.18, p=0.095).
Conclusions: This data supports our hypothesis that the concordance for epilepsy in MZ twins may be driven, at least in part by a common variant burden. This extends our understanding of the impact of our genetic background on the risk of epilepsy and highlights the potential for epilepsy PRS to be used as a predictive marker for the risk of epilepsy in the general population.
Funding: National Health and Medical Research Council Australia
Genetics