Abstract
The occurrence of seizures in childhood is often associated with neurodevelopmental impairments and school underachievement. Common genetic variants associated with epilepsy have been identified and epigenetic mechanisms have also been suggested to play a role. In this study, we analyzed the association of genome-wide blood DNA methylation with the occurrence of seizures in ~ 800 children from the Avon Longitudinal Study of Parents and Children, UK, at birth (cord blood), during childhood, and adolescence (peripheral blood). We also analyzed the association between the lifetime occurrence of any seizures before age 13 with blood DNA methylation levels. We sought replication of the findings in the Generation R Study and explored causality using Mendelian randomization, i.e., using genetic variants as proxies. The results showed five CpG sites which were associated cross-sectionally with seizures either in childhood or adolescence (1–5% absolute methylation difference at pFDR < 0.05), although the evidence of replication in an independent study was weak. One of these sites was located in the BDNF gene, which is highly expressed in the brain, and showed high correspondence with brain methylation levels. The Mendelian randomization analyses suggested that seizures might be causal for changes in methylation rather than vice-versa. In conclusion, we show a suggestive link between seizures and blood DNA methylation while at the same time exploring the limitations of conducting such study.
Highlights
Seizures are episodes of abnormal excessive or synchronous neuronal activity in the brain
As it is likely that other factors may underlie the disease, it has been suggested that epigenetic mechanisms such as DNA methylation are involved in the onset of seizures [11]
In this study, we observed associations between blood DNA methylation and the occurrence of seizures in a longitudinal pregnancy cohort study based in the UK
Summary
Seizures are episodes of abnormal excessive or synchronous neuronal activity in the brain. The two largest genome-wide association studies to date (~ 8600 individuals with epilepsy versus ~ 26000 controls and ~ 15,200 individuals with epilepsy versus ~ 29,600 controls) have identified a total of 24 genetic variants associated with epilepsy [9, 10] Some of these loci are located in the proximity of candidate genes for epilepsy, for instance those coding for ion-channel subunits, and their relevance for epilepsy is supported by other research in humans and animals. A recent study comparing blood DNA methylation in 30 adult patients with mesial temporal lobe epilepsy and 30 controls identified 216 differentially methylated sites between the two groups, including sites on genes involved in ion binding and metabolic activity [14]. A study adopting a rat model of chronic epilepsy corroborated these findings by revealing genome-wide differences in DNA methylation compared to control rats [18]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
