Epigenome-wide association study of seizures in childhood and adolescence

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 p FDR < 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.

Length Polymorphism and Methylation Status of UPS29 Minisatellite of the ACAP3 Gene as Molecular Biomarker of Epilepsy. Sex Differences in Seizure Types and Symptoms

“…Thus, the individual and gender differences noted by us can result in susceptibility to the development of various forms of neurological pathologies, including epilepsy. Furthermore, epigenetic factors (including DNA methylation) play a significant role in brain development and neuronal function and may contribute to the developmental neuropathologies, in particular epilepsy [11][12][13][14]74]. Indeed, we found a significant increase in the frequency of unmethylated UPS29 forms for patients with epilepsy, while there were no differences compared with controls among individuals with Parkinson's disease [72].…”

“…However, possible mutations in such different genes that can lead to epileptic seizures in most cases remain unclear [7][8][9]. The role of epigenetic modifications has been actively studied recently in the development of epilepsy [10][11][12][13][14].…”

“…Our previous studies showed [31] that in the Russian population (East Slavic ethnic group, the sample of individuals from 17 to 90 years old) UPS29 was represented by seven alleles, which differed not only in the number of repeats (6,8,9,10,14,17, and 24 ones) but also in combination of repeated units, as well as in the presence of deletions and/or single-nucleotide polymorphisms (SNPs) in DNA flanking minisatellite ( Figure 1 and Figure S2, Table S3). In the studied cohort, the allele of 17 repeats was predominant (91.5%), but the frequencies of other alleles were lower (from 0.3% to 4.4%).…”

Pharmacological and Therapeutic Approaches in the Treatment of Epilepsy

“…There are approximately 73 genes that are categorized as neurodevelopment-associated epilepsy genes [ 10 ]. Twenty-four genetic variants have been identified by two large genome-wide association studies that are linked with epilepsy [ 12 ]. The defect in the FMR1 gene is responsible for causing Fragile X Syndrome.…”

Analysis of Blood DNA Methylation in Early-Life Seizures

“…Childhood seizures can result in cellular and molecular changes that are potential risk factors for the development of epilepsy, in conjunction with a high association with neurodevelopmental conditions and learning and behavioral disabilities. 12 , 13 Over the years, genome-wide association epilepsy studies have focused on the identification of common genetic variants linked to epilepsy etiology in hopes of developing novel preventive strategies for therapeutic intervention. 14 , 15 However, epigenome-wide association studies (EWAS) have proven to be an additional factor to consider in the identification of high-risk gene loci in epilepsy.…”