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.

中文翻译：

---

儿童和青少年癫痫发作的表观基因组关联研究。

儿童期癫痫发作的发生通常与神经发育障碍和学业成绩不佳有关。已经确定了与癫痫相关的常见遗传变异，并且表观遗传机制也被认为发挥了作用。在这项研究中，我们分析了全基因组血液 DNA 甲基化与来自英国雅芳父母和儿童纵向研究的约 800 名儿童在出生时（脐带血）、儿童期和青春期（外周血液）。我们还分析了 13 岁之前任何癫痫发作的终生发生与血液 DNA 甲基化水平之间的关联。我们寻求复制 R 代研究中的发现，并使用孟德尔随机化（即使用遗传变异作为代理）探索因果关系。结果显示，有 5 个 CpG 位点与儿童期或青春期的癫痫发作横断面相关（pFDR < 0.05 时的绝对甲基化差异为 1-5%），尽管在独立研究中复制的证据很弱。其中一个位点位于 BDNF 基因中，该基因在大脑中高度表达，并与大脑甲基化水平高度对应。孟德尔随机化分析表明，癫痫发作可能是甲基化变化的原因，反之亦然。总之，我们展示了癫痫发作和血液 DNA 甲基化之间的暗示性联系，同时探索了进行此类研究的局限性。尽管在独立研究中复制的证据很弱。其中一个位点位于 BDNF 基因中，该基因在大脑中高度表达，并与大脑甲基化水平高度对应。孟德尔随机化分析表明，癫痫发作可能是甲基化变化的原因，反之亦然。总之，我们展示了癫痫发作和血液 DNA 甲基化之间的暗示性联系，同时探索了进行此类研究的局限性。尽管在独立研究中复制的证据很弱。其中一个位点位于 BDNF 基因中，该基因在大脑中高度表达，并与大脑甲基化水平高度对应。孟德尔随机化分析表明，癫痫发作可能是甲基化变化的原因，反之亦然。总之，我们展示了癫痫发作和血液 DNA 甲基化之间的暗示性联系，同时探索了进行此类研究的局限性。