The epilepsies affect around 65 million people worldwide and have a substantial missing heritability component. We report a genome-wide mega-analysis involving 15,212 individuals with epilepsy and 29,677 controls, which reveals 16 genome-wide significant loci, of which 11 are novel. Using various prioritization criteria, we pinpoint the 21 most likely epilepsy genes at these loci, with the majority in genetic generalized epilepsies. These genes have diverse biological functions, including coding for ion-channel subunits, transcription factors and a vitamin-B6 metabolism enzyme. Converging evidence shows that the common variants associated with epilepsy play a role in epigenetic regulation of gene expression in the brain. The results show an enrichment for monogenic epilepsy genes as well as known targets of antiepileptic drugs. Using SNP-based heritability analyses we disentangle both the unique and overlapping genetic basis to seven different epilepsy subtypes. Together, these findings provide leads for epilepsy therapies based on underlying pathophysiology.

中文翻译：

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全基因组大型分析确定了 16 个位点，并突出了常见癫痫的不同生物学机制。


癫痫影响了全世界大约 6500 万人，并且有大量缺失的遗传成分。我们报告了一项涉及 15,212 名癫痫患者和 29,677 名对照者的全基因组大型分析，揭示了 16 个全基因组重要位点，其中 11 个是新的。使用各种优先排序标准，我们确定了这些位点的 21 个最可能的癫痫基因，其中大多数是遗传性全身性癫痫。这些基因具有不同的生物学功能，包括编码离子通道亚基、转录因子和维生素 B6 代谢酶。汇聚证据表明，与癫痫相关的常见变异在大脑中基因表达的表观遗传调控中发挥作用。结果显示单基因癫痫基因以及抗癫痫药物的已知靶点的富集。使用基于 SNP 的遗传性分析，我们将独特和重叠的遗传基础解开为七种不同的癫痫亚型。总之，这些发现为基于潜在病理生理学的癫痫治疗提供了线索。