Genome-wide mega-analysis identifies 16 loci and highlights diverse biological mechanisms in the common epilepsies
Genome-wide mega-analysis identifies 16 loci and highlights diverse biological mechanisms in the common epilepsies
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DOI：
10.1038/s41467-018-07524-z
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发表时间：
2018-12-10
影响因子：
16.6
通讯作者：
Zimprich, Fritz
中科院分区：
文献类型：
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作者：
Abou-Khalil, Bassel;Auce, Pauls;Zimprich, Fritz
癫痫病影响了全球约6500万人，并且缺少遗传性的成分。我们报告了一项全基因组的大型分析，涉及15,212名癫痫患者和29,677个对照，揭示了16个全基因组重要的基因座，其中11个是新颖的。使用各种优先级标准，我们在这些基因座上查明了21个最有可能的癫痫基因，其中大多数在遗传广义癫痫中。这些基因具有多种生物学功能，包括编码离子通道亚基，转录因子和维生素-B6代谢酶。融合的证据表明，与癫痫相关的常见变异在大脑中基因表达的表观遗传调节中起作用。结果表明，单基因癫痫基因以及已知的抗癫痫药物的靶标的富集。使用基于SNP的遗传力分析，我们将独特的和重叠的遗传基础分解为七个不同的癫痫亚型。这些发现共同提供了基于潜在病理生理学的癫痫疗法的潜在客户。
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.