Centre for Neuroscience, Imperial College London, Charing Cross Hospital, London, UK.
Epilepsy Behav. 2011 Nov;22(3):421-7. doi: 10.1016/j.yebeh.2011.07.031. Epub 2011 Sep 3.
The genetic bases of common, nonmendelian epilepsy have been difficult to elucidate. In this article, we argue for a new approach to genetic inquiry in epilepsy. In the latter part of the 19th century, epilepsy was universally acknowledged to be part of a wider "neurological trait" that included other neuropsychiatric conditions. In recent years, studies of comorbidity have shown clear links between epilepsy and various neuropsychiatric disorders including psychosis and depression, and genetic studies of copy number variants (CNVs) have shown that in some cases, the same CNV underpins neuropsychiatric illness and epilepsy. Functional annotation analysis of the sets of genes impacted by epilepsy CNVs shows enrichment for genes involved with neural development, with gene ontological (GO) categories including "neurological system process" (P=0.006), "synaptic transmission" (P=0.009), and "learning or memory" (P=0.01). These data support the view that epilepsy and some neuropsychiatric conditions share pathogenic neurodevelopmental pathways, and that epilepsy should be included in the spectrum of neurodevelopmental disorders. Yet, most current genetic research in epilepsy has restricted samples to specific types of epilepsy categorized according to the clinical classification schemes on the basis of seizure type, anatomical location, or epilepsy syndrome. These schemes are, to an extent, arbitrary and do not necessarily align with biological reality. We propose an alternative approach that makes no phenotypic assumptions beyond including epilepsy in the neurodevelopmental spectrum. A "'value-free" strategy of reverse phenotyping may be worth exploring, starting with genetic association and looking backward at the phenotype. Finally, it should be noted that there are societal implications to associating epilepsy with other neuropsychiatric disorders, and it is vital to ensure research in this area does not result in increased stigma for patients with epilepsy.
常见的非孟德尔遗传癫痫的遗传基础一直难以阐明。本文提出了一种癫痫遗传研究的新方法。在 19 世纪后期，癫痫被普遍认为是一种更广泛的“神经特征”的一部分，包括其他神经精神疾病。近年来，共病研究表明癫痫与各种神经精神疾病之间存在明显联系，包括精神病和抑郁症，而拷贝数变异（CNV）的遗传研究表明，在某些情况下，相同的 CNV 是神经精神疾病和癫痫的基础。受癫痫 CNV 影响的基因集的功能注释分析显示，与神经发育相关的基因富集，基因本体论（GO）类别包括“神经系统过程”（P=0.006）、“突触传递”（P=0.009）和“学习或记忆”（P=0.01）。这些数据支持癫痫和一些神经精神疾病具有共同的致病神经发育途径的观点，并且癫痫应该被纳入神经发育障碍的范围。然而，目前大多数癫痫的遗传研究将样本限制在特定类型的癫痫中，这些癫痫根据发作类型、解剖位置或癫痫综合征的临床分类方案进行分类。这些方案在一定程度上是任意的，不一定与生物学现实相符。我们提出了一种替代方法，即在神经发育谱中纳入癫痫，而不做任何表型假设。除了将癫痫纳入神经发育谱之外，不做任何表型假设的“无价值”反表型策略可能值得探索。从遗传关联开始，向后追溯表型，可能是一种值得探索的方法。最后，值得注意的是，将癫痫与其他神经精神疾病联系起来会带来社会影响，确保这一领域的研究不会给癫痫患者带来更多的耻辱感是至关重要的。
