Tan Nigel C K, Mulley John C, Scheffer Ingrid E
Department of Neurology, National Neuroscience Institute, Singapore.
Curr Opin Neurol. 2006 Apr;19(2):157-63. doi: 10.1097/01.wco.0000218232.66054.46.
Only two functionally validated susceptibility genes, CACNA1H and GABRD, have so far been identified in the common epilepsies using a candidate gene approach. The difficulty with the alternative statistical approach, where none of the suggested candidates has been functionally validated, may partly be due to the posited genetic architecture of the common epilepsies, such as the idiopathic generalized epilepsies. A subset of both rare and common variants from a much larger pool of susceptibility genes may contribute to disease risk. We review methods and designs for the genetic dissection of common epilepsies.
Genetic association studies, though theoretically more powerful than linkage analysis, have not yet delivered validated susceptibility genes. Methodological flaws can undermine such studies but are correctable. Concerns remain, however, about the extent of underlying genetic heterogeneity in common epilepsies. Genome-wide association studies are increasingly feasible, but issues remain about their conduct and analysis. Meta-analysis may resolve conflicting association studies, facilitated by the establishment of databases of genetic association studies. Newer multi-locus and admixture mapping approaches are attractive alternatives to traditional association studies and may offer new insights into identifying epilepsy genes.
We conclude by emphasizing the importance of deeper endophenotyping using electroclinical, imaging, and molecular approaches to dissect the common epilepsies.
迄今为止，采用候选基因方法在常见癫痫中仅鉴定出两个功能已得到验证的易感基因，即CACNA1H和GABRD。另一种统计方法存在困难，即所提出的候选基因均未经过功能验证，这可能部分归因于常见癫痫（如特发性全身性癫痫）假定的遗传结构。来自大量易感基因库中的罕见和常见变异的一个子集可能会增加疾病风险。我们综述了常见癫痫基因剖析的方法和设计。
遗传关联研究虽然理论上比连锁分析更具效力，但尚未得出经过验证的易感基因。方法学缺陷可能会破坏此类研究，但可以纠正。然而，对于常见癫痫潜在遗传异质性的程度仍存在担忧。全基因组关联研究越来越可行，但在其实施和分析方面仍存在问题。荟萃分析可能会解决相互矛盾的关联研究，遗传关联研究数据库的建立有助于此。更新的多位点和混合映射方法是传统关联研究有吸引力的替代方法，可能为鉴定癫痫基因提供新的见解。
我们强调，通过电临床、影像学和分子方法进行更深入的内表型分析对于剖析常见癫痫至关重要。
