Multicentre search for genetic susceptibility loci in sporadic epilepsy syndrome and seizure types: a case-control study
Multicentre search for genetic susceptibility loci in sporadic epilepsy syndrome and seizure types: a case-control study
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DOI：
10.1016/s1474-4422(07)70247-8
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发表时间：
2007-11-01
期刊：
影响因子：
48
通讯作者：
Goldstein, David B.
中科院分区：
文献类型：
--
作者：
Cavalleri, Gianpiero L.;Weale, Michael E.;Goldstein, David B.
背景 癫痫遗传学 (EPIGEN) 联盟的成立是为了进行具有增强统计能力的基因作图分析，以检测影响常见癫痫形式的发展和治疗的变异。方法我们检查了从四个独立研究中心（英国、爱尔兰、芬兰和澳大利亚）收集的 2717 个病例和 1118 个对照样本中 279 个主要候选基因的常见变异。使用单核苷酸多态性（SNP）和组合组关联分析来检查候选基因中遗传变异对各种形式癫痫的贡献。结果我们没有确定明确的、无可争议的共同遗传风险因素，这些因素有助于多个人群中选定的癫痫亚表型。我们也没有确定一般所有癫痫表型的危险因素。然而，对最显着的 p 值进行的集合关联分析（在排列下评估）表明，众多 SNP 以明显的人群特异性方式对疾病易感性做出了贡献。基因 KCNAB1、GABRR2、KCNMB4、SYN2 和 ALDH5A1 的变异最为显着。 解释 散发性癫痫的潜在遗传成分非常复杂。结果表明，许多 SNP 以明显的人群特异性方式促进疾病易感性。然而，不同群体之间表型的细微差异，加上对癫痫的潜在遗传成分如何与当前表型分类相一致的了解不足，也可能解释了明显的人群特异性遗传风险因素。五个基因的变异需要在独立队列中进行进一步研究，以澄清初步的关联。
Background The Epilepsy Genetics (EPIGEN) Consortium was established to undertake genetic mapping analyses with augmented statistical power to detect variants that influence the development and treatment of common forms of epilepsy.Methods We examined common variations across 279 prime candidate genes in 2717 case and 1118 control samples collected at four independent research centres (in the UK, Ireland, Finland, and Australia). Single nucleotide polymorphism (SNP) and combined set-association analyses were used to examine the contribution of genetic variation in the candidate genes to various forms of epilepsy.Findings We did not identify clear, indisputable common genetic risk factors that contribute to selected epilepsy subphenotypes across multiple populations. Nor did we identify risk factors for the general all-epilepsy phenotype. However, set-association analysis on the most significant p values, assessed under permutation, suggested the contribution of numerous SNPs to disease predisposition in an apparent population-specific manner. Variations in the genes KCNAB1, GABRR2, KCNMB4, SYN2, and ALDH5A1 were most notable.Interpretation The underlying genetic component to sporadic epilepsy is dearly complex. Results suggest that many SNPs contribute to disease predisposition in an apparently population-specific manner. However, subtle differences in phenotyping across cohorts, combined with a poor understanding of how the underlying genetic component to epilepsy aligns with current phenotypic classifications, might also account for apparent population-specific genetic risk factors. Variations across five genes warrant further study in independent cohorts to clarify the tentative association.