背景:建立了癫痫遗传学(EPIGEN)联盟,以进行具有增强统计能力的遗传作图分析,以检测影响癫痫常见形式发展和治疗的变异。
方法:我们在四个独立研究中心(在英国,爱尔兰,芬兰,和澳大利亚)。使用单核苷酸多态性(SNP)和组合集合关联分析来检查候选基因中遗传变异对各种形式的癫痫的贡献。
结果:我们没有确定清楚,无可争议的共同遗传风险因素有助于在多个人群中选择癫痫亚表型。我们也没有确定一般全癫痫表型的危险因素。然而,对最显著P值的集合关联分析,在排列下评估,表明许多SNP以明显的群体特异性方式对疾病易感性有贡献。KCNAB1、GABRR2、KCNMB4、SYN2和ALDH5A1基因的变异最为显著。
结论:散发性癫痫的潜在遗传成分明显复杂。结果表明,许多SNP以明显的人群特异性方式导致疾病易感性。然而,队列中表型的细微差异,加上对癫痫的潜在遗传成分如何与当前的表型分类相一致的理解不足,也可能是明显的群体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,以阐明暂定关联。
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.
RESULTS: 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.
CONCLUSIONS: The underlying genetic component to sporadic epilepsy is clearly 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.