Center for Human Genome Variation, Duke University School of Medicine, Durham, NC 27708, USA.
Am J Hum Genet. 2012 Aug 10;91(2):293-302. doi: 10.1016/j.ajhg.2012.06.016. Epub 2012 Aug 2.
Idiopathic generalized epilepsy (IGE) is a complex disease with high heritability, but little is known about its genetic architecture. Rare copy-number variants have been found to explain nearly 3% of individuals with IGE; however, it remains unclear whether variants with moderate effect size and frequencies below what are reliably detected with genome-wide association studies contribute significantly to disease risk. In this study, we compare the exome sequences of 118 individuals with IGE and 242 controls of European ancestry by using next-generation sequencing. The exome-sequenced epilepsy cases include study subjects with two forms of IGE, including juvenile myoclonic epilepsy (n = 93) and absence epilepsy (n = 25). However, our discovery strategy did not assume common genetic control between the subtypes of IGE considered. In the sequence data, as expected, no variants were significantly associated with the IGE phenotype or more specific IGE diagnoses. We then selected 3,897 candidate epilepsy-susceptibility variants from the sequence data and genotyped them in a larger set of 878 individuals with IGE and 1,830 controls. Again, no variant achieved statistical significance. However, 1,935 variants were observed exclusively in cases either as heterozygous or homozygous genotypes. It is likely that this set of variants includes real risk factors. The lack of significant association evidence of single variants with disease in this two-stage approach emphasizes the high genetic heterogeneity of epilepsy disorders, suggests that the impact of any individual single-nucleotide variant in this disease is small, and indicates that gene-based approaches might be more successful for future sequencing studies of epilepsy predisposition.
特发性全面性癫痫(IGE)是一种具有高度遗传性的复杂疾病,但对其遗传结构知之甚少。已经发现罕见的拷贝数变异可以解释近 3%的 IGE 个体;然而,目前尚不清楚中等效应大小且频率低于全基因组关联研究可靠检测水平的变异是否会显著增加疾病风险。在这项研究中,我们通过使用下一代测序技术,比较了 118 名 IGE 患者和 242 名欧洲血统对照者的外显子组序列。外显子组测序的癫痫病例包括两种 IGE 形式的研究对象,包括青少年肌阵挛性癫痫(n = 93)和失神性癫痫(n = 25)。然而,我们的发现策略并没有假设考虑的 IGE 亚型之间存在常见的遗传控制。在序列数据中,正如预期的那样,没有变异与 IGE 表型或更具体的 IGE 诊断显著相关。然后,我们从序列数据中选择了 3897 个候选癫痫易感性变异,并在一个更大的 878 名 IGE 患者和 1830 名对照者中对它们进行了基因分型。同样,没有变异达到统计学意义。然而,1935 个变异仅在病例中观察到,无论是杂合子还是纯合子基因型。这组变异很可能包括真正的风险因素。在两阶段方法中,单一变异与疾病的关联证据缺乏显著意义,强调了癫痫疾病的遗传高度异质性,表明该疾病中任何单个单核苷酸变异的影响都很小,并表明基因方法可能更适合未来癫痫易感性的测序研究。