Kaibara Felipe S, de Araujo Tânia K, Araujo Patricia A O R A, Alvim Marina K M, Yasuda Clarissa L, Cendes Fernando, Lopes-Cendes Iscia, Secolin Rodrigo
Department of Translational Medicine, School of Medical Sciences, University of Campinas (UNICAMP), Campinas, Brazil.
Brazilian Institute of Neuroscience and Neurotechnology (BRAINN), Campinas, Brazil.
Front Genet. 2021 Jul 8;12:672304. doi: 10.3389/fgene.2021.672304. eCollection 2021.
Genetic generalized epilepsies (GGEs) include well-established epilepsy syndromes with generalized onset seizures: childhood absence epilepsy, juvenile myoclonic epilepsy (JME), juvenile absence epilepsy (JAE), myoclonic absence epilepsy, epilepsy with eyelid myoclonia (Jeavons syndrome), generalized tonic-clonic seizures, and generalized tonic-clonic seizures alone. Genome-wide association studies (GWASs) and exome sequencing have identified 48 single-nucleotide polymorphisms (SNPs) associated with GGE. However, these studies were mainly based on non-admixed, European, and Asian populations. Thus, it remains unclear whether these results apply to patients of other origins. This study aims to evaluate whether these previous results could be replicated in a cohort of admixed Brazilian patients with GGE. We obtained SNP-array data from 87 patients with GGE, compared with 340 controls from the BIPMed public dataset. We could directly access genotypes of 17 candidate SNPs, available in the SNP array, and the remaining 31 SNPs were imputed using the BEAGLE v5.1 software. We performed an association test by logistic regression analysis, including the first five principal components as covariates. Furthermore, to expand the analysis of the candidate regions, we also interrogated 14,047 SNPs that flank the candidate SNPs (1 Mb). The statistical power was evaluated in terms of odds ratio and minor allele frequency (MAF) by the genpwr package. Differences in SNP frequencies between Brazilian and Europeans, sub-Saharan African, and Native Americans were evaluated by a two-proportion Z-test. We identified nine flanking SNPs, located on eight candidate regions, which presented association signals that passed the Bonferroni correction (rs12726617; rs9428842; rs1915992; rs1464634; rs6459526; rs2510087; rs9551042; rs9888879; and rs8133217; -values <3.55e). In addition, the two-proportion Z-test indicates that the lack of association of the remaining candidate SNPs could be due to different genomic backgrounds observed in admixed Brazilians. This is the first time that candidate SNPs for GGE are analyzed in an admixed Brazilian population, and we could successfully replicate the association signals in eight candidate regions. In addition, our results provide new insights on how we can account for population structure to improve risk stratification estimation in admixed individuals.
遗传性全身性癫痫（GGEs）包括已明确的全身性发作癫痫综合征：儿童失神癫痫、青少年肌阵挛癫痫（JME）、青少年失神癫痫（JAE）、肌阵挛失神癫痫、伴眼睑肌阵挛的癫痫（Jeavons综合征）、全身性强直阵挛发作以及仅表现为全身性强直阵挛发作。全基因组关联研究（GWASs）和外显子组测序已鉴定出48个与GGE相关的单核苷酸多态性（SNP）。然而，这些研究主要基于非混血的欧洲和亚洲人群。因此，这些结果是否适用于其他种族的患者仍不清楚。本研究旨在评估之前的这些结果能否在一组混血的巴西GGE患者中得到重复验证。我们从87例GGE患者中获取了SNP阵列数据，并与来自BIPMed公共数据集的340例对照进行比较。我们能够直接获取SNP阵列中17个候选SNP的基因型，其余31个SNP则使用BEAGLE v5.1软件进行推算。我们通过逻辑回归分析进行关联测试，将前五个主成分作为协变量。此外，为了扩大对候选区域的分析，我们还对候选SNP侧翼（1 Mb）的14,047个SNP进行了检测。通过genpwr软件包根据优势比和次要等位基因频率（MAF）评估统计效能。通过两比例Z检验评估巴西人与欧洲人、撒哈拉以南非洲人和美洲原住民之间SNP频率的差异。我们在八个候选区域中鉴定出九个侧翼SNP，它们呈现出通过Bonferroni校正的关联信号（rs12726617；rs9428842；rs1915992；rs1464634；rs6459526；rs2510087；rs9551042；rs9888879；和rs813,3217；P值<3.55e）。此外，两比例Z检验表明，其余候选SNP缺乏关联可能是由于混血巴西人观察到的不同基因组背景。这是首次在混血的巴西人群中分析GGE的候选SNP，我们成功在八个候选区域中重复了关联信号。此外，我们的结果为如何考虑群体结构以改善混血个体的风险分层估计提供了新的见解。
