Genetic determinants of common epilepsies: a meta-analysis of genome-wide association studies.
Genetic determinants of common epilepsies: a meta-analysis of genome-wide association studies.
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DOI：
10.1016/s1474-4422(14)70171-1
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发表时间：
2014-09
期刊：
影响因子：
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通讯作者：
International League Against Epilepsy Consortium on Complex Epilepsies. Electronic address: epilepsy-austin@unimelb.edu.au
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文献类型：
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作者：
International League Against Epilepsy Consortium on Complex Epilepsies. Electronic address: epilepsy-austin@unimelb.edu.au
癫痫是一组临床上异质性的神经系统疾病。尽管有强有力的证据证明遗传性，但全基因组关联研究在识别与癫痫相关的风险位点方面收效甚微，可能是因为样本量相对较小且功效不足。我们的目的是通过对所有癫痫和两种最大的临床亚型（遗传性全身性癫痫和局灶性癫痫）的全基因组关联研究进行荟萃分析来确定风险位点。我们结合了 12 组癫痫患者的全基因组关联数据和基于人群的数据集的对照数据。对照组与病例在种族上相匹配。我们将癫痫患者表型分为遗传性全身性癫痫、局灶性癫痫或未分类癫痫。在对质量控制和插补进行标准化过滤以考虑各个站点的不同基因分型平台后，每个站点的研究人员对每个数据集进行了线性混合模型关联分析。结合汇总统计数据，我们对所有癫痫、局灶性癫痫和遗传性全身性癫痫进行了固定效应荟萃分析。我们将全基因组显着性阈值设置为 p<1·66 × 10−8。我们的分析中纳入了 8696 例病例和 26 157 例对照。对所有癫痫队列的荟萃分析确定了 2q24.3 (p=8·71 × 10−10) 的位点，涉及 SCN1A，以及 4p15.1 (p=5·44 × 10−9) 的位点，包含 PCDH7，PCDH7 编码以前未涉及癫痫的原钙粘蛋白分子。对于遗传性全身性癫痫队列，我们在 2p16.1 (p=9·99 × 10−9) 处注意到一个信号，暗示 VRK2 或 FANCL。没有单核苷酸多态性对局灶性癫痫具有全基因组意义。这项荟萃分析描述了一个以前未涉及癫痫的新基因座，并提供了有关这些疾病的遗传结构的进一步证据，最终目的是协助疾病分类和预后。数据表明，特定位点可以多效性地广泛提高癫痫风险，或者可以产生仅限于特定癫痫亚型的影响。未来的遗传分析可能受益于集中（即，将癫痫类型分组在一起）或分裂（即，对特定临床亚型的分析）。国际抗癫痫联盟以及多个政府和慈善机构。
The epilepsies are a clinically heterogeneous group of neurological disorders. Despite strong evidence for heritability, genome-wide association studies have had little success in identification of risk loci associated with epilepsy, probably because of relatively small sample sizes and insufficient power. We aimed to identify risk loci through meta-analyses of genome-wide association studies for all epilepsy and the two largest clinical subtypes (genetic generalised epilepsy and focal epilepsy). We combined genome-wide association data from 12 cohorts of individuals with epilepsy and controls from population-based datasets. Controls were ethnically matched with cases. We phenotyped individuals with epilepsy into categories of genetic generalised epilepsy, focal epilepsy, or unclassified epilepsy. After standardised filtering for quality control and imputation to account for different genotyping platforms across sites, investigators at each site conducted a linear mixed-model association analysis for each dataset. Combining summary statistics, we conducted fixed-effects meta-analyses of all epilepsy, focal epilepsy, and genetic generalised epilepsy. We set the genome-wide significance threshold at p<1·66 × 10−8. We included 8696 cases and 26 157 controls in our analysis. Meta-analysis of the all-epilepsy cohort identified loci at 2q24.3 (p=8·71 × 10−10), implicating SCN1A, and at 4p15.1 (p=5·44 × 10−9), harbouring PCDH7, which encodes a protocadherin molecule not previously implicated in epilepsy. For the cohort of genetic generalised epilepsy, we noted a single signal at 2p16.1 (p=9·99 × 10−9), implicating VRK2 or FANCL. No single nucleotide polymorphism achieved genome-wide significance for focal epilepsy. This meta-analysis describes a new locus not previously implicated in epilepsy and provides further evidence about the genetic architecture of these disorders, with the ultimate aim of assisting in disease classification and prognosis. The data suggest that specific loci can act pleiotropically raising risk for epilepsy broadly, or can have effects limited to a specific epilepsy subtype. Future genetic analyses might benefit from both lumping (ie, grouping of epilepsy types together) or splitting (ie, analysis of specific clinical subtypes). International League Against Epilepsy and multiple governmental and philanthropic agencies.