Genetic susceptibility in Juvenile Myoclonic Epilepsy: Systematic review of genetic association studies

BackgroundSeveral genetic association investigations have been performed over the last three decades to identify variants underlying Juvenile Myoclonic Epilepsy (JME). Here, we evaluate the accumulating findings and provide an updated perspective of these studies.MethodologyA systematic literature search was conducted using the PubMed, Embase, Scopus, Lilacs, epiGAD, Google Scholar and Sigle up to February 12, 2016. The quality of the included studies was assessed by a score and classified as low and high quality. Beyond outcome measures, information was extracted on the setting for each study, characteristics of population samples and polymorphisms.ResultsFifty studies met eligibility criteria and were used for data extraction. With a single exception, all studies used a candidate gene approach, providing data on 229 polymorphisms in or near 55 different genes. Of variants investigating in independent data sets, only rs2029461 SNP in GRM4, rs3743123 in CX36 and rs3918149 in BRD2 showed a significant association with JME in at least two different background populations. The lack of consistent associations might be due to variations in experimental design and/or limitations of the approach.ConclusionsThus, despite intense research evidence established, specific genetic variants in JME susceptibility remain inconclusive. We discussed several issues that may compromise the quality of the results, including methodological bias, endophenotype and potential involvement of epigenetic factors.PROSPERO registration numberCRD42016036063研究背景：过去三十年间，学界已开展多项遗传关联研究，旨在明确青少年肌阵挛癫痫（Juvenile Myoclonic Epilepsy, JME）的潜在致病变异。本研究对相关积累成果进行系统评估，并为该领域研究提供最新视角。 研究方法：截至2016年2月12日，我们通过PubMed、Embase、Scopus、Lilacs、epiGAD、Google Scholar及Sigle数据库开展系统性文献检索。采用评分量表对纳入研究的质量进行评估，并将其划分为低质量与高质量两类。除结局指标外，研究团队还提取了各项研究的实施场景、人群样本特征及基因多态性相关信息。 研究结果：共有50项研究符合纳入标准，被用于数据提取。除一项研究外，其余所有研究均采用候选基因策略，获取了55个不同基因内部或邻近区域的229个基因多态性相关数据。在独立数据集内检测的遗传变异中，仅GRM4基因的rs2029461单核苷酸多态性（Single Nucleotide Polymorphism, SNP）、CX36基因的rs3743123以及BRD2基因的rs3918149，在至少两种不同背景人群中与JME呈现显著关联。本研究未发现一致关联的原因，可能在于实验设计的差异，或该研究方法本身存在局限性。 研究结论：尽管已有大量深入的研究证据，但与JME易感相关的特定遗传变异仍未得到明确证实。我们讨论了若干可能影响研究结果质量的问题，包括方法学偏倚、内表型及表观遗传因素的潜在参与作用。 PROSPERO注册号：CRD42016036063