Epigenome-wide association study of DNA methylation in narcolepsy: an integrated genetic and epigenetic approach
Epigenome-wide association study of DNA methylation in narcolepsy: an integrated genetic and epigenetic approach
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DOI：
10.1093/sleep/zsy019
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发表时间：
2018-04
期刊：
影响因子：
5.6
通讯作者：
Mihoko Shimada;T. Miyagawa;Hiromi Toyoda;K. Tokunaga;M. Honda
中科院分区：
文献类型：
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作者：
Mihoko Shimada;T. Miyagawa;Hiromi Toyoda;K. Tokunaga;M. Honda
发作性睡病伴猝倒是以白天过度嗜睡和猝倒为特征的嗜睡症，是一种由遗传和环境因素共同引起的多因素疾病。已鉴定出包括 HLA-DQB1*06:02 在内的多种遗传因素；然而，该病的病因仍不清楚。表观遗传修饰，例如 DNA 甲基化，已被认为在复杂疾病的发病机制中发挥着重要作用。在这里，我们检查了嗜睡症和健康对照个体血液样本的 DNA 甲基化谱，并进行了表观基因组范围的关联研究 (EWAS)，以调查与嗜睡症相关的甲基化位点。此外，整合了 EWAS 和之前进行的发作性睡病全基因组关联研究的数据，以寻找与该疾病存在因果关系的甲基化位点。我们发现（1）注释到发作性睡病中排名最高的差异甲基化位置（DMP）的基因与激素分泌和单羧酸代谢途径相关。 (2) 与嗜睡症相关的顶级 DMP 在非 CpG 岛区域显着更丰富，并且在嗜睡症患者中，超过 95% 的此类位点低甲基化。 (3)综合分析确定了CCR3区域，该区域的单个甲基化位点和多个单核苷酸多态性均与该疾病相关，作为导致发作性睡病的候选区域。这项研究的结果表明未来复制研究的重要性，使用具有更广泛基因组覆盖范围和/或更多样本的甲基化技术来确认和扩展这些结果。
Narcolepsy with cataplexy, which is a hypersomnia characterized by excessive daytime sleepiness and cataplexy, is a multifactorial disease caused by both genetic and environmental factors. Several genetic factors including HLA-DQB1*06:02 have been identified; however, the disease etiology is still unclear. Epigenetic modifications, such as DNA methylation, have been suggested to play an important role in the pathogenesis of complex diseases. Here, we examined DNA methylation profiles of blood samples from narcolepsy and healthy control individuals and performed an epigenome-wide association study (EWAS) to investigate methylation loci associated with narcolepsy. Moreover, data from the EWAS and a previously performed narcolepsy genome-wide association study were integrated to search for methylation loci with causal links to the disease. We found that (1) genes annotated to the top-ranked differentially methylated positions (DMPs) in narcolepsy were associated with pathways of hormone secretion and monocarboxylic acid metabolism. (2) Top-ranked narcolepsy-associated DMPs were significantly more abundant in non-CpG island regions and more than 95 per cent of such sites were hypomethylated in narcolepsy patients. (3) The integrative analysis identified the CCR3 region where both a single methylation site and multiple single-nucleotide polymorphisms were found to be associated with the disease as a candidate region responsible for narcolepsy. The findings of this study suggest the importance of future replication studies, using methylation technologies with wider genome coverage and/or larger number of samples, to confirm and expand on these results.