Mol Psychiatry :复旦大学姚音等揭示DNA甲基化在汉族人精神分裂症中的重要作用

2020-12-31 Bio生物世界 Bio生物世界

精神分裂症是一种严重的神经精神疾病,其核心特征包括幻觉、妄想和认知缺陷。越来越多的证据表明,异常的DNA甲基化与精神分裂症的发展有关。

精神分裂症是一种严重的神经精神疾病,其核心特征包括幻觉、妄想和认知缺陷。越来越多的证据表明,异常的DNA甲基化与精神分裂症的发展有关。然而,DNA甲基化变化改变精神分裂症风险的机制仍然很大程度上是未知的。

近日,复旦大学生命科学院生物统计与计算生物学系姚音团队等在 Molecular Psychiatry 杂志(IF=12.384)上发表了题为:Genome-wide DNA methylation analysis of peripheral blood cells derived from patients with first-episode schizophrenia in the Chinese Han population 的研究论文。

通过研究中国汉族人群首发精神分裂症患者(first-episode schizophrenia,FESZ),探讨DNA甲基化在精神分裂症发病机理中的重要作用。

实验内容与结果

该研究中,在2017年至2018年期间,从北京回龙观医院,重庆三峡中心医院和驻马店市精神病医院这三个临床地点招募了499名汉族血统的FESZ患者(25.4±6.3岁;男性207名,女性292名),476名年龄和性别匹配的汉族健康对照者。使用Illumina Infinium Human MethylationEPIC BeadChip对患者外周血基因组DNA甲基化模式进行量化。

在通过质量控制的747372个位点中,总共有4277个探针的校正后P值<0.05(bonferroni校正),表明患者和对照之间dna甲基化水平存在显着差异。这些DMPs(差异甲基化位点)被定位到3346个独特的基因上。在这些位点中,2534个位点高甲基化,而1743个位点低甲基化。

最显著的DMPs被注释到C17orf53、THAP1和KCNQ4 (Kv7.4) 基因上。

大多数DMPs位于调节区域,而较少的DMPs位于基因体内部。大多数DMPs被发现在CpG岛内或附近,而少数DMP则散布在距CpG岛较远位置(距CpG岛> 4 kb)。同样,高甲基化的DMPs表现出类似的模式,而低甲基化的DMPs则倾向于发生在散布在距CpG岛较远位置。


图1. FESZ患者和健康对照之间的甲基化位置差异

在DMP排名前20位的名单中,因为其生理功能,研究人员发现了几个特别感兴趣的基因。包括KCNQ4,其编码kv7家族的电压门控钾通道,该通道与神经元兴奋性有关;以及与神经系统发育相关的LIMK2和TMOD2。


图2. 患者和对照之间重要DMPs的Violin图

接下来,研究人员检测到6325个基因组区域,与6264个独特基因重叠。 最大的差异甲基化片段位于6号染色体上,并与RGL2基因的外显子区域重叠。最重要的DMR位于2号染色体上,跨越19个CpG位点,并对应于HPCAL1基因。这些观察结果表明跨特定基因组区域的连续DNA甲基化差异可能与SZ相关。

随后,研究人员对不同甲基化基因的GO分析进一步确认了神经元网络的强富集,包括神经元投射延伸、轴突形成和神经元凋亡过程。这些观察结果突显了DNA甲基化以及其他表观遗传学修饰在神经发育过程中的重要性。

图3. DMP相关基因和GO terms的显著富集

最后,研究人员提供了与精神分裂症相关的表观遗传改变与遗传易感性位点共定位的证据。研究人员的分析表明,将139个重要DMP定位于126个基因,与133个SZ 风险SNPs共同定位。在查询到的基因中,有42个以前与SZ有关联的证据。在7号染色体上,CpGs岛cg04894216和SNP rs13230421都位于GRM3基因上,这可能通过影响谷氨酸能神经传递和突触可塑性而赋予SZ风险。


图4. SZ-DMP和SZ GWAS基因座的共定位过程

总结

通过关注首发精神分裂症患者,该研究的调查强有力地支持DNA甲基化在精神分裂症发病机制中的重要作用。在精神分裂症患者中观察到的DNA甲基化异常可能为识别诊断生物标志物和开发新的治疗靶点提供有价值的资源,以造福精神分裂症患者。

原始出处:

 Mingrui Li , Yanli Li , Haide Qin , et al. Genome-wide DNA methylation analysis of peripheral blood cells derived from patients with first-episode schizophrenia in the Chinese Han population .Mol Psychiatry . 2020 Dec 5. doi: 10.1038/s41380-020-00968-0.

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    2021-01-02 saikp
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    2021-01-01 ms5000000518166734

    已读,受益匪浅

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