Suicide is the second leading cause of death globally among young people representing a significant global health burden. Although the molecular correlates of suicide remains poorly understood, it has been hypothesised that epigenomic processes may play a role. The objective of this study was to identify suicide-associated DNA methylation changes in the human brain by utilising previously published and unpublished methylomic datasets. We analysed prefrontal cortex (PFC, n = 211) and cerebellum (CER, n = 114) DNA methylation profiles from suicide completers and non-psychiatric, sudden-death controls, meta-analysing data from independent cohorts for each brain region separately. We report evidence for altered DNA methylation at several genetic loci in suicide cases compared to controls in both brain regions with suicide-associated differentially methylated positions enriched among functional pathways relevant to psychiatric phenotypes and suicidality, including nervous system development (PFC) and regulation of long-term synaptic depression (CER). In addition, we examined the functional consequences of variable DNA methylation within a PFC suicide-associated differentially methylated region (PSORS1C3 DMR) using a dual luciferase assay and examined expression of nearby genes. DNA methylation within this region was associated with decreased expression of firefly luciferase but was not associated with expression of nearby genes, PSORS1C3 and POU5F1. Our data suggest that suicide is associated with DNA methylation, offering novel insights into the molecular pathology associated with suicidality.

中文翻译：

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自杀完成者大脑中的全基因组DNA甲基化荟萃分析。

自杀是全球年轻人中第二大死亡原因，代表着巨大的全球健康负担。尽管对自杀的分子相关性还知之甚少，但据推测，表观基因组过程可能起一定作用。这项研究的目的是通过利用以前出版和未出版的甲基化数据集来确定人脑中与自杀有关的DNA甲基化变化。我们分析了自杀完成者和非精神病患者，猝死对照者的前额叶皮层（PFC，n = 211）和小脑（CER，n = 114）DNA甲基化谱图，分别对每个大脑区域的独立队列进行了荟萃分析数据。我们报告的证据表明，与两个与自杀相关的差异甲基化位置的大脑区域相比，自杀病例中几个基因位点的DNA甲基化发生了改变，这些位置丰富了与精神病学表型和自杀性有关的功能途径，包括神经系统发育（PFC）和长期调节期突触性抑郁症（CER）。此外，我们使用双荧光素酶测定法检查了PFC自杀相关的甲基化差异区域（PSORS1C3 DMR）中可变DNA甲基化的功能后果，并检查了附近基因的表达。该区域内的DNA甲基化与萤火虫荧光素酶的表达降低有关，但与附近基因PSORS1C3和POU5F1的表达无关。我们的数据表明自杀与DNA甲基化有关，