University of Exeter Medical School, University of Exeter, Exeter, UK.
Rush Alzheimer's Neurodisease Center, Rush University Medical Center, 600 South Paulina Street, Chicago, IL, 60612, USA.
Transl Psychiatry. 2020 Feb 19;10(1):69. doi: 10.1038/s41398-020-0752-7.
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was to identify suicide-associated DNA methylation changes in the human brain by utilising previously published and unpublished methylomic datasets.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.
自杀是全球年轻人中第二大主要死因，代表着重大的全球健康负担。尽管自杀的分子相关性仍知之甚少，但有人假设表观遗传过程可能发挥作用。本研究的目的是通过利用先前发表和未发表的甲基化组数据集，确定人类大脑中与自杀相关的 DNA 甲基化变化。我们分析了自杀完成者和非精神性、猝死对照者的前额叶皮层（PFC，n=211）和小脑（CER，n=114）的 DNA 甲基化谱，分别对每个脑区的独立队列数据进行了荟萃分析。与对照组相比，我们报告了在自杀病例中，在这两个脑区的多个遗传基因座存在 DNA 甲基化改变的证据，与精神表型和自杀相关的差异甲基化位置富集在与神经发育（PFC）和长期突触抑制调节（CER）相关的功能途径中。此外，我们使用双荧光素酶测定法检查了 PFC 与自杀相关的差异甲基化区域（PSORS1C3 DMR）内可变 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，为与自杀相关的分子病理学提供了新的见解。
