Dwivedi Yogesh, Roy Bhaskar, Korla Praveen Kumar
Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL, 35294, USA.
Neuropsychopharmacology. 2025 Mar;50(4):705-716. doi: 10.1038/s41386-024-02040-9. Epub 2024 Dec 7.
Major depressive disorder (MDD) is a debilitating disorder. Suicide attempts are 5-times higher in MDD patients than in the general population. Interestingly, not all MDD patients develop suicidal thoughts or complete suicide. Thus, it is important to study the risk factors that can distinguish suicidality among MDD patients. The present study examined if DNA methylation changes can distinguish suicidal behavior among depressed subjects. Genome-wide DNA methylation was examined in the dorsolateral prefrontal cortex of depressed suicide (MDD+S; n = 15), depressed non-suicide (MDD-S; n = 17), and nonpsychiatric control (C; n = 16) subjects using 850 K Infinium Methylation EPIC BeadChip. The significantly differentially methylated genes were used to determine the functional enrichment of genes for ontological clustering and pathway analysis. Based on the number of CpG content and their relative distribution from specific landmark regions of genes, 32,958 methylation sites were identified across 12,574 genes in C vs. MDD+/-S subjects, 30,852 methylation sites across 12,019 genes in C vs. MDD-S, 41,648 methylation sites across 13,941 genes in C vs. MDD+S, and 49,848 methylation sites across 15,015 genes in MDD-S vs. MDD+S groups. A comparison of methylation sites showed 33,129 unique methylation sites and 5451 genes in the MDD-S group compared to the MDD+S group. Functional analysis suggested oxytocin, GABA, VGFA, TNFA, and mTOR pathways associated with suicide in the MDD group. Altogether, our data show a distinct pattern of DNA methylation, the genomic distribution of differentially methylated sites, gene enrichment, and pathways in MDD suicide compared to non-suicide MDD subjects.
重度抑郁症（MDD）是一种使人衰弱的疾病。MDD患者的自杀未遂率比普通人群高5倍。有趣的是，并非所有MDD患者都会产生自杀念头或完成自杀行为。因此，研究能够区分MDD患者自杀倾向的风险因素非常重要。本研究探讨了DNA甲基化变化是否能够区分抑郁症患者中的自杀行为。使用850K Infinium甲基化EPIC芯片，对抑郁症自杀患者（MDD+S；n = 15）、抑郁症非自杀患者（MDD-S；n = 17）和非精神疾病对照者（C；n = 16）的背外侧前额叶皮质进行全基因组DNA甲基化检测。使用显著差异甲基化基因来确定基因的功能富集，以进行本体聚类和通路分析。根据基因特定标志性区域的CpG含量及其相对分布数量，在C组与MDD+/-S组的12,574个基因中鉴定出32,958个甲基化位点，C组与MDD-S组的12,019个基因中鉴定出30,852个甲基化位点，C组与MDD+S组的13,941个基因中鉴定出41,648个甲基化位点，MDD-S组与MDD+S组的15,015个基因中鉴定出49,848个甲基化位点。甲基化位点比较显示，与MDD+S组相比，MDD-S组中有33,129个独特的甲基化位点和5451个基因。功能分析表明，MDD组中与自杀相关的通路涉及催产素、γ-氨基丁酸（GABA）、血管内皮生长因子A（VGFA）、肿瘤坏死因子α（TNFA）和雷帕霉素靶蛋白（mTOR）。总之，我们的数据显示，与非自杀性MDD患者相比，MDD自杀患者的DNA甲基化模式、差异甲基化位点的基因组分布、基因富集和通路具有明显差异。
