Epigenetic and Transcriptomic Alterations of Protein Aggregation-Linked Genes in Suicide: A Pilot Study

<b>Background</b><b>/Objectives</b>: Suicide is a significant public health concern with a multifactorial etiology. The biological background of suicide is not sufficiently explored, which encumbers suicide prevention. Epigenetic mechanisms may mediate environmental influences on suicide risk. Recent studies have suggested that protein aggregation occurs in the brains of patients with chronic psychiatric disorders and suicidality, which may influence disease trajectory. However, the intersection between epigenetics and proteinopathy in suicide remains unexplored. Our pilot study investigated whether aggregation-related genes show epigenetic and transcriptional alterations in the post-mortem brains of individuals who had died by suicide. <b>Methods</b>: Brain tissue from 69 male subjects (32 suicide by hanging, 37 sudden cardiac death controls) was collected at autopsy. Genome-wide hippocampal DNA methylation data from our previous reduced representation bisulfite sequencing (RRBS) study were reanalyzed to identify differentially methylated cytosines (DMCs) in candidate aggregation-related genes. The expression of nine candidate and three reference genes in the hippocampus and Brodmann area 46 was assessed by qPCR. Statistical analyses were performed using Student's <i>t</i>-test or Mann-Whitney U test (<i>p</i> < 0.05 was considered significant). <b>Results:</b> Reanalysis revealed hypomethylation in suicide cases within <i>CRMP1</i>, <i>DISC1</i>, <i>MAPT</i>, <i>SOD1</i>, <i>PRKN</i>, <i>GABARAPL1</i>, <i>GRIN2A,</i> and <i>GRIN2B</i>. In the hippocampus, suicides exhibited increased expression of <i>CRMP1</i>, <i>SOD1</i>, <i>PRKN</i>, <i>GABARAPL1</i>, and <i>GRIN2A</i>, and decreased <i>MAPT</i> expression. The <i>GRIN2A/GRIN2B</i> ratio was significantly elevated. In Brodmann area 46, altered expression was limited to increased <i>GRIN2A</i> and decreased <i>DISC1</i>. <b>Conclusions</b>: This is the first study to implicate epigenetic and transcriptional dysregulation of protein aggregation-associated genes in suicide. The findings suggest a possible role for proteostasis disturbances in suicidality, particularly within the hippocampal pathways related to stress response and synaptic signaling. Validation in larger cohorts and protein-level studies are warranted to determine the functional significance of these findings.