Genome-wide DNA methylation meta-analysis in the brains of suicide completers

Abstract

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was to identify suicide-associated DNA methylation changes in the human brain by utilising previously published and unpublished methylomic datasets.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.

Psychoneuroimmunology: The new frontier in suicide research

“…Using postmortem brain samples ( Pandey et al., 2019b ), observed overexpressed protein or mRNA of TLR2-4,6,10 in the prefrontal cortex of depressed suicide decedents. Recent genetic studies have supported involvement of immune-related pathways in suicide ( DiBlasi et al., 2020 ; Policicchio et al., 2020 ). Polygenic risk estimations are undergoing.…”

Epigenetic marks and their relationship with BDNF in the brain of suicide victims

“…In the frontal cortex BDNF is also reduced but it seems to be the effect of gene inhibition based on its methylation. Considering the above knowledge and data from studies indicating both an increase in global DNA methylation [4] and the presence of hypomethylated regions at selected genetic loci in suicides [32,33], it seems justified and necessary to further investigate the role of MeCP2 in the context of mood disorders. HDAC2 increased in HP impaired special memory and synaptic plasticity [74] and with HDAC5 plays important role in MDD patients [75].…”

“…Interestingly, methylomic profiling of brain samples revealed differentially methylated regions (DMRs) in certain genetic loci (especially upstream of the PSORS1C3 gene) associated with suicidal depression. More detailed study of these samples indicated hypomethylated areas within these DMRs and discrete modules of co-methylated loci related with polygenic risk burden only for suicide attempt (not major depression) [32]. On this basis, Murphy et al (2020) conclude the existence of coordinated alterations in DNA methylation that are associated with SB [33].…”

“…So far, DNA methylation is the most frequently studied epigenetic modification of the human genome in the context of mental disorders, including SB [30][31][32][33]. Among others, an associations between stress-related genes like SKA2 (kinetochore-associated protein 2), NR3C1 (Nuclear Receptor Subfamily 3 Group C Member 1), GABA A α1 (Gamma-aminobutyric acid A receptor α1 subunit), hGR (human glucocorticoid receptor), SAT1 (diamine acetyltransferase 1) or HTR2A (5-Hydroxytryptamine Receptor 2A) in brain multiple cohorts and suicidal behavior were demonstrated [34][35][36][37][38].…”

“…On the other hand, numerous modifications of histones and enzymes involved in their formation have been described in post mortem brain tissues [32]. Distinct histone modifications are related with genomic features.…”