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

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was to identify suicide-associated DNA methylation changes in the human brain by utilising previously published and unpublished methylomic datasets.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.This article is freely available via Open Access. Click on the Publisher URL to access it via the publisher's site.NA/Fondation Brain Canada (Fondation Neuro Canada) MR/K013807/1/MRC_/Medical Research Council/United Kingdom NIMH 1R21MH094771/U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH) MR/K013807/1/Brain and Behavior Research Foundation (Brain & Behavior Research Foundation) MR/K013807/1/RCUK | MRC | Medical Research Foundation NA/Fonds de Recherche du Québec-Société et Culture (FRQSC) R21 MH094771/MH/NIMH NIH HHS/United Statespublished version, accepted version, submitted versio