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was to identify suicide-associated DNA methylation changes in the human brain by utilising previously published and unpublished methylomic datasets.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.
Highlights
Suicide represents a global public health problem, with approximately 800,000 people dying worldwide from suicide annually and suicide attempts up to 20 times more frequent than completed suicide[1]
The 20 most significant (P < 5E-05) suicide-associated differentially methylated loci identified in the prefrontal cortex (PFC), listed in Supplementary Table S3, include probes in the vicinity of several loci previously implicated in psychiatric phenotypes
In this study, we utilised previously published and unpublished methylomic datasets to perform a metaanalysis of variable DNA methylation in the brain of suicide completers
Summary
Suicide represents a global public health problem, with approximately 800,000 people dying worldwide from suicide annually and suicide attempts up to 20 times more frequent than completed suicide[1]. Large-scale genome-wide association studies (GWAS)[4,5,6,7] have failed to identify robust associations suggesting that the risk of SB is highly polygenic in nature and that individual gene variants are likely to account only for a small proportion of the total phenotypic variability[8]. Other factors, such as the environment, behavioural traits, psychiatric diagnosis, lifestyle, and coping mechanisms, are essential regulators of suicide risk and likely to account for more sizeable effects[9]. The epigenome is potentially malleable—changing with age[10], in response to specific environmental[11] and psychosocial factors12—providing a mechanism for the interaction between genotype and the environment[13]
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