Epigenetic Dysregulation in the Prefrontal Cortex of Suicide Completers

Abstract

The epigenome is thought to mediate between genes and the environment, particularly in response to adverse life experiences. Similar to other psychiatric diseases, the suicide liability of an individual appears to be influenced by many genetic factors of small effect size as well as by environmental stressors. To identify epigenetic marks associated with suicide, which is considered the endpoint of complex gene-environment interactions, we compared the cortex DNA methylation patterns of 6 suicide completers versus 6 non-psychiatric sudden-death controls, using Illumina 450K methylation arrays. Consistent with a multifactorial disease model, we found DNA methylation changes in a large number of genes, but no changes with large effects reaching genome-wide significance. Global methylation of all analyzed CpG sites was significantly (0.25 percentage point) lower in suicide than in control brains, whereas the vast majority (97%) of the top 1,000 differentially methylated regions (DMRs) were higher methylated (0.6 percentage point) in suicide brains. Annotation analysis of the top 1,000 DMRs revealed an enrichment of differentially methylated promoters in functional categories associated with transcription and expression in the brain. In addition, we performed a comprehensive literature research to identify suicide genes that have been replicated in independent genetic association, brain methylation and/or expression studies. Although, in general, there was no significant overlap between different published data sets or between our top 1,000 DMRs and published data sets, our methylation screen strengthens a number of candidate genes (APLP2, BDNF, HTR1A, NUAK1, PHACTR3, MSMP, SLC6A4, SYN2, and SYNE2) and supports a role for epigenetics in the pathophysiology of suicide.

Differentially methylated regions in bipolar disorder and suicide

“…This approach allowed us to detect DNA methylation variation specific to BD subjects with suicidal behavior in the ARHGEF38 gene. Although our DMR findings show limited overlap with published BD and suicide methylome studies (Abdolmaleky et al, ; Chen et al, ; Dempster et al, ; Guintivano et al, ; Haghighi et al, ; Labonte et al, , ; Mill et al, ; Murphy et al, ; Nagy et al, ; Ruzicka et al, ; Schneider et al, ; Xiao et al, ; Zhao et al, ), our pathway analyses add to converging evidence of specific pathway dysregulation in BD and suicide. Both novel and converging findings are discussed below.…”

“…Correspondingly, using a hypothesis‐free approach, several studies have sought to identify DNA methylation differences throughout the genome in brain tissue samples of BD subjects with notable results providing evidence for genes such as Catenin Alpha 2 ( CTNNA2 ) (Abdolmaleky et al, ; Chen et al, ; Dempster et al, ; Mill et al, ; Ruzicka, Subburaju, & Benes, ; Xiao et al, ; Zhao et al, ). Similarly, genome‐wide studies focusing on suicide have identified genes with altered DNA methylation patterns, such as Glutamate Ionotropic Receptor Kainate Type Subunit 2 ( GRIK2 ), and pathways of interest linked to neuronal plasticity and memory (Guintivano et al, ; Haghighi et al, ; Labonte et al, , ; Murphy et al, ; Nagy et al, ; Schneider, El Hajj, Muller, Navarro, & Haaf, ). One genome‐wide study, looking across disorders in both brain and blood samples, identified a potential suicide biomarker within the Spindle And Kinetochore Associated Complex Subunit 2 ( SKA2) gene (Guintivano et al, ), highlighting the potential for a role of epigenetics in the diagnosis and treatment of suicidal behavior.…”

Identification of gene ontology and pathways implicated in suicide behavior: Systematic review and enrichment analysis of GWAS studies

“…Researchers of suicide behavior are looking for predisposing (distal) and precipitating (proximal) factors (Conejero, Olie, Courtet, & Calati, ; Gerada, ; Gvion & Levi‐Belz, ; Speed et al, ). Besides, there are several biological, genetic, and environmental abnormalities have been reported in SB, but it is not clear which ones are risk factors (Fiori et al, ; Schneider et al, ). On the other hand, the use of GWAS methods came to revolutionize the studies of possible genetic factors for suicide behavior; they let us map the whole genome in search of genetics variants (Galfalvy et al, ; Menke et al, ; Perlis et al, ; Schosser et al, ).…”

“…In this sense, simultaneous investigations of thousands of Single Nucleotide Polymorphisms (SNPs) that individually do not reach statistical significance could explain a greater amount of the heritability (Bani‐Fatemi, Graff, Zai, Strauss, & De Luca, ; Galfalvy et al, ; Menke et al, ; Willour et al, ; Zai et al, ). Nevertheless, suicide attempt (SA), suicide ideation (SI), and suicide victims (SV) might have differences in clinical views, genetic studies show that could be possible to share etiology and have a corresponding common genetic architecture (Schneider, El Hajj, Muller, Navarro, & Haaf, ; Sokolowski, Wasserman, & Wasserman, ; Thornton, Welch, Munn‐Chernoff, Lichtenstein, & Bulik, ; Tombacz et al, ; Zhao et al, ). Therefore, the aim of this study was to perform a comprehensive review which explored genes associated with SB in GWAS methods, to characterize a common gene ontology (GO) and biological pathways that could be implicated in the genetic architecture of suicide.…”

Promoter activity-based case-control association study onSLC6A4highlighting hypermethylation and altered amygdala volume in male patients with schizophrenia

“…In addition to 5-HTTLPR, altered DNA methylation of the promoter region of this gene has been reported to be associated with childhood maltreatment, [14][15][16][17] bullying, 18 low socioeconomic status, 19,20 stressful life events, 21,22 suicide, 23 depressive symptoms, [24][25][26] major depression, 27-30 and bipolar disorder (BD). 31 Although patients with schizophrenia (SZ) frequently exhibit depressive symptoms in various stages of the illness, few studies have analyzed the DNA methylation status of SLC6A4 in SZ.…”