Investigation of correlations between DNA methylation, suicidal behavior and aging

Abstract

Objectives: Suicidal behavior (SB) is a major cause of mortality for patients diagnosed with bipolar disorder (BD). In this study, we investigated epigenetic differences in BD participants with and without a history of SB. Methods:We used suicidality scores constructed from Schedule for Clinical Assessments in Neuropsychiatry (SCAN) interview questions about suicidal thought and behavior to identify individuals from a BD cohort of n=452; participants with the most extreme high (H-SB, n=18) and most extreme low (L-SB, n=22) scores were used as cases and controls, respectively. Epigenome-wide DNA methylation patterns were compared between the two groups using the Illumina Infinium Human Methylation 450 BeadChip microarray. DNA methylation age was compared to chronological tissue age. Results:We observed highly significant differences in methylation between cases and controls in three genomic regions enriched for epigenetic modifications corresponding to gene regulatory regions. BD participants with a history of SB showed less overall methylation in the 5′ untranslated region of Membrane palmitoylated protein 4 (MPP4) (P=7.42×10 ), while exon 1 of Nucleoporin 133 (NUP133) was less methylated in controls (P=1.17x10 -6 ). Moreover, we observed a greater correlation between DNA methylation age and tissue age in controls (r=.91, P<.0001) than in the H-SB group (r=.83, P<.0001). Conclusions:We report significant findings at three loci based on a methylome scan of participants with BD for an SB phenotype, and potentially altered molecular aging in suicide attempters. Despite the small sample size, our proof-of-concept study highlights the potential for epigenetic factors to be useful in understanding the molecular underpinnings of suicide with the ultimate aim of its prevention. whereby predictive factors are described as proximal, such as substance use, mood disorders and adherence to treatment, and distal, such as a family history of SB and adverse childhood experiences.Suicidal ideation and completion have also been associated with

Genetic associations with suicide attempt severity and genetic overlap with major depression

“…The third gene identified for EAs with gene-based association analysis was PGBD5 ; it maps 5 MB from “Nucleoporin 133” ( NUP133 ); the latter locus was epigenome-wide significant in a study using a quantitative suicidality score 37 . Although the authors of that study focused more on NUP133 , PGBD5 was discussed for its proximity to top findings and overlap with findings in panic-induced epigenetic H3K27me3 modifications in mice 38 .…”

“…In summary, we identified several associations in genes or associated pathways that have previously been implicated in suicide. Epigenetic modifications near PGBD5 and NUP133 have been associated with quantitative scores for suicidality 37 . Suicidal ideation state changes have been associated with the increased expression of PHLDB2 in independent studies in men 36 and women 35 .…”

Epigenetics of suicidal behavior

“…Some studies have shown a possible role of modified expression of such genes as MPP4 (membrane palmitoylated protein 4), nucleoporin (NUP133), a member of the TRE2/ BuB2/CDC16 family of domains (TBC1D16), the alpha1 subunit of the gamma-aminobutyric acid receptor (GABRA1) in SB development. In particular, a total decrease in methylation in the 5′-UTR of the MPP4 gene and in intron 3 of the TBC1D16 gene together with increased methylation in exon 1 of the NUP133 gene was observed in patients with bipolar disorder and comorbid SB compared to the control group (Jeremian et al, 2017). In addition, hypermethylation of CpG islands in the promoter of the GABRA1 gene was associated with changes in mRNA expression of the DNA methyltransferase gene (DNMT) in the brain of individuals with completed suicide (Poulter et al, 2008).…”

Genome-Wide Dna Methylation Patterns in Suicide Victims: Identification of New Candidate Genes

“…In a study researchers compared blood methylation profile between patients with bipolar disorder showing suicidal behaviour and patients who showed no such behaviour. They as well observed differential levels of methylation of multiple genome regions in patients with suicidal behaviour, identifying three potential candidate genes (Jeremian et al 2017). One of the biggest studies so far observed methylation levels in blood and a subset sample of prefrontal cortex in patients with major depressive disorder.…”