BDNF methylation and mRNA expression in brain and blood of completed suicides in Slovenia

Abstract

BACKGROUND Suicide is a major public health problem. Worldwide, around 800000 people die by suicide every year. Suicide is a multifactorial disorder, with numerous environmental and genetic risk factors involved. Among the candidate genes, changes in the BDNF locus at the gene, epigenetic, mRNA, and protein expression levels have been implicated in psychiatric disorders, including suicidal behavior and completed suicides. AIM To investigate changes in BDNF methylation and expression of four alternative BDNF transcripts for association with completed suicide. METHODS This case-control study included 42 unrelated male Caucasian subjects, where 20 were control subjects who died following acute cardiac arrest, and 22 were suicide victims who died by hanging. DNA and RNA were extracted from brain tissue (Brodmann area 9 and hippocampus) and from blood. DNA methylation and mRNA expression levels were determined by targeted bisulfite next-generation sequencing and reverse-transcription quantitative PCR. Statistical analysis was done by use of two-tailed Student’s t tests for two independent samples, and the Benjamini-Hochberg procedure was implemented for correction for multiple comparisons. RESULTS In DNA from brain tissue, there were no significant differences in BDNF methylation between the study groups. However, data showed significantly reduced DNA methylation of the BDNF region upstream of exon I in blood samples of suicide victims compared to the controls (5.67 ± 0.57 vs 6.83 ± 0.64, P corr = 0.01). In Brodmann area 9 of the brain of the suicide victims but not in their hippocampus, there was higher expression of BDNF transcript I-IX (NM_170731.4) compared to the controls (0.077 ± 0.024 vs 0.05 ± 0.013, P = 0.042). In blood, expression analysis for the BDNF transcripts was not feasible due to extensive RNA degradation. CONCLUSION Despite the limitations of the study, the obtained data further support a role for BDNF in suicidality. However, it should be noted that suicidal behavior is a multifactorial disorder with numerous environmental and genetic risk factors involved.

Molecular Changes Associated with Suicide

“…However, hypomethylation of the BDNF region upstream of exon I has been found in blood samples of suicide victims. In contrast, no differences in DNA methylation were observed in the hippocampus or the DLPFCx [190].…”

Genetics and epigenetics of self‐injurious thoughts and behaviors: Systematic review of the suicide literature and methodological considerations

“…The most commonly studied gene system was BDNF ( N = 10, including two studies investigating the TrkB.T1 gene; Kang et al, 2018; Ropret, Kouter, Zupanc, & Videtic Paska, 2021; Roy, Shelton, & Dwivedi, 2017; Kim et al, 2015; Kim et al, 2014; Maussion et al, 2014; Kang et al, 2013; Keller et al, 2011; Keller et al, 2010; Ernst et al, 2009). Of the eight studies examining methylation specifically in the BDNF gene, six found BDNF hypermethylation to be implicated across a range of SITB outcomes, while one study of SI found no group differences (Roy, Wang, Palkovits, Faludi, & Dwivedi, 2017), and an SD study found hypomethylation (Ropret et al, 2021).…”

“…Finally, regarding the average methylation level across the Kang et al, 2013;Keller et al, 2011;Keller et al, 2010;. Of the eight studies examining methylation specifically in the BDNF gene, six found BDNF hypermethylation to be implicated across a range of SITB outcomes, while one study of SI found no group differences (Roy, Wang, Palkovits, Faludi, & Dwivedi, 2017), and an SD study found hypomethylation (Ropret et al, 2021).…”

Impact of Baduanjin exercise combined with rational emotive behavior therapy on sleep and mood in patients with poststroke depression: A randomized controlled trial

“…[31][32][33] Reduced BDNF expression can affect the recovery of neurological function in PSD patients, while increased BDNF expression can reduce the accumulation of free radicals, alleviate attacks on neurons, improve the pathological state of neurons, and restore neurological function. [34,35] Extensive evidence suggested that the excessive secretion of glucocorticoids and the decrease of central 5-HT levels are risk factors for depression. The pathogenesis of PSD is related to the dysfunction of the dopaminergic nerve, significantly decreasing 5-HT and norepinephrine levels, which may be an essential cause leading to PSD.…”