Association of BDNF Promoter Methylation and Genotype with Suicidal Ideation in Elderly Koreans

Kim, Jae-Min; Kang, Hee‐Ju; Bae, Kyung‐Yeol; Kim, Sung‐Wan; Shin, Il‐Seon; Kim, Hye‐Ran; Shin, Myung‐Geun; Yoon, Jin‐Sang

doi:10.1016/j.jagp.2014.02.011

Cited by 36 publications

(25 citation statements)

References 43 publications

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“…Specifically, in the Wernicke area of suicide completers, four CpG sites located downstream of transcription initiation site of the promoter in exon 4 of BDNF were more highly methylated in suicide completers than in control individuals, and this increased methylation was associated with markedly lowered BDNF expression, which is consistent with the expected repressive effects of methylation in promoter sequences on transcription 83 . In line with these findings, recent studies have reported that living patients with depression show differential methy lation of the BDNF promoter in peripheral samples [84][85][86] . In addition, studies have revealed that suicide completers have differential methylation in the promoter 79 and in a transcript-specific 3´ untranslated region (UTR) 80 of TRKB in the prefrontal cortex.…”

Section: Impulsive Aggressive Behaviourssupporting

confidence: 65%

The molecular bases of the suicidal brain

2014

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Suicide ranks among the leading causes of death around the world and takes a heavy emotional and public health toll on most societies. Both distal and proximal factors contribute to suicidal behaviour. Distal factors - such as familial and genetic predisposition, as well as early-life adversity - increase the lifetime risk of suicide. They alter responses to stress and other processes through epigenetic modification of genes and associated changes in gene expression, and through the regulation of emotional and behavioural traits. Proximal factors are associated with the precipitation of a suicidal event and include alterations in key neurotransmitter systems, inflammatory changes and glial dysfunction in the brain. This Review explores the key molecular changes that are associated with suicidality and discusses some promising avenues for future research.

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Section: Impulsive Aggressive Behaviourssupporting

confidence: 65%

The molecular bases of the suicidal brain

2014

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“…A recent report has also pointed out higher occurrence of hypermethylation in BDNF exon IV in Wernicke’s area of post-mortem brain of suicidal patients (Keller et al, 2010). Another study in blood cells of MDD patients suggests that suicide is strongly associated with impaired BDNF function due to its altered DNA methylation (Kim et al, 2014). Our current observation of altered BDNF methylation in PBMCs from MDD patients with serious suicidal ideation and a previous study (Dwivedi et al, 2003) showing decreased BDNF expression in post-mortem brain tissue from MDD patients who died by suicide support a strong relationship of DNA modification and reduced expression of BDNF with suicidal behavior in MDD patients.…”

Section: Discussionmentioning

confidence: 99%

“…In this regard, modulation in neuronal functions mediated by epigenomic changes, which cause alteration in chromatin architecture without affecting the nucleotide sequence arrangements in DNA, have been identified as one of the major risk factors in several psychiatric illnesses including depression and suicidal behavior (Haghighi et al, 2014; Higuchi et al, 2011; Keller et al, 2010; Maussion et al, 2014; Numata et al, 2015; Zhang et al, 2014; Zhang et al, 2015). Interestingly, in suicidal patients, a few studies show that these epigenetic modifications can be independent of psychiatric illnesses such as depression (Kang et al, 2013; Kim et al, 2014). The present study was undertaken to further examine whether epigenetic modifications of stress related genes play a role in suicidal behavior and whether these modifications are common to or independent of depression.…”

Section: Introductionmentioning

confidence: 99%

DNA methylation and expression of stress related genes in PBMC of MDD patients with and without serious suicidal ideation

Roy

Shelton

Dwivedi

2017

Journal of Psychiatric Research

108

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Stress plays an important role in major depressive disorder (MDD) and is one of the state dependent factors in suicidal behavior. A dysfunctional hypothalamic-pituitary-adrenal axis is a common feature in this disorder. The involvement of environmental factors has added additional complexity to understanding depression or suicidal behavior. In this regard, epigenetic regulation has been considered a mechanistic interface between environmental stress stimuli and altered functioning of underlying gene network that may increase susceptibility to depression or suicidal behavior. The present study examined whether epigenetic modifications of stress related genes are associated with MDD and whether there are differences in these epigenetic marks between depressed individuals with and without serious suicidal ideation. Using MeDIP analysis in genomic DNA isolated from peripheral blood mononuclear cells (PBMC) of healthy controls (n=20), MDD patients with (n=14) or without serious suicidal ideation (n=10), we studied methylation of the stress-associated genes Brain Derived Neurotrophic Factor (BDNF), Nuclear Receptor Subfamily 3 Group C Member 1 (NR3C1), FK506 Binding Protein 5 (FKBP5), Corticotropin Releasing Hormone Binding Protein (CRHBP), and Corticotropin Releasing Hormone Receptor 1 (CRHR1) . In addition, we determined their transcript levels in RNAs isolated from the same PBMC. We found that BDNF, FKBP5, CRHBP, and NR3C1 gene promoters were significantly hypermethylated in MDD patients with and without suicidal ideation. We also found concomitant reductions in expression of BDNF, FKBP5 transcript variants (1, 2 and 3), and NR3C1 genes in these patients, suggesting that promoter hypermethylation in these genes may functionally be associated with their observed downregulation in MDD patients. In a secondary analysis, methylation of these genes was compared between MDD patients with or without serious suicidal ideation and controls. The MDD with serious suicidal ideation were significantly different from controls while the MDD without were not, although MDD with or without suicidal ideation were not different from each other, likely owning to a relatively small sample size. Thus, our findings underline the importance of epigenetic modifications of stress-associated genes in depression and, possibly, suicidal behavior, which, in future, needs to be confirmed in a larger patient population.

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“…Five studies [11,12,13,14,15] found that the 196A allele was a risk factor for suicidal behavior, while a further 2 studies [16,17] suggested that the 196G allele was the primary risk factor for attempted suicide. On the other hand, other studies [9,18,19,20] did not support the association of the BDNF G196A polymorphism and suicidal behavior. Finally, a meta-analysis [21] suggested that the BDNF G196A was involved in suicidal behavior after combining 11 previously published studies with 1 original sample.…”

Section: Introductionmentioning

confidence: 82%

Association of Brain-Derived Neurotrophic Factor G196A and Attempted Suicide: A Case-Control Study in Rural China

Wang

Wang²,

Wang³

et al. 2015

Neuropsychobiology

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Background: Suicide is an important public problem, the mechanism of which has not been clarified. Many studies have focused on the molecular, biological and genetic mechanisms of suicide. Brain-derived neurotrophic factor (BDNF) G196A is one of the most leading loci in recent studies, but the results are inconsistent. Methods: We conducted a 1:1 age- and sex-matched case-control study in rural areas of Shandong Province, China. A total of 365 pairs of cases and controls were finally recruited into our study. The adjusted odds ratios (AORs) of BDNF 196G/G and their 95% confidence intervals (CIs) were calculated by multivariate conditional logistic regression models. Results: No association between BDNF polymorphisms and attempted suicide was found in the overall population. However, the BDNF 196G/G genotype was significantly related to attempted suicide in the elderly population (AOR = 7.85, 95% CI: 1.12-54.90, p = 0.038), while the associations were not significant in young and middle-aged groups. Conclusion: Our study suggests that the BDNF 196G/G genotype increases the risk of attempted suicide in elderly people.

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Association of BDNF Promoter Methylation and Genotype with Suicidal Ideation in Elderly Koreans

Cited by 36 publications

References 43 publications

The molecular bases of the suicidal brain

The molecular bases of the suicidal brain

DNA methylation and expression of stress related genes in PBMC of MDD patients with and without serious suicidal ideation

Association of Brain-Derived Neurotrophic Factor G196A and Attempted Suicide: A Case-Control Study in Rural China

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