Context: Brain-derived neurotrophic factor (BDNF) plays a pivotal role in the pathophysiology of suicidal behavior and BDNF levels are decreased in the brain and plasma of suicide subjects. So far, the mechanisms leading to downregulation of BDNF expression are poorly understood. Objectives: To test the hypothesis that alterations of DNA methylation could be involved in the dysregulation of BDNF gene expression in the brain of suicide subjects. Design: Three independent quantitative methylation techniques were performed on postmortem samples of brain tissue. BDNF messenger RNA levels were determined by quantitative real-time polymerase chain reaction. Setting: Academic medical center. Patients or Other Participians: Forty-four suicide completers and 33 nonsuicide control subjects of white ethnicity. Main outcomemeasures:The DNA methylation degree at BDNF promoter IV and the genome-wide DNA methylation levels in the brain's Wernicke area. Results: Postmortem brain samples from suicide subjects showed a statistically significant increase of DNA methylation at specific CpG sites in BDNF promoter/exon IV compared with nonsuicide control subjects (P ( .001). Most of the CpG sites lying in the -300/+500 region, on both strands, had low or nomethylation, with the exception of a few sites located near the transcriptional start site that had differential methylation, while genome-wide methylation levels were comparable among the subjects. The mean methylation degree at the 4 CpG sites analyzed by pyrosequencing was always less than 12.9% in the 33 nonsuicide control subjects, while in 13 of 44 suicide victims (30%), the mean methylation degree ranged between 13.1% and 34.2%. Higher methylation degree corresponded to lower BDNF messenger RNA levels. (Abstract truncated at 2000 characters)
COBISS.SI-ID: 26684633
Background: Brain-derived neurotrophic factor (BDNF) mediates neural plasticity, mood, different behaviours, and stress response. A functional BDNFpolymorphism (BDNF Val66Met) was reported to influence the effects of stressful life events or childhood adversity on depression and suicidal behaviour in various psychopathologies. The study evaluated the association between BDNF Val66Met variants and suicide, committed with violent or non- violent methods, in victims with or without stressful childhood experience. Methods: BDNF Val66Met polymorphism was genotyped on 560 DNA samples from 359 suicide victims and 201 control subjects collected on autopsy from unrelated Caucasian subjects and subdivided according to gender, method of suicide, and influence of childhood adversity. Results: A similar frequency of BDNF Val66Met variants was found between all included suicide victims and the control groups, and also between the male groups. The frequency of the combined Met/Met and Met/Val genotypes and the homozygous Val/Val genotype wassignificantly different between the female suicide victims and female controls, between the female suicide victims who used violent suicide methods and female controls, and between all included suicide victims with or without stressful life events. The combined Met/Met and Met/ Val genotypes contributedto this significance. Limitation: A small group of suicide victims with available data on childhood adversity was studied. Conclusions: The combined Met/Met and Met/Val genotypes of the BDNF Val/Met variant could be the risk factor for violent suicide in female subjects and for suicide in victims exposed to childhood trauma. These results confirm a major role of BDNF in increased vulnerability to suicide.
COBISS.SI-ID: 27184089
One of the candidate genes for suicide is also a gene in the pathway for catecholamine degradation encoding an enzyme catehol-O-methyl-transferase (COMT). It harbors a common functional polymorphism, a G to A nucleotide transition resulting in amino acid substitution from valine (Val) to methionine (Met) at position 158 (COMT Val(108/158) Met; rs4680) that has been associated with psychiatric disorders characterized with an increased riskof suicidal behavior. We have performed the first study on Caucasian population examining the association between completed suicide and the COMT Val(108/158) Met polymorphism. The study population consisted of 356 suicide victims and 198 control subjects. Significant difference in COMT Val(108/158) Met variants (genotypes, alleles and Val carriers) distribution was found only in male groups, between controls and suicide victims (p = 0.018; p = 0.031; p = 0.005), and between controls and violent suicide victims (p = 0.026; p = 0.042; p = 0.010). The R value from the standardized residuals revealed that the Met/Met genotype (R = 2.03) in the control group contributedto these significant differences. In contrast to male subjects, no significant differences in the frequency of the COMT Val(108/158) Met variantswere detected between female control and female suicide groups; however the POC (range 0.161-0.680) was below the desired 0.800. In addition, the logistic regression analysis confirmed these significant differences. In conclusion, our results showed the over-presentation of the Met/Met genotype in male control subjects compared to male suicide victims, suggesting that this genotype of the COMT Val(108/158) Met might be a protective factor against suicide.
COBISS.SI-ID: 28292313
In Europe, the countries with the highest suicide rates form a so-called J-curve, which starts in Finland and extends down to Slovenia-a country with one of the worldćs highest suicide rates. So far, the strongest association between suicide and genes has been shown for the serotonergic system. A functional polymorphism 68G)C (Cys23Ser) and a promoter polymorphism- 995G)A of serotonin receptor 2C (HTR2C) have already been investigated, but no associations with suicide were determined. In the present study 334 suicide victims and 211 controls of Slovenian origin were genotyped for the above-mentioned polymorphisms using standard methods. In the case of the polymorphism-995G)A no association with suicide was found. However, a significant association was observed between female suicide victims and polymorphism 68G)C. The significance remained when we combined alleles of female and male populations. An excess of GG genotype and allele G was observed. However, no statistically important differences were present when only males were analyzed. Haplotype analysis on female population showed marginal association of haplotype GCwith suicide. The present study speaks forthe plausible implication of the HTR2C in suicide susceptibility.
COBISS.SI-ID: 25585625