Epigenetics and suicide: investigating altered H3K14ac unveiled differential expression in ADORA2A, B4GALT2 and MMP14.

Background: Environmental factors make an important contribution to suicide. Histone tails are prone to different modifications, leading to changes of chromatin (de)condensation and consequently gene expression. Materials & methods: Level of H3K14ac was studied with chromatin immunoprecipitation followed by high-throughput DNA sequencing. Genes were further validated with RT-qPCR; using hippocampal tissue. Results: We showed lowered H3K14ac levels in individuals who died by suicide. The genes ADORA2A, B4GALT2 and MMP14 showed differential expression in individuals who died by suicide. Identified genetic and protein interactions among genes show interactions with suicide-related genes. Conclusion: Further investigations of histone modifications in association with DNA methylation and miRNA are needed to expand our knowledge of the genes that could significantly contribute to suicide.

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Biomarkers for suicidal behavior: miRNAs and their potential for diagnostics through liquid biopsy - a systematic review.

Background: Given that approximately 70% of miRNAs in the body are neuronal, we critically assessed current studies on miRNAs and suicidal behavior. Materials & Methods: To further define the role of miRNAs in suicide, we searched for studies on extracellular vesicles (exosomes) because miRNAs are particularly enriched in exosomes. miRNAs also have important physiological roles, and they can cross the blood-brain barrier and participate in cell-to-cell communication with both nearby and distant cells. Results & Conclusion: This critical assessment suggests that several miRNAs can be closely related to neurophysiology, suicidal behavior, and psychiatric disorders. However, clear overlap is poor due to either different methodologies applied or to molecular differences between suicidal behaviors and studied psychiatric disorders.

Analysis of promoter polymorphism in monoamine oxidase A (MAOA) gene in completed suicide on Slovenian population.

Suicide is a well-defined public health problem and is a complex phenomenon influenced by a number of different risk factors, including genetic ones. Numerous studies have examined serotonin system genes. Monoamine oxidase A (MAO-A) is an outer mitochondrial membrane enzyme which is involved in the metabolic pathway of serotonin degradation. Upstream variable number of tandem repeats (uVNTR) in the promoter region of MAOA gene affects the activity of transcription. In the present study we genotyped MAOA-uVNTR polymorphism in 266 suicide victims and 191 control subjects of Slovenian population, which ranks among the European and world populations with the highest suicide rate. Genotyping was performed with polymerase chain reaction and agarose gel electrophoresis. Using a separate statistical analysis for female and male subjects we determined the differences in genotype distributions of MAOA-uVNTR polymorphism between the studied groups. Statistical analysis showed a trend towards 3R allele and suicide, and associated 3R allele with non-violent suicide method on stratified data (20 suicide victims). This is the first study associating highly suicidal Slovenian population with MAOA-uVNTR polymorphism.

Aberrant methylation patterns in cancer: a clinical view.

Epigenetic mechanisms, such as DNA methylation, DNA hydroxymethylation, post-translational modifications (PTMs) of histone proteins affecting nucleosome remodelling, and regulation by small and large non-coding RNAs (ncRNAs) work in concert with cis and trans acting elements to drive appropriate gene expression. Advances in detection methods and development of dedicated platforms and methylation arrays resulted in an explosion of information on aberrantly methylated sequences linking deviations in epigenetic landscape with the initiation and progression of complex diseases. Here, we consider how DNA methylation changes in malignancies, such as breast, pancreatic, colorectal, and gastric cancer could be exploited for the purpose of developing specific diagnostic tools. DNA methylation changes can be applicable as biomarkers for detection of malignant disease in easily accessible tissues. Methylation signatures are already proving to be an important marker for determination of drug sensitivity. Even more, promoter methylation patterns of some genes, such as MGMT, SHOX2, and SEPT9, have already been translated into commercial clinical assays aiding in patient assessment as adjunct diagnostic tools. In conclusion, the changes in DNA methylation patterns in tumour cells are slowly gaining entrance into routine diagnostic tests as promising biomarkers and as potential therapeutic targets.

Blood alcohol concentration of suicide victims by partial hanging.

During the investigated period, 2000-2007, 4249 suicides were reported in Slovenia, and 1061 autopsies of suicide deaths from the central, northwestern, and southwestern parts of Slovenia were conducted at the Institute of Forensic Medicine in Ljubljana. To identify a possible role of alcohol use in the selection of suicide method blood samples were collected during medicolegal autopsies of suicide victims in order to establish their blood alcohol concentration (BAC) level at the time of death. The study group consisted of 844 suicide victims that used violent suicide methods and 174 suicide victims that used non-violent suicide methods. Out of the group with violent suicide methods 184 (21.8%) suicide victims by partial hanging and 112 (13.3%) suicide victims by complete hanging were identified. The average age was higher in the group of suicide victims by partial hanging than in the group of suicide victims by complete hanging (p < 0.001; T = 3653; df = 294). The mean BAC was higher (T = 1.604; df = 278; p < 0.05) in the group of suicide victims by partial hanging (0.57 g/kg; SD ± 0.92) than in the group of suicide victims by complete hanging (0.40 g/kg; SD ± 0.82). The proportion of BAC positive suicide victims with blood alcohol concentration above 0.1 g/kg at the time of death was higher in the group of suicide victims who used non-violent suicide methods in comparison to the group of suicide victims who used violent suicide methods (p < 0.001; χ(2) = 14.988, df = 1). Partial hanging was almost twice as common as complete hanging. Higher BAC in the group of suicide victims by partial hanging and more BAC positive suicide victims in the group who died by non-violent suicide methods could give indications about the role of alcohol in the selection of suicide method.

Tryptophan hydroxylase 2 (TPH 2) single nucleotide polymorphisms, suicide, and alcohol-related suicide.

BACKGROUND: Suicide has been identified as a serious public health problem that is often accompanied by alcohol misuse and dependence. It seems that suicide is a result of an interplay between distal (e.g. genetic loading, family history of suicide) and proximal factors (e.g. existence of psychiatric disorder, events conferring acute stress), as well as their interactions. However, like suicide, alcohol dependence seems to be a multifactorial disorder caused by genetic and environmental factors. Serotonergic dysfunction has been implicated to be involved in the pathophysiology of substance abuse, and has also an important role in suicidal behaviour. Studies investigating suicide, alcohol-related suicide and the rate limiting enzyme of serotonin synthesis, tryptophan hydroxylase 2 (TPH2), remain to date rather limited. RESULTS: Recent studies of TPH2 showed a range of strong, mild or no association with suicide and alcohol-related suicide, depending on a study group and genetic variants tested. Overall, to date the clinical effects seems to be quite modest. Among suicide victims with more impulsive and verbal aggressive behaviour more alcohol misuse or dependency was present. CONCLUSIONS: Suicide and alcoholism are often comorbid disorders with a complex nature. They are both strongly linked to serotonin modulation, and therefore association studies of SNPs in genes from the serotonergic system could provide an insight into the genetic background of such disorders. However, based on current results we cannot draw any conclusions, but further research to clarify the interplay between serotonergic system dysfunction, suicide, alcohol dependence, impulsivity and the role of TPH2 enzyme is needed.

The role of brain-derived neurotrophic factor in the pathophysiology of suicidal behavior.

Suicidal behaviour is a major public health concern. It is known that the pathogenesis of suicidal behaviour involves altered neural plasticity, resulting in the aberrant stress response of the central nervous system to environmental factors. Indeed, altered brain structure and function was found in suicide victims. Neurotrophins are growth factors that are involved in the regulation of structural, synaptic, and morphological plasticity and in the modulation of the strength and number of synaptic connections and neurotransmission. Brain-derived neurotrophic factor (BDNF) the most studied and the most widely distributed among neurotrophins binds to a tropomyosin-related kinase B (TrkB) receptor and to a pan75 neurotrophins receptor. It has been reported that BDNF production is decreased in all patients with suicidal behaviour and in all suicide victims regardless of a psychiatric diagnosis. It was also found that the mRNA and protein level of BDNF was significantly lower in both the prefrontal cortex and the hippocampus of suicide subjects. Different mechanisms could be involved in the regulation of BDNF gene expression, among which epigenetic mechanisms seem to play a key role. However, also for a functional polymorphism (rs6265) Val66Metit has been shown that the Met allele is associated with the reduced BDNF activity. Further, a recent meta-analysis including 12 studies showed a trend for the Met-carrying genotypes and Met allele conferring risk for suicide. Among included studies, our study with the largest sample size, indicated that the combined Met/Met and Met/Val genotypes of the BDNF Val66Met variant could be the risk factor for violent suicide in female subjects and for suicide in victims exposed to childhood trauma. In accordance with previous reports, our findings demonstrate that aberrant regulation of BDNF synthesis is associated with suicidal behaviour.

Gene expression profiling of rat fetuses exposed to 2-dimensional ultrasound.

OBJECTIVES: This study evaluated the possible effects of ultrasound (US) on gene expression in brain tissue of rat embryos. METHODS: Four groups (n = 5 each) of pregnant Wistar Han rats were exposed to US for different durations (55, 100, 145, and 195 seconds) via a multifrequency transducer in the 2-dimensional imaging mode with a pulse duration of 1.29 microseconds, a pulse repetition frequency of 1 kHz, and a derated spatial-peak pulse-average intensity of 222.4 W/cm(2) on day 5, 9, 7, or 13 of gestation. Gene expression profiling was performed in fetal brain tissue (n = 5 per group) by quantitative reverse transcription-polymerase chain reaction arrays. RESULTS: The results indicated substantial alterations in gene expression. The most differentially expressed genes were Adamts5, Gadd45a, Npy2r, and Chrna1, which are implicated in important developmental signaling pathways. CONCLUSIONS: On the basis of our findings, routine short US examinations for monitoring fetal development are not contraindicated, but prolonged exposures should be used only when needed to obtain important diagnostic information.

TPH2 polymorphisms and alcohol-related suicide.

Substantial evidence from family, twin, and adoption studies corroborates implication of genetic and environmental factors, as well as their interactions, on suicidal behavior and alcoholism risk. Serotonergic disfunction seems to be involved in the pathophysiology of substance abuse, and has also an important role in suicidal behavior. Recent studies of the tryptophan hydroxylase 2 showed mild or no association with suicide and alcohol-related suicide. We performed SNP and alcohol analysis on 388 suicide victims and 227 controls. The results showed association between suicide (Pχ²=0.043) and alcohol-related suicide (Pχ²=0.021) for SNP Rs1843809. A tendency for association was determined also for polymorphism Rs1386493 (Pχ²=0.055) and alcohol-related suicide. Data acquired from psychological autopsies in a subsample of suicide victims (n=79) determined more impulsive behavior (Pχ²=0.016) and verbal aggressive behavior (Pχ²=0.025) in the subgroup with alcohol misuse or dependency. In conclusion, our results suggest implication of polymorphisms in suicide and alcohol-related suicide, but further studies are needed to clarify the interplay among serotonergic system disfunction, suicide, alcohol dependence, impulsivity and the role of TPH2 enzyme.

The association between brain-derived neurotrophic factor polymorphism (BDNF Val66Met) and suicide.

BACKGROUND: Brain-derived neurotrophic factor (BDNF) mediates neural plasticity, mood, different behaviours, and stress response. A functional BDNF polymorphism (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 560DNA 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 was significantly 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 contributed to 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 Val66Met 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.

No association between polymorphisms in four serotonin receptor genes, serotonin transporter gene and alcohol-related suicide.

BACKGROUND: Serotonin (5-HT) is an important neurotransmitter with wide-ranging functions. Its disfunction in the central nervous system seems to play an important role in many psychiatric disorders and suicidal behavior. The objective of this study was to examine the association between polymorphisms in different serotonin receptor genes (HTR): HTR1A (polymorphism -1019C>G), HTR1B (polymorphisms 861G>C and -161A>T), HTR1F (polymorphism -78C>T) and HTR2A (polymorphism -1420C>T), and serotonin transporter gene (5-HTT) (polymorphism LPR in promoter and VNTR in the second intron), and completed alcohol-related suicide, as well as between alcohol-dependent suicide victims. SUBJECTS AND METHODS: The study subjects were 373 Slovenian suicide victims (mean age ± SD: 48.8 ± 17.7 years) autopsied in the years 2002 through 2005. During autopsy venous blood was drawn, and afterwards DNA extraction and alcoholimetric analysis were performed. Relatives of 79 suicide victims were interviewed using a semi-structured questionnaire designed according to Slovenian cultural and economic conditions. They provided information about the alcohol abuse of the suicide victims. Amongst the suicide victims were 25 alcohol misusers and 54 non-misusers. RESULTS: Association between polymorphisms in the selected serotonin receptor genes, transporter gene and completed alcohol-related suicide, as well as between alcohol-dependent suicide victims was not established. CONCLUSIONS: Present results suggest that selected polymorphisms of the 5-HT receptor genes and transporter gene are not involved in genetic susceptibility to completed suicide under acute influence of alcohol or among alcohol-dependent individuals, but further studies in a larger sample are needed.