GENOME-WIDE DNA METHYLATION PATTERNS IN SUICIDE VICTIMS: IDENTIFICATION OF NEW CANDIDATE GENES

Suicide is a major global public health problem with significant impact on society. According to the World Health Organization, every year about 800.000 people commit suicide, while at the global level suicide accounts for 50 % of all violent deaths among men and for 71 % among women. Suicide is a complex phenomenon which cannot be attributed to a single causal factor, but to a combination of simultaneous effects of multiple factors which are expressed in the form of psychological, biological and sociological indicators. Analysis of epigenetic mechanisms (methylation of the DNA, modifications of histone proteins and (networks of) miRNA), which link the interaction between genes and the environment, could importantly contribute to better understanding of suicidal behaviour. Recent studies on suicidal behaviour and DNA methylation show differences in DNA methylation pattern, with numerous sites among suicide victims. Using next generation sequencing, genome-wide studies helped identify novel candidate genes while studies of already known candidate genes (such as glucocorticoid receptor and BDNF) gave us better insight into the interplay of genetics and epigenetics. Epigenetic studies importantly contribute to elucidation of new biomarkers for suicidal behaviour. However, present studies are very different in design and often performed on very small samples, and these limitations could be overcome with more careful study preparation

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

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

Whole genome sequencing characterization of Slovenian carbapenem-resistant Klebsiella pneumoniae, including OXA-48 and NDM-1 producing outbreak isolates

Objectives The first hospital outbreak of carbapenemase-producing Enterobacteriaceae in Slovenia occurred in 2014-2016. Whole genome sequencing was used to analyse the population of carbapenem-resistant Klebsiella pneumoniae collected in Slovenia in 2014-2017, including OXA-48 and/or NDM-1 producing strains from the outbreak. Methods A total of 32 K. pneumoniae isolates were analysed using short-read sequencing. Multilocus sequence typing and core genome multi-locus sequence typing were used to infer genetic relatedness. Antimicrobial resistance markers, virulence factors, plasmid content and wzi types were determined. Long-read sequencing was used for six isolates for detailed analysis of plasmids and their possible transmission. Results Overall, we detected 10 different sequence types (STs), the most common being ST437 (40.6%). Isolates from the initial outbreak belonged to ST437 (12/16) and ST147 (4/16). A second outbreak of four ST15 isolates was discovered. A new ST (ST3390) and two new wzi types (wzi-556, wzi-559) were identified. blaOXA-48 was found in 17 (53.1%) isolates, blaNDM-1 in five (15.6%), and a combination of blaOXA-48/NDM-1 in seven (21.9%) isolates. Identical plasmids carrying blaOXA-48 were found in outbreak isolates sequenced with long-read sequencing technology. Conclusions Whole genome sequencing of Slovenian carbapenem-resistant K. pneumoniae isolates revealed multiple clusters of STs, two of which were involved in the first hospital outbreak of carbapenem producing K. pneumoniae in Slovenia. Transmission of the plasmid carrying blaOXA-48 between two STs was likely to have occurred. A previously unidentified second outbreak was also discovered, highlighting the importance of whole genome sequencing in detection and/or characterization of hospital outbreaks and surveillance of drug-resistant bacterial clones

Genetic predisposition of suicidal behavior: variants in GRIN2B, GABRG2, and ODC1 genes in suicide attempt and completed suicide In two Balkan populations

Introduction: Suicidal behavior ranges between suicidal ideation and completed suicide. Completed suicide accounts for over 700,000 deaths worldwide, while attempted suicide is 20 times more frequent. Genetic background is an important factor contributing to suicidal behavior, and candidate genes linked to several neurotransmitter systems have been investigated. Alternations in glutamate, γ-aminobutyric acid (GABA) and polyamine systems have been detected in suicidal behavior. Our aim was to differentiate genetic predispositions underlying two different types of suicidal behavior, attempted and completed suicide, in two Balkan populations. Methods: The study sample included 173 suicide attempters with comorbid psychiatric disorders (major depressive disorder, bipolar affective disorder, or schizophrenia), 216 non-suicidal psychiatric patients and 172 healthy controls from Serbia, and 333 suicide completers and 356 non-suicidal autopsy controls from Slovenia. Variants in the genes GRIN2B (rs2268115 and rs220557), GABRG2 (rs424740), and ODC1 (rs1049500 and rs2302614) were genotyped by TaqMan assays and analyzed using PLINK. Results: The CA genotype of rs220557 in the GRIN2B gene increases the risk for completed suicide (OR=1.51, p=0.021), and particularly violent suicide (OR=1.49, p=0.037), compared to controls. In the ODC1 gene, the CA genotype of rs2302614 decreases the risk for completed suicide compared to suicide attempt (OR=0.32, p=0.012). Marginally, the AC haplotype for variants rs1049500-rs2302614 in the ODC1 gene decreases the risk for completed suicide compared to suicide attempt (OR=0.50, p=0.052). Conclusion: Specific genetic variants of the glutamate and the polyamine systems are differently distributed among diverse suicidal phenotypes, thus providing further information on the implication of these systems in suicidality