Alja Videtič Paska

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.

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.

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.

Gene Expression Profiling of Rat Fetuses Exposed to 2-Dimensional Ultrasound

This study evaluated the possible effects of ultrasound (US) on gene expression in brain tissue of rat embryos.

Reduced Blood Alcohol Concentration in Suicide Victims in Response to a New National Alcohol Policy in Slovenia

Background: Addiction is a major social and health problem. Studies on suicide and alcohol at the individual and aggregated level have confirmed a link between alcohol and suicide. Aim: To assess the impact of the new national alcohol policy in Slovenia on the blood alcohol concentration (BAC) in BAC-positive suicide victims before, during and after the implementation of the new national alcohol policy in 2003. Method: Blood samples were collected by forensic pathologists during medicolegal autopsies of suicide victims in order to establish their BAC levels at the time of death. BAC was measured using two routine independent headspace gas chromatography methods (HSS-GC-FID) and expressed in grams per kilogram. Results: During the period before the implementation of the act which limited the availability of alcohol in Slovenia, the BACs of BAC-positive suicide victims were higher than those tested in the period after the implementation of the act. Conclusion: Despite certain limitations, this study demonstrates that legislation measures restricting alcohol availability may be an effective measure of BAC reduction in BAC-positive suicide victims.

Investigating the associations between polymorphisms in the NTRK2 and NGFR genes and completed suicide in the Slovenian sample

Objective The most abundant neurotrophin in the mammalian brain is brain-derived neurotrophic factor (BDNF), which acts through binding to neurotrophic tyrosine kinase receptor type 2 (NTRK2) and to nerve growth factor receptor (NGFR). Our previous work showed an association of the single nucleotide polymorphism (SNP) rs6265 in the BDNF gene with completed suicide in the Slavic population. Therefore, we extended the investigation to the SNPs within NTRK2 and NGFR genes and searched for associations with the completed suicide phenotype. Materials and methods In 775 Caucasian individuals, namely, 486 suicide completers and 289 controls, we performed genotyping of five SNPs within the NTRK2 (rs11140714, rs1147198, rs1187323, rs10780691, and rs10868235) and six SNPs within the NGFR (rs2072446, rs7219709, rs7224806, rs734194, rs741071, and rs741072) genes. Results We did not find evidence for an association of the SNPs studied with the phenotype either on the single marker or on the haplotype level. Conclusion To our knowledge, this is the first study that has examined SNPs in the NTRK2 and NGFR genes for associations with the completed suicide phenotype. However, our findings suggest that these SNPs may not be associated particularly with completed suicide in Slovenia, although they might have a relevant informative value as the study has been carried out on a sample from a population that has one of the highest suicide rates in the world.

Single nucleotide polymorphisms in the BDNF gene and suicide in the Slovenian sample.

In recent years, brain-derived neurotrophic factor (BDNF) and sequence variations within and near the BDNF gene have been studied for associations with various psychiatric disorders, including suicidal behavior. Since our previous work on completed suicide in Slavic population showed an association of the functional single nucleotide polymorphism (SNP) rs6265 in the BDNF gene, we decided to extend the investigation and test additional SNPs in the BDNF gene, rs7124442, rs10767664, rs962369, rs12273363, rs908867, rs1491850, and rs1491851, for association with completed suicide. Our study subjects were Caucasians, and included 486 suicide completers and 289 controls. The case/control comparisons of allele, genotype and haplotype frequency distributions were performed by means of Pearsons X(2) tests. Analyses of allele and genotype frequency distributions of the sudied SNPs did not reveal any significant differences between the controls and suicide completers. Haplotype analysis (rs7124442-rs10767664-rs962369-rs12273363-rs908867) showed an association of the haplotype C-A-T-C-C (p(corr)=0.038) with completed suicide, indicating that these SNPs on a haplotype level may play a role in completed suicide phenotype in our study sample.

Summaries from the XIX World Congress of Psychiatric Genetics, Washington, DC, September 10-14, 2011.

The XVIII World Congress of Psychiatric Genetics (WCPG), sponsored by The International Society of Psychiatric Genetics (ISPG) took place in Washington, DC on September 10–14, 2011. Approximately 540 participants gathered to discuss the latest findings in this rapidly advancing field. The topics covered can be subdivided into the following categories: the latest results from Genome-Wide Association Studies (GWAS) examining the effects of common allele variation, the new focus on sequencing studies, other genomic mechanisms that include epigenetic gene modification and rare copy number variations, biologic and other endophenotypes, the genetics of post-traumatic stress disorder, substance abuse, gene functioning, pharmacogenomics, and other miscellaneous topics of genetic interest. Some notable reported findings introduced at this congress included: several new or replicated associations for common alleles in GWAS for schizophrenia (a SNP located near the hyaluronan binding protein 2 gene (HABP2) on chromosome 10, an SNP in the Transmembrane protein 45B gene (TMEM45B) on chromosome 11, some popular schizophrenia candidate genes, TCF4, NOTCH4, ZNF804A, and the MHC region replicated, and several novel genes reported, POM121L2, AS3MT, CNNM2, NT5C2; for major depression, the neuronal transporter gene SLC6A15; for bipolar disorder, TRANK1 gene, as well as LMAN2L, PTGFR and the SYNE1 gene encoding Nesprin. Some initial exome sequencing results were reported, but very preliminary, although promising. Endophenotypes that specifically were discussed included amygdala volume and prefrontal cortex activation, suicidal behavior, and impulsivity. There was a large emphasis on nicotine dependence in the substance abuse sessions and an association between smoking quantity and genetic loci on the chromosome 15q25 region was clearly demonstrated. The GABRA2 association to alcohol dependence was confirmed. There were several presentations of candidate gene polymorphisms associated with antidepressant and mood stabilizer response from large pharmacological treatment trials, but no one finding was confirmed and to be definitive yet to be able to be used commercially in the clinic. The complete report summarizing the findings reported at this meeting was written by junior travel awardees, as well as other individuals in training who were volunteers from meeting attendees. Each was assigned sessions as rapporteurs. The entire manuscript represents topics covered in oral presentations during the conference and can be found on line as a journal supplement. It is clear from this 2011 congress that multi-international collaborative efforts to solve the genetic tendency for all major psychiatric disorders are necessary and underway. It is impressive to find that the field has come together in such a collegial fashion in order to make progress toward alleviating the suffering of people with mental illnesses. It is now important to be able to decipher which if any of the accumulating findings are ready for communication to clinicians and implementation clinically. Ethical considerations to their use in treatment of patients will be a continuing ongoing discussion.

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.

Differences in SNP genotype distributions between complex and simple suicides

Dysregulations in serotonin neurotransmission can be a strong contributing factor in suicide and impulsive-aggressive personality traits. Victims of suicide form a heterogeneous group in terms of planning, lethality and number of used methods. In this study, we tested single nucleotide polymorphisms (SNPs) of the monoamine oxidase (MAO) A and B genes on the Slovenian population, which has one of the highest suicide rates in the world. Genotyping was performed on 77 victims of complex suicide, 406 victims of simple suicide and 289 controls. The differences in allele distribution were investigated with the two-tailed χ2 test. Haplotype analysis was performed on 740 subjects. Significant or tendency for significant differences in distribution was observed for all studied polymorphisms in the MAOA gene when comparing male victims of complex suicide, victims of simple suicide and controls. Minor allele frequencies in male victims of complex suicide were A 6.7% for rs3027407, C 13% for rs909525 and T 12.7% for rs1137070; in victims of simple suicide, A 36.3% for rs3027407, C 39.5% for rs909525 and T 36.4% for rs1137070; and in controls, A 25.2% for rs3027407, C 30.4% for rs909525 and T 25.8% for rs1137070. The distribution analysis of polymorphism rs1799836 in the MAOB gene and all studied polymorphisms in the MAOA gene in females failed to show any significant results. GTC haplotype (for rs3027407, rs909525, rs1137070) in MAOA polymorphisms was more frequent in victims of complex suicide compared to that in controls and victims of simple suicide. Compared to victims of complex suicide, male victims of simple suicide were more often carriers of MAOA alleles that are, according to literature, associated with higher levels of impulsivity and anger. These differences in SNP distribution could serve as an additional method of differentiating between victims of complex and victims of simple suicide. Further studies including psychological autopsies should be carried out in order to identify personality traits and behavioural differences among distinct groups of suicide victims.