Effect of VNTR Polymorphism of the AS3MT Gene and Obstetrical Complications on the Severity of Schizophrenia.

The role of the VNTR polymorphism of the AS3MT gene in determining the clinical features of schizophrenia and schizophrenic spectrum disorders was studied. The analysis included 670 individuals. We found no differences in PANSS scores for positive, negative, and common psychopathological symptoms between the carriers of different genotypes. The interaction of the studied polymorphism and obstetrical complications as an environmental factor was found. The genotype-environment interactions were identified for one of the characteristics reflecting the severity of schizophrenia: the level of negative symptoms. Women with the V2/V2 genotype, who have obstetrical complications, showed significantly higher negative symptoms scores, which was associated with a poor prognosis of the disease.

[Isolation of neurospheres and neural progenitor cells from the olfactory epithelium]. / Poluchenie neirosfer i neironal'nykh progenitornykh kletok iz oboniatel'nogo épiteliia.

The olfactory epithelium (OE) is an accessible source of neural stem cells and progenitor cells. The objective of the study was to compare the effectiveness of various biopsy sites to isolate and propagate neural progenitor cells from the olfactory epithelium (OE). The authors assessed OE cell count in OE in different sites of the nasal cavity and showed the possibility of isolation neurospheres from nasal biopsies. In total, 45 inpatinets were included in the study. Biopsy specimens were obtained from 30 patients undergoing septoplasty and/or turbinate surgery. Three areas of OE were biopsied: lower third section of the nasal septum (A), anterior part of the middle turbinate (B), upper third of the nasal septum (C). Immunocytochemistry and fluorescence-activated cell sorting showed that OE cells were NCAM-positive. Mean percentage of NCAM+ cells was 7.8% for A, 42.7% for B and 18.2% for C. The difference was significant between A and B (p=0.0001) and B and C (p=0.01). Therefore, the anterior part of the middle turbinate was an easily accessible and safe site to obtain neural cells. To confirm this, neurospheres were obtained in 15 patients with schizophrenia who underwent in-office endoscopy.

[Methylation of the Reelin Gene Promoter in Peripheral Blood and Its Relationship with the Cognitive Function of Schizophrenia Patients].

There is a decrease in the expression of the reelin gene (RELN) in the brain of schizophrenia patients, which can underlie observed cognitive abnormalities. It is suggested that this decrease is caused by the hypermethylation of the RELN promoter. The aim of the study was to investigate methylation of the RELN promoter in the peripheral blood of schizophrenia patients and its association with their cognitive deficits. A modified SMRT-BS (single-molecule real-time bisulfite sequencing) was used. We determined the methylation rate of 170 CpG sites within a 1465 bp DNA region containing the entire CpG island in the RELN promoter in 51 schizophrenia patients and 52 healthy controls. All subjects completed a battery of neuropsychological tests. There were no DNA methylation changes associated with schizophrenia. Most CpGs sites were unmethylated in both groups. At the same time, there was a variability in the methylation level of different regions within the promoter. The methylation level in the area from -258 to -151 bp relative to RELN transcription start site was a significant predictor of the index of patients' cognitive functioning if sex, age, smoking, education, and polymorphism rsl858815 had been considered. The positive correlation between the methylation rate in this region and cognitive index suggests that the hypomethylation of the RELN promoter could contribute to the development of cognitive deficits in schizophrenia.

[Analysis of the association of interleukin 4 and interleukin 10 gene variants with basic personality traits].

There is growing evidence that serum levels of various inflammation markers are associated with personality traits. However, only few studies investigated the link between genetic variants of cytokine encoding genes and psychological characteristics. In this study, we examined genotypes in 297 individuals to assess the association between common variants of interleukin 4 (IL-4) and interleukin 10 (IL-10) genes and basic personality traits of extraversion and neuroticism, measured using the Eysenck Personality Questionnaire (EPQ). We found that, in homozygous female carriers of high expression alleles Т (IL-4 C-589T) and G (IL-10 G-1082A), neuroticism scores were higher (p = 0.045 and p = 0.08, respectively). In turn, extraversion scores were significantly higher in both male and female carriers of heterozygous variants CT and GA (p = 0.01). Our results are in accordance with the behavioral immune system hypothesis, and the general paradigm on the role of personality traits in health and longevity.

Association of -717A>G Polymorphism in the C-Reactive Protein Gene (CRP) with Schizotypal Personality Traits.

Associations between schizotypal traits and genes coding for inflammation markers (Creactive protein and TNF-α) were studied in 222 healthy men who completed the Schizotypal Personality Questionnaire (SPQ-74). CRP -717A>G and TNFα -308 G>A polymorphisms were genotyped. Carriers of low-active allele G of the CRP gene differed from subjects with genotype AA by a trend toward more manifest schizotypal traits in general and scores on the Interpersonal factor, which corresponds to negative syndrome in schizophrenia, and Constricted affect and Odd behavior scales. These results could be interpreted in favor of the hypothesis on a compensatory increase of CRP concentrations in subjects with abnormalities of CNS development that predispose to schizophrenia.

[Polymorphism C366G of gene GRIN2B and verbal episodic memory: No association with schizophrenia].

The present study searched for associations between gene GRIN2B (glutamate receptor, ionotropic, N-methyl-D-aspartate, subunit 2B) and component processes of verbal episodic memory in schizophrenic patients. The Rey Auditory Verbal Learning Test (RAVLT) as a part of a large neuropsychological battery was administered to 302 patients with schizophrenic spectrum disorders (sample PI). Also, 285 patients (sample P2) and 243 healthy controls (sample C2) performed the "10 words" test that measures short-term memory. The GRIN2B rs7301328 (C366G) polymorphism was genotyped for each subject. There were no associations between the polymorphism and any measure of the RAVLT either in the whole PI sample or in a subsample of patients with a severe cognitive deficit. The GRIN2B influenced immediate recall and proactive interference in the "10 words" test in the control group: homozygotes CC recalled fewer words and showed a lower effect of proactive interference than carriers of other genotypes. The results suggest that the C366G polymorphism could influence verbal episodic memory in the general population, but this influence is absent in schizophrenic patients.

[The Association of Brain-Derived Neurotrophic Factor and Serotonin Transporter Genes with the Parameters of Early Event-Related Potentials During the Passive Perception of Words].

We explored the association of brain-derived neurotrophic factor (BDNF) and serotonin transporter genes with neurophysiological characteristics of the early stages of verbal information processing in the brain in the groups of patients with schizophrenia and schizophrenia spectrum disorders and healthy people. It has been shown that Val66Met and 5-HTTLPR polymorphisms are associated with P100 and N170 during the passive reading of single words written in Russian presented with different occurrence frequency. The healthy carriers of the ValVal genotype (BDN F Val66Met) allele or the SS (5-HTTLPR) genotype performed the task better compared to those with an Met or an L allele. The differences were significant in healthy people and observed as a trend in thepatients.

[Interaction Between Personality, Pain, and Genes in Ischemic Heart Disease].

Personality traits of the patient with ischemic heart disease (IHD) are thought to determine disease course. Their level depends on clinical presentations of IHD including the presence of cardiac pain. The aim of the study was to identify the modifying effect of genes coding for serotonin transporter (5-HTTLPR), serotonin receptor type 2A (A-1438G) and 2C (Cys23Ser) as well as brain-derived neurotrophic factor (Val66Met) on personality traits in pain and painless forms of IHD. We found interaction between pain and personality factors mediated by genetic variant. Pain syndrome was associated with higher neuroticism scores in carriers of allele S (5-HTTLPR), allele Ser (5-HTR2C), and the genotype ValVal (BDNF) and with higher hostility levels in patients with allele Ser. The results may be used for purposes of personalized examination of IHD patients directed to prevention of unfavorable course of the disease.

Convergent lines of evidence support CAMKK2 as a schizophrenia susceptibility gene.

Genes that are differentially expressed between schizophrenia patients and healthy controls may have key roles in the pathogenesis of schizophrenia. We analyzed two large-scale genome-wide expression studies, which examined changes in gene expression in schizophrenia patients and their matched controls. We found calcium/calmodulin (CAM)-dependent protein kinase kinase 2 (CAMKK2) is significantly downregulated in individuals with schizophrenia in both studies. To seek the potential genetic variants that may regulate the expression of CAMKK2, we investigated the association between single-nucleotide polymorphisms (SNPs) within CAMKK2 and the expression level of CAMKK2. We found one SNP, rs1063843, which is located in intron 17 of CAMKK2, is strongly associated with the expression level of CAMKK2 in human brains (P=1.1 × 10(-6)) and lymphoblastoid cell lines (the lowest P=8.4 × 10(-6)). We further investigated the association between rs1063843 and schizophrenia in multiple independent populations (a total of 130 623 subjects) and found rs1063843 is significantly associated with schizophrenia (P=5.17 × 10(-5)). Interestingly, we found the T allele of rs1063843, which is associated with lower expression level of CAMKK2, has a higher frequency in individuals with schizophrenia in all of the tested samples, suggesting rs1063843 may be a causal variant. We also found that rs1063843 is associated with cognitive function and personality in humans. In addition, protein-protein interaction (PPI) analysis revealed that CAMKK2 participates in a highly interconnected PPI network formed by top schizophrenia genes, which further supports the potential role of CAMKK2 in the pathogenesis of schizophrenia. Taken together, these converging lines of evidence strongly suggest that CAMKK2 may have pivotal roles in schizophrenia susceptibility.

[Association between serotonin receptor 2C gene Cys23Ser polymorphism and social behavior in schizophrenia patients and healthy individuals].

The purpose of this work was to search for associations between the serotonin receptor 2C gene (HTR2C) and the peculiarities of social behavior and social cognition in schizophrenia. To do this, patients with schizophrenia spectrum disorders and healthy control subjects were genotyped for the Cys23Ser HTR2C marker and underwent psychological examination, including assessment of Machiavellianism, recognition of emotions in facial expression, and theory of mind. In addition, we estimated the trait anxiety level as a potential factor affecting the relationship between the gene HTR2C and social behavior. We found a significant association between the Ser allele and a reduction of estimates on the Mach-LV Machiavellianism scale in the total sample of patients (n = 182) and control subjects (n = 189), which did not reach the confidence level in either of the groups. A tendency towards a HTR2C gene influence on the trait anxiety level was also revealed. The association between HTR2C and Machiavellianism was retained if the anxiety level was taken into account. The results suggest a pleiotropic effect of HTR2Con anxiety and Machiavellianism.

[Anxiety and Polymorphism Val66Met of BDNF gene Predictors of Depression Severity in Ischemic Heart Disease].

In a framework of search for early predictors of depression in patients with ischemic heart disease (IHD) we studied effect of molecular- genetic factors (polymorphism of brain-derived neirotrophic factor - BDNF), personality traits (anxiety, neuroticism), IHD severity, and psychosocial stressors on manifestations of depression in men with verified diagnosis of IHD. Severity of depression was assessed by Hamilton Depression Rating Scale 21-Item (HAMD 21), anxiety and neuroticism were evaluated by the Spielberger State-Trait Anxiety Inventory and "Big Five" questionnaire, respectively. It was shown that personal anxiety and ValVal genotype of BDNF gene appeared to be predictors of moderate and severe depression.

[Anxiety and polymorphism Val66Met of BDNF gene--predictors of depression severity in ischemic heart disease].

In a framework of search for early predictors of depression in patients with ischemic heart disease (IHD) we studied effect of molecular-genetic factors (polymorphism of brain-derived neirotrophic factor--BDNF), personality traits (anxiety, neuroticism), IHD severity, and psychosocial stressors on manifestations of depression in men with verified diagnosis of IHD. Severity of depression was assessed by Hamilton Depression Rating Scale 21-item (HAMD 21), anxiety and neuroticism were evaluated by the Spielberger State-Trait Anxiety Inventory and "Big Five" questionnaire, respectively. It wa shown that personal anxiety and ValVal genotype of BDNF gene appeared to be predictors of moderate and severe depression.

[The moderating effect of the Va166Met polymorphism of brain-derived neurotrophic factor gene on the clinical and psychological features of patients with schizophrenia].

The brain-derived neurotrophic factor (BDNF) gene is a prominent candidate gene for schizophrenia. The BDNFVal66Met polymorphism has been extensively studied for association to this disease. There is accumulating evidence that the polymorphism is associated with clinical presentations of schizophrenia and not with the disease itself. We compared the allele and genotype distribution in patients (n=1785) and healthy controls (n = 1092) and did not find association of the Va166Met polymorphism with schizophrenia. No association was found with affective syndromes. At the same time, the ValVal genotype was associated with the higher anxiety level assessed with the PANSS in male patients. We studied personality characteristics using personality questionnaires EPI, MMPI, STAI (n=363) and cognitive functions (attention (n=227) and verbal fluency (n=392). Patients with the ValVal genotype demonstrated higher levels of anxiety assessed by the MMPI and better performance on the neurocognitive tests. The interaction effect of genotype and trait anxiety, measured with the STAI, on cognitive functions was identified. In patients with higher anxiety, the performance on cognitive tests did not depend on the genotype, while in patients with lower levels of anxiety the ValVal gen- otype was associated with the better performance. This effect should be taken into account when studying the association of the Val66Met polymorphism with cognitive functions in patients with schizophrenia.

Association of 5-HTR2A and 5-HTR2C serotonin receptor gene polymorphisms with depression risk in patients with coronary heart disease.

Associations between 5-HTR2A -1438A/G and 5-HTR2C Cys23Ser polymorphisms and depression and its severity were studied in CHD patients with consideration for the trigger factors, pathogenetic characteristics of CHD, and personal anxiety. The study was carried out in 169 men aged 31-84 (59.0 ± 8.8) years with verified CHD. Depression was more severe (Hamilton score) if it was caused by manifestation or exacerbation of CHD (nosogenic factor) and in the presence of the painful syndrome caused by the cardiac disease, high personal anxiety, and presence of allele G polymorphism - 1438A/G in the genotype. The risk of medium-severe and severe depression in allele G carriers was 2.4-fold higher than in AA genotype carriers. The nosogenic factor modulated the association between allele G and severity of depression symptoms. The risk of medium-severe and severe depression was almost 4-fold higher in carriers of this allele in the presence of this factor.

[Association of kynurenine-3-monooxygenase gene with schizophrenia].

Neurotoxic products produced during tryptophan metabolism via the kynurenine pathway could be involved in schizophrenia pathogenesis. It has been shown that kynurenine-3-monooxygenase (KMO) is indirectly involved in these products' formation. KMO polymorphic loci rs2275163 (C/T) and rs1053230 (A/G) were examined in 187 schizophrenia patients and 229 healthy subjects. A genetic combination of allele T and genotype GG was observed more often in a patient group compared with healthy controls (p = 0.003, OR 2.0 (95% CI 1.2-2.9). In the latter group, this combination was associated with schizophrenia endophenotype (p = 0.04), which manifested in a higher expression of schizotypal personality traits assessed using the MMPI test.

[Effects of anxiety and the COMT gene on cortical evoked potentials and performance effectiveness of selective attention].

We studied influence of the anxiety-related trait Harm Avoidance and the COMT gene, which is an important modulator of prefrontal functioning, on event-related potentials in oddball paradigm and performance effectiveness of selective attention. For 50 individuals accuracy and time of searching words among letters at any desired rate and then under an instruction to perform the task as quickly and accurate as possible were measured. Scores on the Harm Avoidance scale from Cloninger's Temperament and Character Inventory, N100 and P300 parameters, and COMTVa1158Met genotypes were obtained for them as well. Searching accuracy and time were mainly related to N100 amplitude. The COMT genotype and Harm Avoidance did not affect N100 amplitude; however, the N100 amplitude modulated their effects on accuracy and time dynamics. Harm Avoidance was positively correlated with P300 latency. The results suggest that anxiety and the COMT gene effects on performance effectiveness of selective attention depend on cognitive processes reflected in N100 parameters.

[Genome-wide studies of comorbidity of somatic and mental diseases]. / Polnogenomnye issledovaniya komorbidnosti somaticheskikh i psikhicheskikh zabolevanii.

Studies of the genomic architecture of complex phenotypes, which include common somatic and mental diseases, have shown that they are characterized by a high degree of polygenicity, i.e. participation of a large number of genes associated with the risk of developing these diseases. In this regard, it is of interest to establish the genetic overlapping between these two groups of diseases. The aim of the review is to analyze genetic studies of the comorbidity of somatic and mental diseases in terms of the universality and specificity of mental disorders in somatic diseases, the reciprocal relationships of these types of pathologies, and the modulating influence of environmental factors on comorbidity. The results of the analysis indicate the existence of a common genetic predisposition to mental and somatic diseases. At the same time, the presence of common genes does not exclude the specificity of the development of mental disorders depending on a specific somatic pathology. It can be assumed that there are genes that are both unique to a particular somatic and comorbid mental illness, and genes that are common to these diseases. Common genes may have varying degrees of specificity, that is, they may be of a universal nature, which, for example, manifests itself in the development of MDD in various somatic diseases, or be specific only for a couple of individual diseases (schizophrenia - breast cancer). At the same time, common genes can have a multidirectional effect, which also contributes to the specificity of comorbidity. In addition, when searching for common genes for somatic and mental diseases, it is necessary to take into account the modulating influence of such confounders as treatment, unhealthy life style, behavioral characteristics, which can also differ in specificity depending on the diseases under consideration.

[Immune mechanisms of complicity of somatic pathology in the pathogenesis of mental disorders]. / Immunnye mekhanizmy souchastiya somaticheskoi patologii v patogeneze psikhicheskikh rasstroistv.

Understanding the mechanisms of the relationship between the nervous and immune systems within the framework of the concept of the key role of inflammation, taking into account the involved genetic factors in the development of a wide range of combined forms of somatic and mental diseases, is of interest for research as well as for the development of new approaches to early diagnosis and more effective treatment of these diseases. This review analyzes the immune mechanisms of the development of mental disorders in patients with somatic diseases, in particular, the transmission of an inflammatory signal from the periphery to the CNS and the implementation of the influence of inflammatory factors on neurochemical systems that determine the characteristics of mental functioning. Particular attention is paid to the processes underlying the disruption of the blood-brain barrier caused by peripheral inflammation. Modulation of neurotransmission, changes in neuroplasticity, changes in regional activity of the brain in areas associated with the functions of threat recognition, cognitive processes and memory function, the effect of cytokines on the hypothalamic-pituitary-adrenal system are considered as mechanisms of action of inflammatory factors in the brain. The need to take into account variations in the genes of pro-inflammatory cytokines, which may be the cause of increased genetic vulnerability associated with the risk mental disorders in patients suffering from a certain somatic disease, is emphasized.

[Effects of oxytocin pathway gene polymorphisms and adverse childhood experiences on emotion recognition in schizophrenia spectrum disorders]. / Effekty polimorfizma genov oksitotsinergicheskogo puti i neblagopriyatnogo detskogo opyta na raspoznavanie emotsii pri rasstroistvakh shizofrenicheskogo spektra.

OBJECTIVE: To study a role of the interaction of oxytocin pathway gene polymorphisms and adverse childhood experiences (ACE) in facial emotion recognition (FER) deficits in schizophrenia. MATERIAL AND METHODS: Patients with schizophrenia spectrum disorders (n=699) completed cognitive testing, which included a FER task. We determined patients' genotypes for common polymorphisms in three of the oxytocin pathway genes which were previously associated with face perception: OXTR (rs53576, rs7632287), CD38 (rs3796863) and ARNT2 (rs4778599). The presence of ACE in the patient's history was assessed via an analysis of medical records. RESULTS: In our sample, 49% of participants experienced ACE. ANCOVA adjusted for age and gender revealed a significant interaction effect of OXTR rs53576 with ACE on FER scores (F=11.51; p<0.001; η2p=0.02). The effect remained significant when accounting for cognitive functioning and negative symptoms. Carriers of the A allele without ACE recognized emotions worse than GG homozygotes without ACE (p=0.039) and carriers of the A allele with ACE (p=0.009). CONCLUSION: The results are consistent with the notion of the A (rs53576) allele's role in sensitivity to childhood experiences that influence the psychosocial development and can be used in further studies of the oxytocin treatment of social cognition and social adaptation of patients with schizophrenia.

Effect of BDNF Val66Met polymorphism on normal variability of executive functions.

Associations of BDNF Val66Met polymorphism with such components of executive functions as verbal fluency, working memory, attention set shifting, and response inhibition were evaluated. A total of 401 healthy volunteers were genotyped. The effect of polymorphism on working memory during the counting test was detected. The test performance in heterozygotic carriers was much worse than in homozygotic ones. Individuals with the MetMet genotype demonstrated the best results, presumably due to molecular mechanisms compensating for the neuropeptide secretion deficiency.