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Objective: To evaluate the association of polymorphisms in the TAAR1-9 gene cluster on chromosome 6 with cognitive functions in patients with schizophrenia spectrum disorders and healthy controls., Material and Methods: Patients with schizophrenia spectrum disorders ( n =216) and healthy people without a family history of mental disorders ( n =240) completed a battery of cognitive tests, from which individual indices of cognitive functioning were derived. Associations of the cognitive index with 22 polymorphisms in the TAAR genes were assessed using ANCOVA controlling for sex, age, genetic structure of the sample, and polygenic risk scores of schizophrenia and intelligence., Results: An interaction effect between group and genotype on the cognitive index was found at the rs3813355 site in the TAAR5 gene (F=6.68; p =0.010; η 2 p =0.02). A post hoc analysis revealed genotype-related differences in the patient group. Homozygotes for the common A allele had a milder cognitive deficit than carriers of the minor G allele ( t =2.75; p =0.032; Cohen's d=0.38). The effect of genotype on cognitive index remained significant after the inclusion of disease duration and negative symptoms in the model (F=7.99; p =0.005; η 2 p =0.04). Of the individual cognitive indicators, associations with genotype were found for working memory and attention (F=8.25; p =0.005; η 2 p=0.05), cognitive flexibility (F=5.82; p =0.017; η 2 p =0.05) and verbal episodic memory (F=6.75; p =0.011; η 2 p =0.05)., Conclusion: The results are consistent with the assumption of the role of the TAAR5 genetic polymorphism in the variability of cognitive deficits in patients with schizophrenia.

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.

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; η 2 p =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.

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.

The authors present the data indicating that the formation of psychopathological symptoms of schizophrenia is due to complex and diverse genetic factors associated with various functional and metabolic pathways at different stages of ontogenesis. Despite the fact that at present the genetic basis of positive and negative symptoms as the main pathophysiological manifestations of schizophrenia remains largely unknown, the current level of research allows the identification of some common and unique associations for positive and negative disorders. Based on the analysis of the literature, the specificity of the association of genetic variants with negative symptoms of schizophrenia is shown. It has been also suggested that genes of the immune system may be specifically associated with negative symptoms of schizophrenia. The relevance of studying the relationship of immune system genes, in particular, pro- and anti-inflammatory cytokines, with dimensional characteristics of negative symptoms (abulia-apathy and expressive deficit) is substantiated. Studies of this type have not yet been conducted, despite accumulating data indicating that the heterogeneity of negative symptoms is based on different neurobiological mechanisms. It is concluded that the immunological and molecular genetic study of the subdomains of psychopathological symptoms can be promising as part of the transition to deep phenotyping, which seems to be especially relevant for the study of such an extremely heterogeneous disease from a clinical point of view as schizophrenia. The development of this area is important for solving the problems of precision medicine, which aims to provide the most effective therapy for a particular patient by stratifying the disease into subclasses, taking into account their biological basis.

Schizophrenia is a severe mental illness, in the etiology and pathogenesis of which hereditary factors make a significant contribution. Studies of the genetic causes of schizophrenia are conducted using a variety of models. This brief review introduces the reader to cellular and supracellular models that, because of their simplicity, low cost, and low labor intensity, help to effectively investigate the complex molecular mechanisms associated with schizophrenia. The potential of cellular and supracellular models is greatly enhanced by the use of the CRISPR/Cas9 genome editing technology. Genetically modified models make it possible to achieve a previously inaccessible depth and detail of understanding of the role of genetic factors in the onset and development of schizophrenia. The information obtained can be used in the design of new drugs for personalized treatment of schizophrenia patients.

Objective: Based on the hypothesis that activation of the immune system is one of the mechanisms of influence of early environmental factors on the onset and course of schizophrenia, we investigated the effects of the interaction of childhood adversity and IL-1β rs16944, IL-4 rs2243250 and TNF-α rs1800629 polymorphisms on schizophrenia symptomatology., Material and Methods: The sample consisted of 546 patients with schizophrenia spectrum disorders. The presence of childhood adversity was determined based on the analysis of medical records and a questionnaire completed by the patient. We used the 5-factor model of the Positive and Negative Syndrome Scale (PANSS) with the nested two-factor negative syndrome model., Results: After adjusting for multiple comparisons, a significant effect of the interaction of childhood adversity and TNF-α on the cognitive/disorganization factor was found, with a difference between genotypes in the group without childhood adversity (pFDR <0.018; η 2 p= 0.03). A significant effect of the interaction of childhood adversity and genotype on the cognitive disorganization syndrome was established (F=5.87; p= 0.003; η 2 p= 0.03). Stereotyped thinking and avolition on PANSS had the highest correlations with cognitive disorganization factor (ro=0.84 and ro=0.82, respectively) and the highest significance of differences depending on the interaction of genotype and childhood adversity (Kruskal-Wallis test, H=12.28, p= 0.006 and H=12.79, p= 0.005, respectively)., Conclusion: Childhood adversity modifies the relationship between the pathogenesis of schizophrenia and the TNF-α promoter polymorphism rs1800629, which is also an enhancer of another 60 genes located in the major histocompatibility complex.

Objective: To study the impact of family history of mood disorders (FHMD), comprising genetic factors associated with depression, on the association between adverse childhood experience (ACE) and suicidality in depression., Material and Methods: This multicenter cross-sectional study included 200 in- and outpatients (64% ( n =128) women, mean age - (M (SD)) 36.21 (15.09) yrs.) with depression. Self-reports about FHMD and lifetime suicide attempts were obtained in clinical interview. The lifetime intensity of suicidal ideas and behavior was assessed by the Columbia-Suicide Severity Rating Scale (C-SSRS), ACE - by the Adverse Childhood Experience International Questionnaire (ACE-IQ)., Results: FHMD did not affect the prevalence of ACE, suicide attempts and C-SSRS scores. We found that FHMD weakens the link between ACE and the risk of suicide attempt. The emotional neglect itself increased the risk of suicide attempt ( p =0.001, OR=4.428, CI 95% [1.797-10.911]), but reduced it in patients with FHMD ( p =0.03, OR=0.128, CI 95% [0.018-0.893]). GLM analysis revealed that FHMD significantly affected the association between suicidal ideas and domestic violence ( p =0.045) and between suicidal behavior and emotional neglect ( p =0.015) and abuse ( p =0.044)., Conclusion: FHMD may weaken the link between ACE and suicidality in patients with depression. Suicidality in these patients may be underlined by mechanisms not involved in the response to ACE although more studies are needed.

Genotype - phenotype relationships are considered in view of recent advances in our understanding of genome structure. Different DNA elements can contribute to phenotype formation. Genotype - phenotype relationships are mediated by epigenetic effects that can have various origins - from the most studied to date methylation of certain sites in the genome to only developing ideas about the role of remote regulatory genomic elements in the development of schizophrenia. The transition to a more in-depth study of genotype - phenotype relationships is relevant for the current period of molecular-genetic studies of schizophrenia. Obviously, the concept of phenotype as applied to schizophrenia is not limited to a causal reflection of changes in the structure of a particular gene, but is the product of the combined effect of environmental factors and epigenetic changes that affect gene expression, taking into account tissue specificity and the degree of cell stimulation.

The need to use large samples to identify the genetic risk loci of mental disorders has led us to the dilemma of phenotyping quality. Especially this problem relates to such common mental disorders as depression (lifetime prevalence 16.2%). On the one hand, there is a very resource-intensive method of capturing patient data by physicians using diagnostic criteria of mental disorders (DSM-V/ICD-10). On the other, there is a popular method of minimal phenotyping using hospital registers, self-reports of respondents on symptoms, diagnosis and treatment of depression. To date, there is no ideal method for phenotyping depression because all of them focus only on its clinical symptoms. The active usage of minimal phenotyping in Genome-Wide Association Study (GWAS) has led to a significant increase in both clinical and genetic heterogeneity of depression. However, an important limitation of using DSM-V/ICD-10 is the high cost of phenotyping due to the involvement of medical specialists. Thus, the most rational is to use electronic diagnostic questionnaires based on DSM-V/ICD-10 criteria. Such an approach will accelerate the increase in research capacity, but will preserve all internal contradictions inherent in official diagnostic classifications (heterogeneity of phenotypes, absence of objective diagnostic criteria, categorical approach, etc.). In this regard, the critical role of psychiatric epidemiology is growing both in the development of standardized tools for operationalized diagnostic criteria and in future GWAS by introducing new phenotypic subtypes of depression and its dimensions.

Objective: To search for the associations between genes of the oxytocinergic pathway and psychosocial functioning in schizophrenia, namely, the ability of schizophrenic patients to form interpersonal relationships, taking into account the influence of such an environmental factor as perinatal complications., Material and Methods: The study included 383 people (140 women and 243 men, mean age 32.6±11.4 years), of whom 107 had a history of perinatal complications, and 276 did not. Psychosocial functioning was assessed using the Personal and social relationships domain of The Personal and Social Performance scale (PSP). Polymorphisms rs53576, rs4686302, rs1042778 in the oxytocin receptor gene (OXTR) and polymorphism rs3796863 in the transmembrane glycoprotein (CD38) gene were genotyped., Results: There is the association between the OXTR rs53576 polymorphism and scores on the interpersonal relations domain ( p =0.005). Significant differences are found between carriers of the GG genotype and carriers of the A allele ( p =0.003). In the group without perinatal complications, the genotype does not have a significant effect on PSP score. There are no associations between other polymorphisms and the level of interpersonal relationships in any of the studied groups., Conclusion: The results are in accordance with the notions accepted on the basis of numerous evidences that link the genes of the oxytocinergic system with social behavior. We obtained new data on the influence of the known polymorphism OXTR rs53576 on the phenotype, which has not been studied previously in this aspect - the ability to form interpersonal relationships in patients with schizophrenia, while it was shown that the effect of the genotype depends on the environmental risk factor (perinatal complications).

Objective: To compare the groups of schizophrenic patients with different levels of functional outcome and different frequency of risk variants in polymorphic loci of five candidate genes to create a multigene panel and to test its predictive ability for long-term outcome of the disease., Material and Methods: According to the proposed typology, the patients included in the studies were divided into three groups, which differed in the level of social functioning. Group 1 was characterized by the highest level, in group 2 this indicator was significantly lower, and in group 3 the lowest. The multigenic panel included genes for serotonin receptor type 2a (5-HTR2A T102C), serotonin transporter (5-HTTLPR), C-reactive protein (CRP -717A>G), angiotensin II receptor type 1 (AGTR1 A1166C), and brain neurotrophic factor (BDNF Val66Met). A multi-gene risk score was calculated for each patient by summing the total number all his/her risk alleles. For each polymorphism, a score of 2 was assigned to homozygous high-risk genotypes, a score of 1 to heterozygous genotypes and a score of 0 to homozygous low-risk genotype. Accordingly, the multi-gene risk score for a patient could vary from 0 to 10 risk alleles., Results: A significant effect of the group on the multi-gene risk score was shown ( p <0.0001). Between-group differences were significant as well ( p <0.01). In group 1, there were no carriers of ≥6 risk alleles, and the number of carriers of less than 5 alleles exceeded 50%. In group 2, the number of carriers of ≥6 risk alleles was 19.4%, and in group 3 - 31.7%. Moreover, in these groups there were no carriers of 0-2 risk alleles, while in group 1 their number was 20.7%., Conclusion: The multi-gene risk score predicts the level of functional outcome in patients with schizophrenia. In the case of a smaller number of risk alleles (0-4) in an individual, a favorable functional outcome can be predicted with a high probability in the long-term period of the disease.

Objective: Analysis of clinical features of development and course of depression in patients with FH of mood disorders taking into account sex differences., Material and Methods: This multicenter cross-sectional study included patients over 18 years of age with depressive episode/recurrent depressive disorder. Clinical characteristics of depression, presence of comorbid mental illness and family history (FH) information were obtained in a structured clinical interview., Results: One hundred and seventy-one patients (mean age (M (SD)) 40.87 (15.86) y.o.), including 64.5% of women, were enrolled in the study. FH was revealed in 30.2% of patients. The proportion of FH did not differ in men and women ( p =0.375). Generalized anxiety disorder (GAD) was more frequent in FH positive patients ( p =0.016). Logistic regression also revealed that FH is a risk factor for concomitant GAD ( p =0.019, OR=2.4). The GLM demonstrated a significant joint effect of FH and sex on the maximum duration of a depressive episode ( p =0.044), as well on the number of suicide attempts ( p =0.055) and the number of depressive episodes as a trend ( p =0.072)., Conclusion: We have demonstrated the specific interaction of FH of mood disorders with sex on clinical course of depression. Thus, the manifestation of a genetic influence on the clinical phenotype of depression can be significantly moderated by sex.

Depression is one of the leading causes of decreased quality of life and social functioning of patients. In the context of preventive medicine, the prevention of depression becomes a priority. To achieve the goals of prevention, it is necessary to identify specific population risk groups - individuals with a high genetic risk of depression. The paper describes the project aimed at developing a genetic test system based on polygenic risk scores (PRS) for depression, considering the multi-ethnicity and multicultural diversity of the Russian population. As a result of the study, data on the genetic architecture of depression (GWAS) and PRS for depression will be obtained for the first time. The emergence of a genetic test system developed in the study of the Russian population and in the conditions of a constant decrease in the cost of genetic research will allow an effective transition to preventive medicine in the area of mental health.

Objective: To study the association of the C677T polymorphism of the methylenetetrahydrofolate reductase (MTHFR) gene with the risk of schizophrenia in a large sample, including schizophrenic patients and mentally healthy people, and to investigate the relationship of this polymorphism with the severity of schizophrenia symptoms and genotype-environment interaction effects on these symptoms., Material and Methods: The sample for genotyping consisted of 1357 patients with schizophrenia and schizophrenia spectrum disorders and 711 people of the control group. The severity of symptoms was assessed with the PANSS. Obstetrical complications and a traumatic brain injury in medical history were studied as environmental factors., Results and Conclusion: No association was found between MTHFR C677T polymorphism and schizophrenia. There was no genotype effect on the severity of symptoms on the PANSS subscales. The effect of genotype-environment interactions on the severity of schizophrenia symptoms was not detected. The results do not confirm the data of a number of studies on the relationship of MTHFR C677T polymorphism with schizophrenia symptoms.

Establishing the structure of schizotypal traits and its cross-cultural and demographic universality is an important condition for increasing the effectiveness of prognosis of schizophrenic spectrum disorders and basic research on their etiology. The present study aimed to explore the structure of schizotypal traits measured by the Schizotypal Personality Questionnaire (SPQ-74) in the Russian population. Exploratory and confirmatory factor analyses of the factor structure of SPQ-74 were performed using a sample of 1316 people of a wide age range. It is shown that, in the Russian population, the four-factor «paranoid» model of N. Stefanis et al. had the best fit for the data. The multivariate confirmatory analysis evidenced the gender invariance of the model.

Aim: To search for genetic variants associated with premorbid personality in patients with schizophrenia., Material and Methods: The sample included 272 men diagnosed with schizophrenia or schizoaffective disorder. Patients were divided into 3 groups based on premorbid personality difficulties: mild (group 1, n=110), moderate (group 2, n=113), marked (group 3, n=49). The following polymorphisms were genotyped: 5-HTR2A (T102C), 5-HTTLPR, BDNF (Val66Met), CRP (-717A>G)., Results: A significant increase in the frequency of the CC (5-HTR2A T102C), LL (5-HTTLPR) and Met/Met (BDNF Val66Met) genotypes was identified in group 3 compared to group 1. Frequencies of CC and LL genotypes were significantly higher in group 2 compared to group 1 as well. The differences between group 2 and group 3 were found only for the Met/Met genotype. There were no between-group differences in the frequencies of CRP (-717A>G) genotypes., Conclusion: 5-HTR2A (T102C), 5-HTTLPR, BDNF (Val66Met) polymorphisms previously reported to modify schizophrenia course are also associated with premorbid personality in schizophrenic patients.

Aim: To study the association between proinflammatory cytokine genes and depression., Material and Methods: IL-1B С-511T and TNF-a G-308A gene polymorphisms were studied in patients diagnosed with depression and age and sex-matched healthy controls., Results and Conclusion: The IL-1B С-511T and TNF-a G-308A polymorphisms were associated with depression; CC genotype (р=0,001, OR=1.9 CI 1,3-2,7) and GG genotype (р=0,001, OR=3,0 CI 1,8-4,9) were the risk factors. The results suggest that immune factors may play a role in the development of depression. The authors highlight the role of clinical polymorphism of depression that makes it difficult to form homogenous groups of patients and to select phenotypes for biological studies.

Aim: To evaluate the association of the DRD2 gene and DRD2 x HTR2C interaction with hedonic and activational aspects of approach motivation in schizophrenia., Material and Methods: Genotypes at polymorphic loci DRD2 rs1800497 and HTR2C rs6318 (Cys23Ser) were identified in a sample that included 174 patients with schizophrenic spectrum disorders and 268 healthy subjects without a family history of psychoses. The participants completed the BIS/BAS and Temporal Experience of Pleasure Scale (TEPS)., Results and Conclusion: A MANCOVA with sex and age as covariates revealed the effect of the 'DRD2 x HTR2C x diagnosis' interaction on the BAS scores (p=0.033). The effect was significant for the Fun-Seeking and Drive scales. Among patients, the carriers of the DRD2 TT/CT x HTR2C GG/G genotype showed the highest scores on the both scales, and those with the minor alleles in the two loci had the lowest ones. Differences between these groups were nominally significant for both the Fun-Seeking and Drive, but did not survive the correction for multiple comparisons. Among controls, subjects without minor alleles demonstrated the highest scores on these two scales. They differed significantly from the carriers of the DRD2 TT/CT+HTR2C GG/G genotype on the Fun-Seeking (p=0.008). No effects of DRD2 and HTR2C on TEPS scores were found. In general, the results of the study can be interpreted in favor of the hypothesis about the role of the HTR2C and DRD2 genes interaction in the variability of the activational aspects of approach motivation in schizophrenia and healthy subjects. However, the lack of differences survived correction for multiple comparisons makes it difficult to interpret the revealed effects.

Aim: To study the role of polymorphism rs7341475 and methylation of the reelin gene in symptoms of schizophrenia and semantic verbal fluency., Material and Methods: Genotypes at the locus rs7341475 were identified in 556 patients with schizophrenic disorders. PANSS scores were obtained for 549 patients and 221 patients performed a test for semantic verbal fluency. The association of the reelin promoter methylation with the PANSS and verbal fluency measures was evaluated in 35 patients. A five-factor model of the PANSS was used., Results: The interaction effect of sex with genotype on the PANSS scores was found (F=2.70, p=0.020). Schizophrenic men homozygous for a common allele G had the lowest scores of the positive syndrome. Verbal fluency was related to the reelin promoter methylation., Conclusion: The results suggest that polymorphism rs7341475 may be associated with the variability of positive symptomatology in schizophrenic men. At the same time, the reelin gene methylation pattern, which consists of a higher methylation level in the region of the transcription start site and a lower one in the distal region of the promoter, may be beneficial for verbal fluency.

Olfactory neuroepithelium (OE) is shown to be a suitable experimental model to study neuronal biomarkers of psychiatric diseases including schizophrenia. Olfactory neuronal precursors can be useful for studying neurodevelopmental stages, neuronal markers, pharmacological screening. However, a limited number of research groups have used this cell model in a small number of patients and healthy people that can be explained by several factors. Based on literature reports and own research, the authors analyze the advantages and limitations of OE-derived cell/tissue models. The main limitations of these models are decreased rate of harvesting and culturing OE-derived cell and low percentage of patients who agreed to participate in the study. Our results showed that only 10% of patients with schizophrenia signed informed consent for nasal biopsy, 80% of them underwent biopsy.

Aim: To explore the relationship of depression and its endophenotypes (neuroticism and trait anxiety) with inflammatory genes in patients with coronary heart disease (CHD)., Material and Methods: A sample consisted of 78 male CHD patients with depression, 91 CHD patients without depression and 127 healthy men. Polymorphisms of the genes encoding interleukine-4 (IL-4 -589 C/T), interleukine-6 (IL-6 -174 G/C), tumor-necrosis factor alpha (TNF-α -308 G/A) and C-reactive protein (CRP -717A/G) were studied., Results: There was the association between the IL-6 -174 G/C and depression comorbid to CHD (р=0.01; OR=2.3 CI 95% 1.2-4.3). The frequency of the 'high expression' allele G in this group was higher compared to controls. The association between IL-4 -589 C/T and CHD was found. Compared to the control group, the frequency of the IL-4 -589CC genotype was higher in patients regardless of whether they had symptoms of depression (р=0.007; OR=2.1 CI 95% 1.2-3.4). No association between the TNF-α -308G/A and the CRP -717A/G with depression in CHD was observed. There were no differences between neuroticism and anxiety scores in patients with different IL-4 -589 C/T, IL-6 -174 G/C, TNF-α -308 G/A, CRP -717A/G genotypes., Conclusion: The finding of the association between the IL-6 -174G/C and depression, comorbid to CHD, is in line with literature on a role of IL-6 in the development of depression in patients with CHD.

Aim: To evaluate the interaction effects of season of birth and immune system genes on the personality traits 'Novelty seeking' (NS) and 'Self-directedness' (SD). Based on results on an influence of the immune system on the brain processes, the authors hypothesized that the interaction of immune system genes and season of birth, which is relevant for immune phenotype, can contribute to the development of personality traits., Material and Methods: NS and SD were measured in 336 healthy volunteers, aged from 16 to 67 years, using the Temperament and Character Inventory (TCI-125). IL1B C3954T, IL4 C-589T, IL13 C1112T and TNFA G-308A polymorphisms were genotyped., Results: An interaction effect of IL4 C-589T and season of birth on the personality traits was found (F2,322=6.03, pcorr=0.011, η2=0.04). Carriers of the minor allele T, who were born in winter, had lower NS and higher SD. There was a nominal main effect of genotype on SD (F=5.44, p=0.020) as well, with higher SD scores in carriers of the allele T compared to the CC genotype., Conclusion: The results suggest that the etiology of personality and immune characteristics can share common genetic elements including IL-4.

Aim: To develop a strategy for the search for candidate genes and targets for epigenetic studies of cognitive impairments in patients with schizophrenia., Material and Methods: A search for literature on epigenetics of schizophrenia and cognitive functions was performed. Single nucleotide polymorphisms (SNPs) that can create or abolish a site for DNA methylation or transcription factor sites were determined using a custom script., Results and Conclusion: Eight candidate genes, including BDNF, COMT, RELN, SNRPN, PSMA4, FAM63B, IL-1RAP, MAD1L1, as well as 750 targets in CpG islands in the linkage regions identified in GWAS of schizophrenia and 406 targets in SNV located within transcription factor binding sites were selected.

Aim: To search for genetic mechanisms of facial emotion recognition (FER) impairment, one of the features of schizophrenia that affects social adaptation of patients. Based on the view implicating the interplay between dopaminergic and glutamatergic systems into the pathogenesis of schizophrenia, authors explored the interaction effects of the C366G polymorphism in the GRIN2B gene encoding NMDA receptor subunit NR2B with ANKK1/DRD2 Taq1A and 48-VNTR DRD4 polymorphisms on FER., Material and Methods: GRIN2B -DRD2 interaction effects were studied in a sample of 237 patients and 235 healthy controls, GRIN2B - DRD4 in 268 patients and 208 controls., Results and Conclusion: Both effects were significant in combined samples of patients and controls (GRIN2B X DRD2, F=4.12, p=0.043; GRIN2B X DRD4, F=6.43, p=0.012). Further analysis confirmed the interaction effect of GRIN2B and DRD2 polymorphisms on FER in patients with schizophrenia. In patients with a less efficient allele of the DRD2 in the absence of the minor allele of the GRIN2B C366G polymorphism, the results were close to normal values while patients with minor alleles of both polymorphisms showed the worst results. This finding is in line with the conceptions on a possible role of NMDA-receptor hypofunction and D2-mediated regulation of NMDA-receptor activity in FER impairments in schizophrenia.

Objective: To search for the association between the GRIN2B gene and signs of thought and speech disorders which may be the result of decreased accessibility to the mental lexicon., Material and Methods: The association between the GRIN2B polymorphism rs7301328 with semantic verbal fluency and five symptoms of thought and speech disorders, as assessed with the PANSS, was studied in 552 patients with schizophrenia-spectrum disorders., Results and Conclusion: There was the association of the GRIN2B gene with verbal fluency and the PANSS item «Difficulty in Abstract Thinking». The association was not modified by verbal fluency. The results suggest that the GRIN2B gene may modify the linguistic processes involved in the retrieval of information from the mental lexicon on the basis of semantic traits and, moreover, contribute to the variability of clinical symptoms of impairment of abstract thinking in patients with schizophrenia. The heterozygous genotype may be protective against the development of thought and speech disorders.

This review highlights the basic paradigms and directions of molecular genetic studies of cognitive deficits in schizophrenia. Along with the traditional approach based on functional candidate genes, it covers genome-wide association studies (GWAS) for cognition in general population and schizophrenic patients, attempts to integrate GWAS results in polygenic profiles that can be used in personalized care of schizophrenic patients, and a search for biological pathways implicated in the development of cognitive impairments with bioinformatics methods. However, despite significant advances in understanding the genetic basis of the disease and a rapidly growing amount of data on genes associated with cognitive functions, most of the variability of cognitive impairments in patients remains unexplained. The data on the functional complexity of the genome accumulated in the fields of molecular biology and genetics underscore the importance of studying epigenetic mechanisms of cognitive deficits in schizophrenia.

Aim: The present research examines the association between two basic dimensions of personality and genes of inflammatory cytokines and mediators reported to be elevated in schizophrenia and affective disorders. Genes of interleukin-1B (IL-1B), interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-α), C-reactive protein (CRP) and alpha 1-antitrypsin (A1AT) were studied., Material and Methods: A total of 639 healthy subjects, aged from 17 to 69 years, participated in the study. The following polymorphisms were genotyped: IL-1B С-511Т (rs16944) and С3954Т (rs1143634), IL-6 G-174C (rs1800795), TNF-α G-308A (rs1800629), CRP (rs279452), A1AT 374G/A (rs709932). Basic personality dimensions Extraversion and Neuroticism were assessed using the Eysenck Personality Inventory., Results and Conclusion: The levels of Extraversion and Neuroticism were not associated with IL-1B, IL-6, TNF-α G and CRP polymorphisms. The association between the A1AT 374G/A polymorphism and Extraversion (р=0.036) was shown. There was a trend towards the association between the A1AT 374G/A polymorphism and Neuroticism (p=0,05) in women. Because this is the first study of the effect of IL-1B, IL-6, TNF-α and A1AT on personality dimensions, the results should be considered as preliminary and need to be replicated.

Aim: To study the association between the kynurenine 3-monooxygenase (KMO) and depression., Material and Methods: КМО rs2275163 (C/T) and rs1053230 (A /G) polymorphisms were genotyped in patients diagnosed with depression (the main group) and age - and sex-matched healthy people., Results: The rs2275163 polymorphism was not associated with depression. There was the association between the rs1053230 polymorphism and depression. The frequency of the low expression genotype GG was higher in the main group compared to controls (р=0.001, ОШ 2.8 (95% ДИ 1.73-4.24). This genotype was earlier reported to be associated with the increased levels of kynurenic acid in patients with bipolar disorders., Conclusion: The genotype GG can be considered as a risk factor of depression.

Advanced genome technologies, including genome-wide association studies, next generation sequencing analysis, whole exome sequencing, encourage the development of theoretical insights on the role of genetic factors in schizophrenia. In this context, the author considers a monogenic model of schizophrenia and its evolution.

Objective: The brain-derived neurotrophic factor (BDNF) gene is thought to be a candidate gene for schizophrenia. At the same time, many studies failed to find the association between BDNF and the disease though the contribution of the BDNF Val66Met polymorphism to the variance of characteristics of schizophrenia has been confirmed. Authors suggested that this contribution was the consequence of the involvement of this gene in the formation of "cognitive reserve" that had a protective effect on the different aspects of the disease. This protective effect should emerge in relatively intact cognitive function in patients with the protective Val66Met genotype as well as in the accumulation of the protective genotypes in unaffected relatives., Material and Methods: We examined 169 patients with schizophrenia spectrum disorders, 320 their first-degree relatives and control groups using molecular-genetic and experimental psychological methods., Results: No effect of the Val66Met polymorphism on verbal memory, executive functions and total index of cognitive functioning was found. Besides, we did not find any differences in Val66Met genotype frequencies in first-degree relatives of patients with schizophrenia and healthy people without family history of schizophrenia., Conclusion: The results do not support our hypothesis that BDNF is a gene of "cognitive reserve".

Perspectives of molecular-genetic approaches to the establishment of mechanisms of development and causes of heterogeneity of neurocognitive impairment are discussed. The current results indicate that candidate genes for depression can contribute to the variance of memory and regulatory functions in patients. At the same time, these genes are closely related to affective information processing and .cortisol level. By that fact, it can't be excluded that affective processes moderate the association between cognition and genes. EEG parameters could be useful phenotypes in the search for and understanding of genetic mechanisms of cognitive deficit in depression. Parameters of resting EEG and its reactive changes are known to reflect the certain cognitive processes. They are influenced by genetic factors and are sensitive indicators of mechanisms that might underlie cognitive impairment in depressive patients. Accumulating data on molecular-genetic correlates of normal electric brain activity may be a source of choosing new candidate genes for cognitive impairment in depression.

Objective: To compare psychometric and molecular-genetic characteristics of depression caused by ischemic heart disease (IHD) and depression in patients with IHD caused by other psychogenic factors., Material and Methods: One hundred and thirty-five patients with depression comorbid to ischemic heart disease (IHD) were examined. Depression was associated with IHD in 71 patients (group 1). In 64 patients, depression was caused by other psychogenic factors (group 2). The HAMD-21 scale was used to measure depressive symptoms., Results and Conclusion: The comparative analysis of the core symptoms of depression demonstrated that group 1 had a peculiar psychometric profile with marked apathy, which was not accompanied by marked hypothymia, guilt feelings or anxiety, compared to group 2. The molecular-genetic correlate of this profile was found. It included a combination of an allele S (5-HTTLPR) of the serotonin transporter gene, an allele G (A-1438G) of the serotonin receptor type 2A gene and the genotype ValVal (Val66Met) of the brain-derived neurotrophic factor gene.

Objective: Neurotoxic metabolites of the kynurenine pathway are thought to be implicated in the pathogenesis of schizophrenia. The enzyme indoleamine 2,3-dioxygenase (IDO) catalyzes the initial step of the kynurenine pathway that converts tryptophan to kynurenine metabolites. IDO is induced by proinflammatory cytokines. We studied IL-1Β T-511C (rs16944), IL-1Β C3954T (rs1143634), IDO VNTR and IDO rs9657182 polymorphisms in patients with schizophrenia and controls., Material and Methods: Genotyping was performed in 296 patients with schizophrenia (ICD-10 F20.0) and 355 healthy controls., Results: The multiple dimension reduction (MDR) analysis revealed a combination included alleles С (T-511C), Т (C3954T), V1 (VNTR) and С (rs9657182), which was associated with schizophrenia (OR 3,3 CI 95% 2,3-4,8)., Conclusion: This is the first report of the interaction between IL-1Β and IDO genes. Further research into genes of the kynurenine pathway is needed.

The 5-HTTLPR SLC6A4 and catechol-o-methyltransferase (COMT) Val158Met polymorphisms are reported to be associated with processing of facial expressions in general population. Impaired recognition of facial expressions that is characteristic of schizophrenia negatively impacts on the social adaptation of the patients. To search for molecular mechanisms of this deficit, we studied main and epistatic effects of 5-HTTLPR and Val158Met polymorphisms on the facial emotion recognition in patients with schizophrenia (n=299) and healthy controls (n=232). The 5-HTTLPR polymorphism was associated with the emotion recognition in patients. The ll-homozygotes recognized facial emotions significantly better compared to those with an s-allele (F=8.00; p=0.005). Although the recognition of facial emotions was correlated with negative symptoms, verbal learning and trait anxiety, these variables did not significantly modified the association. In both groups, no effect of the COMT on the recognition of facial emotions was found.

Cognitive reserve (CR) postulates that individual differences in the cognitive processes or neural networks underlying task performance allow some people to cope better than others with brain damage. An aim of the study was to search for candidate genes for CR in schizophrenia. We propose that higher frequencies of low risk alleles is observed in healthy relatives of schizophrenic patients compared to patients and controls and in patients without neurocognitive deficit and with less severity of the disease compared to other patients and controls. Besides, frequencies of these alleles in patients should be similar to those in general population. Authors studied SNAP-25 and DTNBP1 genes. The polymorphism T1065G of SNAP-25 was genotyped in 278 patients with schizophrenia, 126 their relatives and 207 controls and the polymorphism P1763 of DTNBP1 was genotyped in 202 patients, 229 relatives and 262 controls. There was a trend towards the increase in the frequency of an G allele of SNAP-25 in siblings of patients. The frequency of this allele was higher in patients without neurocognitive deficit compared to patients with cognitive deficit (p=0.003) and controls (p=0.002). The allele was associated with index of cognitive functioning in patients (p=0.012) and controls (p=0.006) and with the severity of negative symptoms in patients (p=0.023). At the same time, the polymorphism T1065G was not associated with schizophrenia. Therefore, an allele G may be considered as a marker for higher CR.

Authors investigated effects of the Val66Met polymorphism of the brain-derived neurotrophic factor (BDNF) gene and level of trait anxiety on attention in 90 patients with schizophrenia or schizoaffective psychosis. Attention was assessed using auditory event-related brain potentials (ERPs) and neuropsychological testing. There was a significant effect of the BDNF genotype, but not anxiety, on performance on the neuropsychological test and on the P300 amplitude in frontal and temporal leads. Carriers of a Met allele performed worse and showed lower P300 amplitude during the attention task than those with the ValVal genotype. The interaction effect of the genotype and anxiety was observed for non-target N100 amplitude in central and parietal leads. This effect depended on the level of anxiety: the interaction was significant only in the group with the lower level of anxiety. In this group, a Met allele was associated with the lower N100 amplitude. It was suggested that BDNF genotype does not contribute to brain electrical activity at the first stage of stimulus recognition (N100) because highly anxious people tend to be more attentive, regardless of genotype, due to the fear about their ability to cope with the task requirements.

To evaluate a role of dopamine transmission in the theory of mind (ToM) dysfunction in schizophrenia, authors studied the association of ToM with COMT and DRD2 gene polymorphisms in 209 patients with schizophrenia and 172 healthy people. All subjects performed second-order false belief (FB2) and faux pas stories. The association between the COMT Val158Met polymorphism and performance on FB2 was found. The association was sex-specific. The worse performance was associated with a Met allele in female patients and with the ValVal genotype in male ones. A correlation analysis of the COMT Val158Met polymorphism, performance on FB2 task, neurocognitive and clinical symptoms suggests that in female patients the association was modified, in part, by the higher stress sensitivity caused by the severity of clinical symptoms and its consequences for cognitive functioning.

Depression is commonly present in patients with coronary heart disease (CHD). Identification of early predictors of depression in CHD patients is an important direction of current research in the field of psychosomatic medicine. Serotonin transporter gene polymorphism (5-HTTLPR) was earlier reported to contribute to the development of depression comorbid to CHD. The present study aimed at investigating the role of the 5-HTTLPR polymorphism, stress factors and personality traits in the prediction of depressive symptoms in patients with CHD. The study included 169 male patients, aged from 31 to 84 years, mean age 59±8.8 years. Depression was diagnosed in 135 (79.9%) patients; in 71 (42%) patients it was related to the presence of CHD (nosogenic factor). Severity of depressive symptoms as defined by HAM-D-21 was associated with the interaction between the 5-HTTLPR polymorphism, nosogenic factor and trait anxiety. Risk of depression was 7.0 times higher in carriers of an S allele in the presence of the nosogenic factor. In other combinations of a 5-HTTLPR variant with the presence or absence of the nosogenic factor, trait anxiety contributed significantly to the variance of depressive symptoms. Patients with higher scores on the Spilberger STAI had 5 and 7 times higher risk of moderate and marked depression compared to those with moderate and low anxiety scores. The approach suggested in the study may be useful for the prediction of depression and its severity in patients with CHD.

Growing evidence suggest that interleukin-1beta (IL-1B) and interleukin-1 receptor antagonist (IL-1RN) are involved in the pathogenesis of schizophrenia. The objective of this study was to test the association of the functional promoter polymorphism 511T>C of the IL-1B gene and the VNTR polymorphism of the IL-1RN gene with clinical symptoms of schizophrenia. We studied 758 patients, 415 men and 343 women, with the ICD-10 diagnosis of schizophrenia. Symptoms of schizophrenia were measured using the Positive and Negative Symptome Scale (PANSS). The sample was stratified by gender and type of schizophrenia (chronic or episodic). We found the association between the VNTR IL-1RN polymorphism and PANSS negative symptoms (p = 0.02) in men. Male patients with the genotype 2*2 had lower scores than those with 1*2 and 1*1 genotypes. The genotype 2*2 was associated with a more severe illness course (shorter illness duration and smaller number of hospitalizations) as well. The results suggest that the VNTR polymorphism in the IL-1RN gene may be a predictor of outcome of schizophrenia in men.

NRG1 is a strong candidate for schizophrenia though its role in the pathogenesis of the disease remains unknown. One of the approaches to study mechanisms underlying the association between NRG1 and schizophrenia is to investigate the association between a gene and an endophenotype of schizophrenia, e.g., cognitive dysfunctions. Authors looked for the association of 478B14-848 и 420M9-1395 microsatellites with semantic verbal fluency, working and episodic memory in 338 patents with schizophrenia, 162 their unaffected relatives and 316 healthy controls from the Russian population. It was found associations between allele 0 at 478B14-848 (220 bp) and long-term episodic memory and between allele 0 at 420M9-1395 (274 bp) and short-term memory in schizophrenic patients. The frequency of homozygotes for 420M9-1395 was higher in the group of patients as compared to controls. In conclusion, the risk allele 0 at 420M9-1395 is associated with the short-term memory deficit while allele 0 at 478B14-848 is protective for long-term memory deficits.

Platelet serotonin content in patients in the acute period of stroke is an important index of clinical changes during the post stroke period as well as a predictor of development of mental disorders. We studied the association between two polymorphisms (5-HTTLPR and Val66Met BDNF) and the platelet serotonin content in 47 patients with stroke. We also investigated the moderating effect of genetic variants on the association between platelet serotonin content and development of affective and anxiety disorders in stroke patients in the acute period of stroke. The interaction effect of two polymorphisms on levels of platelet serotonin was found. The lowest level was observed in patients with the diplotype LL*ValVal, the highest level--in the group of patients with the LL genotype and genotypes containing at least one copy of a Met allele. No moderating effect of genetic variants on the relationship between serotonin content and affective or anxiety disorder was found.

The aim of the study was to find molecular-genetic variants associated with nosologically independent schizoaffective disorder (SAD) which clinical presentations had been specified earlier. Authors studied a sample of 230 patients including 39 with "nuclear" (nosologically independent) and marginal (intermediate) variants of SAD, 53 with schizophrenia with schizoaffective states and 81 with schizophrenia with affective disorders in the structure of psychotic attacks. In these groups, authors studied the following polymorphisms: 5-HTTLPR, Val66Met BDNF, T102C 5-HTR2a and С677Т MTHFR. Frequencies of genotypes were compared to those in a sample of healthy controls (328 people). It has been shown that the "nuclear" variant has a genetic profile represented by a combination of genetic variants (SS*ValVal*TT*CC) that distinguishes this clinical entity from other groups and controls. The results may be used as an additional criteria for clinical and nosological differentiation of SAD from schizophrenia.

Schizophrenia with early onset is a relatively rear form of the disease which characterized by severe chronic course and poor outcome. In the present paper, we studied several genes possibly involved in the pathogenesis of this form. These are genes for brain-derived neurotrophic factor (Val66Met polymorphism), serotonin transporter (5-HTTLPR), serotonin receptor type 2A (T102C) and dopamine receptor D2 (Taq1A). Sixty-five patients (age at onset before 15 years) and 111 healthy controls were included in the study. Out of all genes tested, the association was found only for the Val66Met BDNF polymorphism. Frequency of the ValVal genotype was higher in the group of patients (p=0.03; OR 2.1 CI 1.1-4.0) compared to the controls. These results were consistent with our previous study which was carried out on the sample of schizophrenic patients with later age of disease onset. In this study, the frequency of the ValVal genotype was higher only in the group of patients with chronic schizophrenia compared to the controls. It is concluded that the ValVal BDNF genotype may be considered as a marker of schizophrenia with more severe course.

The elevated level of homocysteine has been repeatedly observed in patients with schizophrenia. Molecular-genetic studies revealed the association between schizophrenia and polymorphisms of two genes - methylenetetrahydrofolate reductase (MTHFR) and cystathionine-beta-synthase (CBS) involved in the conversion of homocysteine to methionine and cysteine, respectively. Authors have studied the association of C677T MTHFR and 844ins68 CBS polymorphisms with attention in 105 schizophrenic patients (56 women and 49 men) by measuring auditory evoked potentials and concentration of attention. Women with a genotype containing an insertion (Ins+) had the shorter latency of N100 in the frontal leads compared to those with the Ins- genotype. The results of the neuropsychological study revealed that women with Ins+ genotypes performed better on the test as well. In conclusion, the 844ins68 CBS polymorphism is associated with attention in patients with schizophrenia.

Genetic factors are thought to contribute to schizotypal dimensions. Recently, a number of genetic variants associated with schizotypal traits in psychiatrically healthy people have been found. Authors reported earlier the association between the SERT 5-HTTLPR polymorphism and schizotypal traits measured with MMPI. The present study aimed at the replication of association on a larger sample using other questionnaires and methods of data analysis. The sample comprised 657 people from the Russian population. MMPI, SPQ-74 and TCI-125 were used to measure personality traits. Based on the results of psychological testing, the sample was divided into high risk and control groups. For MMPI, the high risk group included people with the elevation on scale Schizophrenia, for SPQ-74 - people with a total score more than 25 and for TCI-125 - people with lower scores on scale Cooperation and higher scores on Self-Transcendence. In all high-risk groups assessed by different psychological instruments, the frequency of the SS 5-HTTLPR genotype was significantly lower as compared to the corresponding control groups. MANCOVA also showed that individuals with the SS genotype had lower scores on scales related to schizotypal traits. Thus, we have confirmed our previous results on the association between the 5-HTTLPR polymorphism and schizotypal traits in psychiatrically healthy subjects.

An association study of variations in the DTNBP1 (P1763 and P1578) and 5-HTR2A (T102C and A-1438G) genes with short-term verbal memory efficiency and its component process variables was carried out in 405 patients with schizophrenia and 290 healthy controls. All subjects were asked to recall immediately two sets of 10 words. Total recall, List 1 recall, immediate recall or attention span, proactive interference and a number of intrusions were measured. Patients significantly differed from controls by all memory variables. The efficiency of test performance, efficiency of immediate memory, effect of proactive interference as well as number of intrusions were decreased in the group of patients. Both 5-HTR2A polymorphisms were associated with short-term verbal memory efficiency in the combined sample, with the worst performance observed in carriers of homozygous CC (T102C) and GG (A-1438G) genotypes. The significant effect of the P1763 (DTNBP1) marker on the component process variables (proactive interference and intrusions) was found while its effect on the total recall was non-significant. The homozygotes for GG (P1763) had the worst scores. Overall, the data obtained are in line with the conception of DTNBP1 and 5-HTR2A involvement in different component process variables of memory in healthy subjects and patients with schizophrenia.

The association of 5-HTTLPR and Val66Met BDNF genotypes with symptoms of anxiety and depression related to stress caused by severe chronic psychiatric disease of a family member has been studied. Genotyping has been conducted in the group of 214 unaffected parents of patients with schizophrenia and 100 healthy age-matched controls. The diplotype Met*ss was associated with higher scores of depressive symptoms as assessed by MMPI in the group of parents but not in the control group. The most marked differences were seen in the subgroup of parents whose children had the greatest severity of symptoms. The results suggest that the interaction of 5-HTT and BDNF genes may moderate the association between objective and subjective burden of disease.