[Willingness to expend effort for rewards in individuals at clinical high-risk for psychosis: a relationship with the severity and stability of negative symptoms]. / Gotovnost' prilagat' usiliya v gruppe klinicheskogo vysokogo riska razvitiya psikhoza: svyaz' s vyrazhennost'yu i stabil'nost'yu negativnoi simptomatiki.

OBJECTIVE: To identify the deficit in willingness to expend effort and its association with negative symptoms in the high-risk for psychosis (CHR) group. MATERIAL AND METHODS: The study included young men: 45 patients, who met CHR criteria and were treated for a depressive episode, and 15 controls. All subjects completed a modified version of the Effort Expenditure for Rewards Task (EEfRT). The CHR group was assessed with the SOPS, SANS and HDRS at the beginning and at the end of treatment. EEfRT was performed only at the end of treatment. RESULTS: The CHR group was significantly less likely to choose high effort tasks across reward probability and magnitude levels compared with the control group (all p<0.001). No significant correlations were found between the rate of selecting the high effort task and the negative syndrome domains of amotivation and diminished expression. The subgroups of CHR with stable and transient (i.e., with a reduction >50% during treatment) negative symptoms, which were identified by a cluster analysis, did not differ in the willingness to expend effort. CONCLUSION: The study confirmed a decrease in the willingness to expend effort in the CHR group; however, this deficit was only weakly correlated with negative symptoms and persisted after the symptoms reduction during treatment, which requires future studies to investigate mechanisms underlying impaired effort expenditure for rewards in CHR.

[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.

[Genetic polymorphism of cytokines IL-1ß, IL-4 and TNF-α as a factor modifying the impact of childhood adversity on schizophrenia symptoms]. / Geneticheskii polimorfizm tsitokinov IL-1ß, IL-4 i TNF-α kak faktor, modifitsiruyushchii vliyanie neblagopriyatnogo detskogo opyta na simptomatiku shizofrenii.

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-1ß 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; η2p=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; η2p=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.

[Structure of schizotypal traits in the Russian population]. / Struktura shizotipicheskikh chert v rossiiskoi populyatsii.

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 «paranoid¼ model of N. Stefanis et al. had the best fit for the data. The multivariate confirmatory analysis evidenced the gender invariance of the model.

[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.

[Relationships of rs7341475 polymorphism and DNA methylation in the reelin gene with schizophrenia symptoms]. / Sviaz' polimorfizma rs7341475 i metilirovaniia DNK v gene rilina s proiavleniiami shizofrenii.

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.

[The interaction effect of ANKK1/DRD2 TaqIA and HTR2C Cys23Ser on approach motivation in schizophrenic patients and normals]. / Éffekt vzaimodeistviia polimorfizmov ANKK1/DRD2 TaqIA i HTR2C Cys23Ser na pobuditel'nuiu motivatsiiu u bol'nykh shizofreniei i zdorovykh.

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.

[Epigenetic research of cognitive deficit in schizophrenia: some methodological considerations]. / Épigeneticheskie issledovaniia kognitivnogo defitsita pri shizofrenii: nekotorye metodologicheskie problemy.

AIM: To highlights the problems of assessing cognitive deficits in schizophrenia, relevant to the epigenetic, as well as a wide range of other approaches to the search for biological bases of cognition. MATERIAL AND METHODS: The literature on the weaknesses in the evaluation of cognitive functions in patients with schizophrenia are summarized and discussed. The analysis is illustrated by our experience in developing a cognitive battery and a sample to examine relationships between DNA methylation in blood cells and cognitive deficits in schizophrenia. RESULTS AND CONCLUSION: It has been shown that to assess cognitive deficits in patients and to reduce the influence of confounders in epigenetic analysis it is necessary (1) to use a battery with the existing co-normative data in the target population, which allows to evaluate representativeness of control and patients included in the study sample, (2) to verify the theoretically driven battery structure using normative population and a cohort of patients, (3) to balance groups of cases and controls on the number, age and sex, for which an individual matching of cases and controls is best suited, (4) to conduct an additional statistical analysis controlling for education and smoking.

[Effect of cytokine genes and season of birth on personality]. / Vliianie genov tsitokinov i sezona rozhdeniia na nekotorye osobennosti lichnosti.

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.

[A search of target regions for association studies between DNA methylation and cognitive impairment in schizophrenia]. / Poisk mishenei dlia obnaruzheniia sviazi mezhdu metilirovaniem DNK i neirokognitivnym defitsitom pri shizofrenii.

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.

[A role of interactions between N-methyl-D-aspartate and dopamine receptors in facial emotion recognition impairment in schizophrenia]. / Rol' vzaimodeistviia genov NMDA- i dofaminovykh retseptorov v narushenii raspoznavaniia émotsional'noi mimiki pri shizofrenii.

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.

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.

[A study of the effect of the genes of inflammatory proteins on basic personality dimensions]. / Issledovanie effekta genov vospalitel'nykh faktorov na bazovye cherty lichnosti.

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.

[The association between the GRIN2B gene and verbal fluency and impairment of abstract thinking 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 Thinking¼. 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.

[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.

[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.

[Results and promises of genetics of cognitive impairment in schizophrenia: molecular-genetic approaches]. / Rezul'taty i perspektivy geneticheskikh issledovanii kognitivnykh narushenii pri shizofrenii: molekuliarno-geneticheskie podkhody.

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.

[Molecular-genetic and electroencephalographic markers of neurocognitive processes in depressive disorders].

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.

[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.