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It is known that the neurohormone oxytocin plays an important role in the pathogenesis of mental illness and also models the relationship between stress factors, especially those acting in the early stages of development, and the development of mental disorders. On the basis of these data, we investigated the effects of the interaction of the environmental factor, in the capacity of which the childhood adversity (CA) and the oxytocin receptor (OXTR) genotypes in the polymorphic sites rs4686302 and rs7632287 were considered, on the severity of negative symptoms of schizophrenia. The study involved 592 patients with schizophrenia (code F20, according to ICD-10). Information about the presence of CA was obtained from case histories and patient interviews. Analysis of covariance (GML) was used for statistical data processing; in post hoc pairwise comparison, Tukey's test was used. A significant effect of the interaction between CA and OXTR gene polymorphism rs7632287 (G/A) on the severity of negative symptoms in patients with schizophrenia was revealed. In patients without CA, polymorphisms did not have a significant effect on the studied phenotype. Thus, our study showed for the first time that the rs7632287 (G/A) polymorphism and CA have a mutual effect on the severity of negative symptoms of schizophrenia. [ABSTRACT FROM AUTHOR]

The MIR137 gene encodes microRNA-137 (miR-137), which is a brain-enriched miR that is highly expressed in various brain regions. miR-137 has been identified as a modulator of processes involved in the pathogenesis of neuropsychiatric disorders. Functional polymorphism of variable number of tandem repeats (VNTR) rs58335419 was found in the regulatory region of the MIR137 gene. It is associated with a change in the expression of miR-137 and, as a result, with an increased risk of developing psychopathologies, including schizophrenia. In this study, we for the first time have analyzed the distribution of frequencies of alleles and genotypes of MIR137 VNTR in a large sample from the Russian population. The association of VNTR with the risk of schizophrenia has been studied. It was found that the presence of VNTR alleles with more than three repeats, as well as a genotype homozygous for such alleles, is associated with an increased risk of developing schizophrenia (OR = 1.4, 95% CI: 1.01–1.95). [ABSTRACT FROM AUTHOR]

Objectives. To assess the role of interactions between oxytocin pathway gene polymorphisms and adverse childhood experiences (ACE) in deficits of the recognition of emotion in schizophrenia. Materials and methods. Patients with schizophrenia spectrum disorders (n = 699) underwent cognitive testing in which they performed a facial emotion recognition task. Patients were then genotyped for common polymorphisms in oxytocin pathway genes which have previously been associated with face perception: OXTR (rs53576, rs7632287), CD38 (rs3796863), and ARNT2 (rs4778599). The presence of ACE factors was assessed by review of medical records. Results. ACE was found in 49% of patients. Analysis of covariance with control for sex and age revealed an interaction effect between OXTR rs53576 and ACE on emotion recognition in patients (F = 11.51; p < 0.001; η p 2 = 0.02). This effect remained significant when controlling for cognitive functioning and negative symptoms. Carriers of the A allele without ACE were worse at recognizing emotions than GG homozygotes without ACE (p = 0.039) and carriers of the A allele with ACE (p = 0.009). Conclusions. The present results are consistent with the role of the A allele (rs53576) in sensitivity to the characteristics of childhood experiences able to affect psychosocial development and are of value for further studies of the use of oxytocin to improve social cognition and social adaptation of patients with schizophrenia. [ABSTRACT FROM AUTHOR]

The association of the rs1344706 polymorphism of the ZNF804A gene with EEG rhythm synchronization/ desynchronization parameters during the visual perception of semantic and meaningless verbal information was studied in patients with schizophrenia and schizophrenia spectrum disorders (n = 93) and mentally healthy subjects (n = 93). On reading verbal information, regardless of mental status, subjects with the AA genotype showed lower synchronization of the θ rhythm than carriers of the C allele. As compared with carriers of the C allele, healthy carriers of the AA allele showed lower synchronization of the θ rhythm in the posterior cortical areas of the left hemisphere, no difference in synchronization of the γ rhythm, and desynchronization of the μ rhythm on perception of semantic and meaningless verbal information. Patients carrying the AA variant, as compared with carriers of the C variant, showed a lower degree of μ-rhythm desynchronization, which correlated with the severity of speech disorders on the PANSS. The results obtained here indicate that the rs1344706 polymorphism of the ZNF804A gene has a modulating effect on the neurophysiological characteristics of the reading process and contributes to the variability of clinically expressed speech disorders. [ABSTRACT FROM AUTHOR]

Objectives. Working from the hypothesis that activation of the immune system is one of the mechanisms whereby early environmental factors influence the onset and course of schizophrenia, we studied the effects of the interaction of adverse childhood experiences (ACE) and genotypes at the polymorphic loci rs16944 of the IL1B gene, rs2243250 of the IL4 gene, and rs1800629 of the TNF-α gene on the severity of different groups of schizophrenia symptoms. Materials and methods. The cohort consisted of 546 patients with schizophrenia spectrum disorders. ACE was detected by analysis of medical records and a questionnaire completed by the patients. A five-factor Positive and Negative Syndrome Scale (PANSS) model with a built-in two-factor model of the negative syndrome was used. Results. The interaction of ACE and TNF-α was found to have a significant effect on the cognitive disorganization factor after adjusting for multiple comparisons, with discrimination of carriers of different genotypes in the group without ACE (pFDR < 0.018; = 0.03). The interaction of ACE and genotype was found to have a significant effect on the cognitive disorganization syndrome (F = 5.87; p = 0.003; = 0.03). Stereotyped thinking and volitional disorder identified on the PANSS showed the strongest correlations with the cognitive disorganization factor (ro = 0.84 and ro = 0.82, respectively) and the most significant differences depending on the interaction of genotype and ACE (Kruskal–Wallis test, H = 12.28, p = 0.006 and H = 12.79, p = 0.005, respectively). Conclusions. ACE modifies the relationship between the pathogenesis of schizophrenia and the rs1800629 polymorphic locus located in the TNF-α gene promoter, which is also an enhancer of 60 more genes located in the major histocompatibility complex. [ABSTRACT FROM AUTHOR]

The AS3MT gene encodes arsenic(III) methyltransferase. VNTR polymorphism of the AS3MT gene is characteristic only for the human genome. It is associated with the expression of a human-specific AS3MTd2d3 protein isoform, which is a potential risk factor for the development of schizophrenia. In this study, we have analyzed for the first time the distribution of frequencies of alleles and genotypes of VNTR polymorphism in a large sample of ethnic Russians. The association of VNTR with the risk of schizophrenia has been studied. This study included 1002 patients with schizophrenia and schizophrenia spectrum disorders and 1510 people of the control group. Women with the V3/V3 genotype have an increased risk of schizophrenia (OR = 1.4, 95% CI: 1.11–1.77). [ABSTRACT FROM AUTHOR]

Research suggests that, in contrast to circulating C-reactive protein (CRP), genetic variants conferring higher CRP levels have protective effects against schizophrenia and moderate influences of season of birth on the development of the disease. This study aimed to explore whether the CRP gene also moderates the relations between childhood adversity and clinical characteristics of schizophrenia. The relations between childhood adversity, genotypes at rs2794521 within the CRP locus, syndromes measured as five factors and two negative subfactors of the Positive and Negative Syndrome Scale, and history of suicide attempts were analyzed in 921 schizophrenia patients. A significant effect of genotype on suicide attempts in patients exposed to childhood adversity was found. The result suggests a moderating role of genetic determinants of inflammation in translating early life psychological stress effects into risk of suicide attempts in schizophrenia. [ABSTRACT FROM AUTHOR]

Objectives. To identify any relationship between the genes of the oxytocinergic pathway and psychosocial functioning in schizophrenia, i.e., the ability of schizophrenia patients to form interpersonal relationships, taking account of the influence of environmental factors such as perinatal complications. Materials and methods. The study involved a total of 383 people (140 women and 243 men, mean age 32.6 ± 11.4 years), of whom 107 had perinatal complications and 276 did not. Psychometric studies used a points assessment of the level of social functioning (the interpersonal relationships domain of the Personal and Social Performance Scale (PSP)). Genotyping addressed the rs53576, rs4686302, and rs1042778 polymorphisms in the oxytocin receptor gene (OXTR) and the rs3796863 polymorphism of the transmembrane glycoprotein gene (CD38). Results. The group with perinatal complications showed an association with OXTR polymorphism rs53576 and the level of interpersonal relationships (p = 0.005). Significant differences were found between carriers of the GG genotype (rs53576) and carriers of the A variant (p = 0.003). In the group without perinatal complications, the genotype did not show any significant effect on this parameter. Other polymorphic sites showed no association with the level of interpersonal relationships in either group. Conclusions. The results obtained here are consistent with concepts based on extensive evidence linking oxytocinergic system genes with social behavior. We obtained new data on the influence of the known OXTR polymorphism rs53576 on a phenotype not previously studied from this point of view – the ability to form interpersonal relationships – in schizophrenia patients; the genotype effect was found to depend on the environmental risk factor (perinatal complications). [ABSTRACT FROM AUTHOR]

Objectives. To compare groups of schizophrenia patients with different levels of functional outcomes and different frequencies of risk variants at polymorphic loci of five candidate genes to create a multigene panel and to test its predictive value for long-term disease outcomes. Materials and methods. Patients included in this study were divided in terms of the typology used here into three groups with different levels of social functioning. Group 1 patients had the highest levels, while values were significantly lower in group 2 and lowest in group 3. The multigene panel included genes for the type 2A serotonin receptor (5-HTR2a T102C), the serotonin transporter (5-HTTLPR), C-reactive protein (CRP-717A>G), the type 1 angiotensin II receptor (AGTR1 A1166C), and brain-derived neurotrophic factor (BDNF Val66Met). Computation of multigene risk (MGR) was by summation of all the risk alleles carried by a particular patient. For each polymorphism, carriers of the genotype homozygous at the high-risk allele had a value of 2 and heterozygotes had a value of 1; homozygotes at the low-risk allele had a value of 0. MGR Values for a patient could range from 0 to 10 risk alleles. Results. Group was found to have a significant effect on MGR (p < 0.0001). Between-group differences were also significant (p < 0.01). Group 1 contained no carriers of six or more risk alleles and more than 50% were carriers of fewer than five alleles. In group 2, 19.4% of patients were carriers of ≥6 risk alleles, while 31.7% of patients in group 3 carried ≥6 risk alleles. These groups had no carriers of 0–2 risk alleles, while 20.7% of patients group 1 carried 0–2 risk alleles. Conclusions. MGR may be a predictor of functional outcome in schizophrenia patients. Low levels of risk alleles (0–4) allowed individuals to be predicted with high probability to have favorable functional outcome in the long-term period of illness. [ABSTRACT FROM AUTHOR]

Objective. To assess the association of the DRD2 gene and its interaction with the HTR2C gene with the characteristics of the hedonistic and activatory aspects of approach motivation in schizophrenia. Materials and methods. Genotypes at the polymorphic loci rs1800497 of DRD2 and rs6318 (Cys23Ser) of HTR2C were identified in a cohort including 174 patients with schizophrenia spectrum disorders and 268 healthy subjects. Subjects completed scales assessing approach motivation (BIS/BAS) and the Temporal Experience of Pleasure Scale (TEPS). Results and conclusions. Analysis taking account of sex and age identified an effect of the interaction between the DRD2 and HTR2C genes and diagnosis (p = 0.033) on assessments on the BAS scales. The effect was significant on the Fun-Seeking and Drive subscales. Among patients, the highest scores on both scales were seen with the combination of the DRD2 TT/CT and HTR2C GG/G genotypes and the lowest in carriers of the diplotypes with the minor alleles at both loci. Differences between these group were nominally significant for both scales, but were not significant after correction for multiple comparisons. Among healthy subjects, the highest levels of motivation were seen in people lacking the minor alleles. They were significantly different from those in carriers of the DRD2 TT/CT and HTR2C GG/G diplotype on the Fun-Seeking subscale (pcorr = 0.008). DRD2 and HTR2C were not found to have any effect on TEPS evaluations. Our results can be interpreted as indicating a role for the interaction of the DRD2 and HTR2C genes in the variation of the activatory aspects of approach motivation in both schizophrenia patients and healthy subjects. However, the absence of highly significant (persisting after the Bonferroni correction) differences between groups with different diplotypes makes it difficult to interpret this effect. [ABSTRACT FROM AUTHOR]

Because of the involvement in motivational processes, opioid receptors are potential targets for apathy treatment in schizophrenia. We therefore searched for associations between the opioid receptor gene polymorphisms (OPRM1 (rs1799971) and OPRD1 (rs1042114, rs533123)) and apathy measured with the Apathy Evaluation Scale-S in a group of 284 schizophrenia patients. We analyzed individual genotypes, haplotypes, and the digenic interaction and observed nominally significant associations of rs1042114 genotypes and the rs1042114*rs1799971 interaction with behavioral apathy scores. The associations, however, did not withstand correction for multiple comparisons. Thus, the results did not provide enough evidence for the opioid receptor gene effects on apathy in schizophrenia patients. [ABSTRACT FROM AUTHOR]

Objectives. To study the association between proinflammatory cytokines and depression. Materials and methods. The: IL-1β C-511T and TNF-α G-308A gene polymorphisms were studied in patients with diagnoses of "depression" (study group) and mentally healthy subjects of comparable sex and age (controls). Results and conclusions. An association between the IL-1β C-511T polymorphism and depression was found, where the variant with the risk of depression was the CC variant (p = 0.001, OR = 1.9, CI 1.3–2.7). An association was found between the TNF-α G-308A polymorphism and depression, where the risk variant was the GG genotype (p = 0.001, OR = 3.0, CI = 1.8–4.9). These data confirm the role of immune factors in the development of depression. The authors emphasize the role of the clinical polymorphism of depression, which makes it difficult to form homogeneous cohorts and to select phenotypes for biological studies. [ABSTRACT FROM AUTHOR]

To explore for the first time an effect of gene × environment (G × E) interactions on the clinical characteristics of schizophrenia, we studied the ZNF804A rs1344706 polymorphism, a genome-wide supported risk variant of psychosis, and obstetrical complications (OC) as a risk-modifying factor for psychiatric disorders, in 369 patients with schizophrenia (203 women, mean age 29.7 ± 10.1 years, age at disease onset 21.6 ± 7.3 years). A history of at least one definite OC was present in 111 patients, while 258 patients had no history of OC. Clinical characteristics, including age at disease onset and severity of symptoms assessed with PANSS, were compared by the ZNF804A genotype in the groups with and without OC. Patients with the risk AA genotype and OC had higher scores on the subscale of general psychopathological symptoms compared to the carriers of the CC genotype without OC (p = 0.007). The results demonstrated an additive effect of ZNF804A rs1344706 and OC on symptoms severity in schizophrenia. [ABSTRACT FROM AUTHOR]

Objectives. To seek the genetic mechanisms of impairments to the recognition of emotions, which is a sign of schizophrenia which degrades social adaptation of patients. This search was based on the view that the interaction between the dopaminergic and glutamatergic systems has a role in the pathogenesis of schizophrenia. The effects of the interaction between the polymorphic C366G locus in the gene encoding the NR2B subunit of the NMDA receptor - GRIN2B - the polymorphic loci in the dopamine receptor genes ANKK1/DRD2 Taq1A and DRD4 48-VNTR on the recognition of emotional expressions were studied. Materials and methods. The effects of the interaction between GRIN2B and DRD2 were studied in cohorts of 237 patients and 235 healthy subjects; those between GRIN2B and DRD4 were studied in cohorts of 268 and 208, respectively. Results and conclusions. Both effects reached significance in the combined cohorts of patients and healthy subjects (GRIN2B × DRD2, F = 4.12, p = 0.043; GRIN2B × DRD4, F = 6.43, p = 0.012). The effect of the interaction between the polymorphic loci in the GRIN2B and DRD2 genes on the recognition of expressed emotions in schizophrenia patients was confirmed. In patients with the less effective allele of the DRD2 gene and not bearing the minor allele of the GRIN2B gene, results were close to normal, while the genotype containing the minor alleles of both genes produced the worst results. This result is consistent with concepts of the possible role of the hypofunction of NMDA receptors and D2-mediated regulation of their activity in the production of schizophrenia endotypes such as the recognition of expressed emotions. [ABSTRACT FROM AUTHOR]

Objective. To study the association between the kynurenine-3-monooxygenase (KMO) gene and depression. Materials and methods. Polymorphic loci rs2275163 (C/T) and rs1053230 (A/G) of the KMO gene were studied in patients with depression (study group) and mentally healthy subjects of comparable gender and age (control group). Results and conclusions. The rs2275163 polymorphism was not associated with depression. An association between the rs1053230 polymorphism and depression was found. The frequency of the GG genotype, linked with lower KMO activity and increased kynurenic acid levels in patients with endogenous psychoses, was greater in the study group than the control group (p = 0.001, OR 2.8 (95% CI 1.73-4.24). thus, the GG genotype can be regarded as a risk allele for developing depression. [ABSTRACT FROM AUTHOR]

Synaptosomal protein SNAP-25 is involved in the process of transmitting nerve spikes in the CNS and in the consolidation of memory traces in the hippocampus. Two independent studies have demonstrated associations between SNAP-25 gene polymorphisms and intellectual functions in a group of mentally healthy subjects and patients with schizophrenia. The aim of the present work was to perform a comparative study of the association between the MnlI polymorphism of SNAP-25 and cognitive functions (verbal memory, attention/executive functions) in 66 patients with endogenous psychoses, 75 of their mentally healthy relatives, and 136 healthy control subjects. Statistical analysis showed that the effectiveness of performing cognitive tests was significantly affected by group assignment (p = 0.00001) and genotype (p = 0.012). The interaction between genotype and group assignment also had an influence (p = 0.02). In all groups, carriers of the TT genotype had worse measures than carriers of other genotypes. The similar nature of the influences of the MnlI polymorphism on variations in measures in all groups indicates that this gene is related to overall intellect. [ABSTRACT FROM AUTHOR]