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

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

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

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

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

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

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

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

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

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

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

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

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

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

[Polymorphic variants in the cluster of genes encoding trace amine receptors and cognitive functioning in patients with schizophrenia spectrum disorders and healthy controls]. / Polimorfnye varianty v klastere genov, kodiruyushchikh retseptory sledovykh aminov, i kognitivnoe funktsionirovanie u patsientov s rasstroistvami shizofrenicheskogo spektra i zdorovykh.

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; η2p=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; η2p=0.04). Of the individual cognitive indicators, associations with genotype were found for working memory and attention (F=8.25; p=0.005; η2p=0.05), cognitive flexibility (F=5.82; p=0.017; η2p=0.05) and verbal episodic memory (F=6.75; p=0.011; η2p=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.

[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.

[Association of the insulin-like growth factor II (IGF2) gene with human cognitive functions].

Active search for candidate genes whose polymorphisms are associated with human cognitive functions has been in progress in the past years. The study focused on the role that the insulin-like growth factor II (IGF2) gene may play in the variation of cognitive processes related to executive functions. The ApaI polymorphism of the IGF2 gene was tested for association with selective attention during visual search, working memory/mental control, and semantic verbal fluency in a group of 182 healthy individuals. The ApaI polymorphism was associated with the general cognitive index and selective attention measure. Carriers of genotype AA displayed higher values of the two parameters than carriers of genotype GG. It was assumed that the ApaI polymorphism of the IGF2 gene influences the human cognitive functions, acting possibly via modulation of the IGF-II level in the central nervous system.

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

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

Dataset on negative symptoms factors in patients with schizophrenia.

Schizophrenia is a severe mental disorder characterized by positive and negative symptoms. The negative symptoms are highly relevant to the disease course and outcome. Because negative symptoms show considerable heterogeneity, there is substantial interest in elucidating the negative symptom domains that are characteristic of patient subgroups. It has been proposed that patients with schizophrenia should be classified into deficit and non-deficit groups based on the severity of their negative symptoms. Another method suggested the assessment of the factor structure of negative symptoms to understand its mechanisms. Factor analysis of the different negative symptom rating scales reveals two distinct negative symptom subdomains: diminished expression (DE) and avolition/apathy (AA). These characteristics suggest different pathophysiological mechanisms for the development of AA and DE. We present a large dataset of negative symptom factors calculated for 3006 patients with schizophrenia in the Russian population. Sex, age, age at disease onset and data of birth, including season of birth (SOB), family history of schizophrenia are presented. Negative symptoms were assessed with the Positive and Negative Syndromes Scale (PANSS). We calculated negative symptoms factors as suggested by Liemburg et al. (2013). The data will be useful in assessing the impact of such factors as sex, season of birth (SOB) and family history on the scores of negative symptoms subdomains; such data can help us to better understand the heterogeneity of the negative symptoms of 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.

[Associations between the oxytocinergic system genes, perinatal complications and interpersonal relationships in patients with schizophrenia]. / Issledovanie svyazi mezhdu genami oksitotsinergicheskoi sistemy, perinatal'nymi oslozhneniyami i formirovaniem mezhlichnostnykh otnoshenii u bol'nykh shizofreniei.

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).

[Prognosis of the functional outcome of schizophrenia using a multigene panel]. / Otsenka prognoza funktsional'nogo iskhoda shizofrenii s pomoshch'yu mul'tigennogo testa.

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.

[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.

Copy number variations of satellite III (1q12) and ribosomal repeats in health and schizophrenia.

OBJECTIVE: Earlier we studied the copy number variations (CNVs) of ribosomal repeat (rDNA) and the satellite III fragment (1q12) (f-SatIII) in the cells of schizophrenia patients (SZ) and healthy controls (HC). In the present study we pursued two main objectives: (1) to confirm the increased rDNA and decreased f-SatIII content in the genomes of enlarged SZ and HC samples and (2) to compare the rDNA and f-SatIII content in the same DNA samples of SZ and HC individuals. METHODS: We determined the rDNA CN and f-SatIII content in the genomes of leukocytes of 1770 subjects [HC (N = 814) and SZ (N = 956)]. Non-radioactive quantitative hybridization method (NQH) was applied for analysis of the various combinations of the two repeats sizes in SZ and HC groups. RESULTS: f-SatIII in human leukocytes (N = 1556) varies between 5.7 and 44.7 pg/ng DNA. RDNA CN varies between 200 and 896 (N = 1770). SZ group significantly differ from the HC group by lower f-SatIII content and by rDNA abundance. The f-SatIII and rDNA CN are not randomly combined in the genome. Higher rDNA CN values are associated with higher f-SatIII index values in SZ and HC. The f-SatIII variation interval in SZ group increases significantly in the subgroup with the high rDNA CN index values (>300 copies). CONCLUSION: Schizophrenia patients' genomes contain low number of f-SatIII copies corresponding with a large ribosomal repeats CN. A scheme is proposed to explain the low f-SatIII content in SZ group against the background of high rDNA CN.

Data on association of the variation (rs1344706) in the ZNF804A gene with schizophrenia and its symptoms in the Russian population.

The polymorphism rs1344706 in the ZNF804A gene is one of the best-supported risk variants for schizophrenia. The association between ZNF804A rs1344706 and the disease was demonstrated in many studies but only few of them investigated large samples (above 2000 patients and controls). Data presented show the genotypic distribution of ZNF804A rs1344706 in 1265 patients with schizophrenia and 1051 healthy controls from the Russian population. Statistical analysis confirmed the association between rs1344706 and schizophrenia (p = 0.034). The frequency of the risk genotype AA was significantly higher in the group of patients compared to that in controls. In addition, the article provides the data on the severity of schizophrenia symptoms measured with the Positive and Negative Syndrome scale (PANSS) in 951 patients. The severity of symptoms was significantly higher in the carriers of the risk genotype AA compared to the AC genotype and the CC genotype.

[Genetic variations associated with premorbid personality in patients with schizophrenia]. / Geneticheskie polimorfizmy, assotsiirovannye s razlichnoi stepen'iu vyrazhennosti premorbidnykh lichnostnykh anomalii u bol'nykh shizofreniei.

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.

The modulatory influence of polymorphism of the serotonin transporter gene on characteristics of mental maladaptation in relatives of patients with endogenous psychoses.

A number of studies have reported an association between 5-HTTLPR, a polymorphism of the serotonin transporter gene, and the development of depressive states in response to a variety of distal and proximal stressors. We report here studies of the effects of the 5-HTTLPR polymorphism on the probability that an individual will develop mental maladaptation in 224 close relatives of patients with severe chronic mental disorders - schizophrenia and schizoaffective and affective psychoses. The ss genotype of the serotonin transporter gene contributes to the formation predominantly of manifestations of distress, reflected by increases on the hypochondriasis scale of the MMPI scale of factors such as the extent of the autonomic component of anxiety reactions and increased attention to own health, as well as increases in sensitivity. At the same time, the ss genotype was less likely to influence the appearance of depression and anxiety, as determined on the depression scale. These tendencies were more marked in males than females. Furthermore, males with the ss genotype were characterized by some increase in tension, suspicion, detachment, and attention difficulty (on the paranoia and schizophrenia scales). These data can be regarded as supporting the role of the short allele of the serotonin transporter gene in enhancing and modulating psychopathological reactions to chronic stress situations in relatives of mental patients.