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Introduction Understanding the relations between genetic (G) and environmental (E) factors in the development of schizophrenia is important for psychosis prevention. These relations may vary from G x E correlations to G x E interactions and independent additive effects of genetic load and environment. The G x E interactions mean that genetic variants associated with schizophrenia make an individual vulnerable to specific environmental exposures thus enhancing the risk of disease manifestation in those who possess such genetic variants. In the case of independent effects, environmental exposure might serve as the main cause or an additional to genetic load external trigger which is needed for the illness development. Thus, the rate of independent environmental risk factors is expected to be higher in patients with a lower genetic liability to schizophrenia. Objectives The study aimed to confirm this hypothesis by comparing schizophrenia patients with higher and lower polygenic risk scores for schizophrenia (SZ-PRS) on the rate of urbanicity, winter birth and obstetric complications (OC), as previous data suggested their independence from the genetic burden of the disease. Methods SZ-PRS were calculated for 861 patients with schizophrenia spectrum diagnoses (ICD-10, F2), predominantly of Slavic decent, based on the latest GWAS. For patients comprising the highest and lowest SZ-PRS deciles, information on the environmental risk factors was extracted from medical records. Each environmental factor was coded as present/absent. The presence were defined as being born in the most urban environment (a city’s population > 5 million), in winter months and having at least one OC from a predefined list (Alfimova et al. Int J Mol Sci 2022; 23: 12629). In addition, hypoxia/asphyxia, and low birth weight were analyzed separately. Polyenvirommental risk scores (PERS) aggregating the three factors were calculated using natural logarithms of the odds ratios (OR) from an umbrella review (Radua et al. World Psychiatry 2018; 17: 49-66). Logistic regression adjusted for ancestry-related principal components, demographic, and technical variables was applied to compare the SZ-PRS deciles on each factor and PERS. Results None of the factors alone or PERS predicted SZ-PRS decile membership. Conclusions The results did not support the hypothesis. Future research needs reliable data on the frequency of the studied factors in the general population where the patients come from.The study was supported by the Russian Science Foundation, grant no. 21-15-00124. Disclosure of Interest None Declared

Introduction Schizotypy is conceptualized to be on the continuum of the risk for psychosis. However, previous studies that used the dimensional approach to schizotypy failed to confirm the expected relations between schizotypal traits and polygenic risk scores (PRS) for schizophrenia. A taxonic approach is an alternative way of looking at schizotypy, but to the best of our knowledge it has not been used to explore the genetic architecture of this construct. Objectives The present study aimed to fill this gap by comparing groups with different profiles of schizotypal traits on PRS for schizophrenia and related phenotypes. Methods To find clusters with different combinations of schizotypal traits, we conducted data mining of an ethnically homogeneous cohort of 1377 healthy individuals completed the Schizotypal Personality Questionnaire. Four clusters emerged, termed low, positive, negative, and high mixed schizotypy. Approximately equal groups from each cluster were selected for genotyping. After quality control, PRS for schizophrenia, depression, neuroticism, and educational attainment were calculated for 320 individuals (mean age = 31.74, SD 12.25 years, 59% women) based on the summary statistics of the largest genome-wide association studies of the respective traits. The groups from different clusters were then compared on PRS. Results The schizotypy groups were similar in age and sex composition but differed in educational attainment and neuroticism (as measured by the Eysenck Personality Inventory), with the high mixed schizotypes having the lowest education and highest neuroticism scores among the schizotypy groups. There were no statistically significant differences between the groups in any PRS. However, the high mixed schizotypy group showed the largest PRS for schizophrenia, neuroticism, and depression. At a nominally significant level, it differed from negative and positive schizotypes in schizophrenia PRS and from low schizotypy in neuroticism PRS. The positive and negative schizotypal groups had non-significantly lower schizophrenia PRS than low schizotypy subjects. Conclusions Our study showed no reliable difference between groups with different schizotypal profiles in PRS of schizophrenia and related phenotypes. At the same time, a number of trends were observed suggesting that only the high mixed schizotypy might be viewed as a condition with an elevated genetic risk of schizophrenia. This is in line with Meehl’s quasi-dimensional model of schizotypy and warrants further investigation in larger samples. This work was supported by the Russian Foundation for Basic Research under Grant 20-013-00230. Disclosure of Interest None Declared

Introduction A large body of evidence shows that both genetic and environmental factors play an important role in the etiology of schizophrenia. There is also growing evidence of an interaction between these factors. Objectives To investigate the influence of family history of schizophrenia, which reflects the contribution of genetic factors, and birth in the winter months, considered as an important environmental risk factor for this disease, on the clinical characteristics of schizophrenia. Methods The results of a clinical examination of 1590 inpatients with schizophrenia (F20.0 ICD-10) were analyzed. The analysis included clinical characteristics of the disease (age of onset of the disease, severity of symptoms, which were assessed by PANSS), information about the family history of schizophrenia, and the season of birth (SOB) of the patient. Data analysis was carried out using multivariate analysis of variance, in which clinical characteristics were used as a dependent variable, and the presence/absence of schizophrenia in first-degree relatives of the patient, patient’s birth in the winter months/birth in other months of the year, sex were independent factors. Results The study group included 1153 women and 437 men. Family history was present in 569 patients (427 women) and absent in 1021 (726 women). In 415 (26.1%) cases, patients born in the winter months. In the group without family history, the percentage of births in the winter months did not differ from that in the group with family history. There was an effect of sex on the age of onset of the disease as well as on the severity of positive symptoms, which were higher in women (p =0.0000). Family history of schizophrenia had a significant, sex-independent effect on the age of onset. The disease manifested at an earlier age in patients with family history. Being born in the winter months was not associated with either age of onset or positive symptoms. There were significant main effects of family history (p=0.018) and birth in the winter months (p=0.044) on negative and general psychopathological symptoms, which were not mediated by sex. The additive effect of these factors was found at the trend level (p=0.08), while the greatest severity of negative symptoms was observed in the group with a family history and birth in the winter months (p=0.02). A significant additive effect (p=0.012) of family history and birth in the winter months on general psychopathological symptoms was found. As in the case of negative symptoms, the greatest severity was noted in the presence of both factors. Conclusions Family history and birth in the winter months are not only risk factors for the development of schizophrenia, but also affect the severity of the disease. The results indicate the feasibility of further molecular genetic studies on this sample, both using candidate gene analysis and genome-wide analysis with polygenic risk assessment. Disclosure of Interest None Declared

Introduction Oxytocin is considered as potential treatment targeting social dysfunctions in psychoses. However, results of clinical trials are inconsistent which may be due to genetic variation in the oxytocin system involved in social information processing. Objectives To examine the effect of the OXTR polymorphism and its interaction with childhood adversity (CA) on facial affect recognition (FAR) in psychotic patients. Methods Patients with schizophrenic and affective psychotic disorders (n=934) completed a task that required labeling six basic and three social emotions. The polymorphisms rs53576 and rs7632287 within the OXTR locus were genotyped and dichotomized based on prior research. For 65% of the sample, information on CA defined as parental alcoholism or psychiatric illness was collected. The polymorphisms’ role in FAR was assessed using ANCOVAs adjusted for sex, age, and diagnosis. Results After Bonferroni correction, there was a significant effect of rs53576, mainly driven by the difference between genotypes in the affective patients. GG-homozygotes recognized emotions better than A-allele carriers. A nominally significant effect in the expected direction was also found for rs7632287. CA influenced FAR but did not interact with any genotype. Conclusions The results provide further evidence that OXTR impacts social cognition and behavior in diverse cohorts, including psychotic patients, with rs53576 GG-homozygotes having enhanced social competencies. However, we have failed to confirm that OXTR modulates the relations between CA and FAR in psychosis. The difference in FAR between genotypes was more pronounced in affective patients, which might be due to more severe FAR deficits in schizophrenia. Disclosure No significant relationships.

Introduction Negative symptoms (NS) are a core feature of schizophrenia. NS show heterogeneity proven by factor analysis, which revealed two distinct negative symptoms subdomains: diminished expression (DE) and avolition/apathy (AA) (Marder et al. 2017, Fleischhacker et al. 2019). Some studies showed the different effects of these subdomains on clinical features of schizophrenia that suggest different pathophysiological mechanisms for their development (Stanculete 2021). It has been also shown that the levels of peripheral interleukins (IL) specifically correlate with NS (Enache et al. 2021), in particular, increased IL levels were determined in patients with deficit syndrome compared to non-deficit schizophrenia (Goldsmith et al. 2018). Objectives To search for the association of genes for IL-4, IL-6, IL-10 and C-reactive protein (CRP) with NS subdomains. Methods The total sample included 551 patients (women 51,4%, aged 18-72 years) with ICD-10 diagnosis of schizophrenia. NS were assessed by PANSS. PANSS-derived factors include AA (items N2, N4, G16) and DE (N1, N3, N6, G5, G7, G13). Genotyping was performed for the following polymorphisms: C-589T IL-4, C-174G IL-6, C-592A IL-10, G-1082A IL-10, CRP (rs2794521). Results There are effects of C-592A IL-10 (p=0.017) and G-1082A IL-10 (p=0.012) on AA subdomain. Post-hoc Bonferroni corrected comparisons show that carriers of the haplotype AA (C-592A)- AA (G-1082A) have the highest AA score. A significant effect of CRP (rs2794521) on AA is identified (p=0.007). There is a trend towards the association of C-589T IL-4 and C-174G IL-6 with AA. No association of these polymorphisms with DE was found. Conclusions AA and DE may have different genetic background. Disclosure No significant relationships.

Introduction Fetal or neonatal hypoxia (FoNH) is a known risk factor for schizophrenia. It has been hypothesized that FoNH induced expression of schizophrenia susceptibility genes (Schmidt-Kastner et al. 2012, Giannopoulou et al. 2018). Objectives To test this hypothesis, we explore the effects of FoNH and some genetic variants on age at onset (AAO) of schizophrenia. Methods The study included 1670 patients (women 1021 (61.1%), mean age 34.6 (SD 13.6), mean age at disease onset 25.4 (10.5) years) with ICD-10 diagnosis of schizophrenia or schizoaffective psychosis. The effects of FoNH in interaction with sex, family history (FH) and genetic variants on AAO of schizophrenia were evaluated. Polymorphisms rs2514218 DRD2 (n=943), Val66Met BDNF (n=820) and VNTR AS3MT (n=804) were genotyped. Results Among all patients studied 179 (10.8%) had experienced FoNH. Regression model showed that FoNH, sex and FH of schizophrenia contribute significantly (p=0.000) to AAO. In the FoNH group, AAO was lower compared to the group without FoNH (20.7 (6.2) vs 25.5 (10.) years). When comparing men and women, there was a difference between FoNH and non- FoNH subgroups only in women (p=0.000). No interaction between FH and FoNH was observed though positive FH had an effect on AAO. There was the interaction effect of VNTR AS3MT and FoNH on AAO. In the FoNH group, carriers of 2 repeats had younger AAO compared to the carriers homozygous for 3 repeat variant (19.6 (4.9) vs 22. (7.6) years). Conclusions We demonstrate the interaction effects of FoNH and VNTR AS3MT polymorphism on AAO of schizophrenia. Disclosure No significant relationships.

Introduction Stress caused by childhood adversity (CA) is known to contribute to schizophrenia risk and symptoms. Its effects might be mediated by epigenetic mechanisms, specifically DNA methylation (meDNA) within relevant genes, and predominantly influence the hippocampus and prefrontal cortex (PFC). CYP17A1 is a candidate, as it situates within a schizophrenia risk locus and is involved in glucocorticoid synthesis. Objectives To explore meDNA within CYP17A and its relations to hippocampus- and PFC-dependent schizophrenia symptoms: depression and deficits of declarative memory and executive functions. Methods We assessed meDNA at each CpG within a CYP17A fragment (chr10:104594471-104595887, hg19) in blood of 66 schizophrenia patients using the third-generation sequencing. Immediate memory, depression, cognitive shifting and cognitive inhibition (CI) were assessed with the RAVLT, PANSS, TMT-B and Stroop word-color test, respectively. ANCOVA and regression models adjusted for sex and age were applied to explore the relations between the phenotypes, local haplotype, meDNA and CA, defined as the presence of parental alcoholism or psychiatric illness. Results MeDNA at CpG-SNP rs3781286 correlated with CI (corrected p=0.01). However, there were no main or interaction effects of CA either on meDNA at this site or on CI. Both CI and meDNA associated with haplotype, but subsequent analysis showed that meDNA did not mediate the relation between haplotype and CI. Conclusions Our findings suggest that CYP17A associates with PFC-dependent cognitive deficits in schizophrenia but did not support the hypothesis that CA plays a role in this association via meDNA or any other mechanism. Grant support: 21-15-00124/Russian Science Foundation https://rscf.ru/project/21-15-00124/. Disclosure No significant relationships.

Introduction: Clinical and family studies suggest that alterations of theory of mind (ToM) represent a marker of genetic liability to schizophrenia. Findings regarding ToM in schizotypy are less consistent. The study aimed to explore whether this might be due to an insufficient account of the heterogeneity of schizotypy in prior research and/or the fact that in psychometric schizotypy ToM alterations could manifest as subtle peculiarities rather than overt errors of mentalising. Methods: Individuals without a family history of psychosis ( n  = 150) were assigned to low, positive, negative, and high mixed schizotypy classes based on a cluster analysis of 1322 subjects who completed the Schizotypal Personality Questionnaire. The classes were compared on their performance of faux pas tasks with 77 adult first-degree relatives of schizophrenia patients, who represent individuals at genetic risk for schizophrenia. Besides overt errors, subtle alterations in ToM were analysed using expert judgment. Results: The relatives tended to make overt errors and demonstrated specific features of intentional reasoning. None of the schizotypal classes showed similar trends. Conclusions: The results complement the literature on the subjective-objective disjunction in psychometric schizotypes and did not provide evidence that ToM anomalies are a marker of genetic liability to schizophrenia in this cohort.

As genetic and environmental influences on schizophrenia might converge on DNA methylation (DNAm) within loci which are both associated with the disease and implicated in response to environmental stress, we examined whether DNAm within CYP17A1 , a hypothalamus-pituitary-adrenal axis gene which is situated within the schizophrenia risk locus 10q24.32, would mediate genetic and environmental effects on stress-related schizophrenia symptoms. DNAm within an exonic-intronic fragment of CYP17A1 was assessed in the blood of 66 schizophrenia patients and 63 controls using single-molecule real-time bisulfite sequencing. Additionally, the VNTR polymorphism of the AS3MT gene, a plausible causal variant within the 10q24.32 locus, was genotyped in extended patient and control samples ( n = 700). The effects of local haplotype, VNTR and a polyenviromic risk score (PERS) on DNAm, episodic verbal memory, executive functions, depression, and suicidality of patients were assessed. Haplotype and PERS differentially influenced DNAm at four variably methylated sites identified within the fragment, with stochastic, additive, and allele-specific effects being found. An allele-specific DNAm at CpG-SNP rs3781286 mediated the relationship between the local haplotype and verbal fluency. Our findings do not confirm that the interrogated DNA fragment is a place where genetic and environmental risk factors converge to influence schizophrenia symptoms through DNAm.

Background: Schizophrenia is a severe mental illness manifested by various symptoms. Negative symptoms (NS) are associated with disability and poor function of patients. The study of NS neurobiology is complicated by their heterogeneity. Factor analysis revealed two distinct NS subdomains with different pathophysiological mechanisms: volitional pathology, including avolition and apathy (AA), and diminished expression (DE). Inflammation is one mechanism that may underlie NS, including their heterogeneity., Aims: To search for the association between genes for interleukins ( IL-6 -174 G/C , IL-10 -592 C/A , and IL-10 -1082 G/A ) and NS subdomains., Materials and Methods: The study included 275 patients with schizophrenia. NS factors were calculated based on the Positive and Negative Syndromes Scale., Results: There was a significant main effect of IL-10 polymorphisms on the AA, but not the DE subdomain. Mean score on the AA subdomain was higher in the IL-10 -592 AA compared to the CC genotype. Differences between IL-10 -1082 G/A genotypes were dose dependent. The lowest score was observed for the IL-10 -1082 GG genotype. The association between the IL-6 -174 G/C polymorphism and AA scores was close to the level of significance. Patients with the IL-6 -174 GG genotype had higher score compared to the AA genotype., Conclusion: The results provide further neurobiological evidence for the validity of the NS factor categorization. An imbalance between pro-inflammatory and anti-inflammatory cytokines because of genetic variations is associated with the AA NS subdomain that is supposed to be a more severe aspect of psychopathology compared to the DE., Competing Interests: There are no conflicts of interest., (Copyright: © 2022 Indian Journal of Psychiatry.)