IntroductionNeuroticism is a personality domain with prognostic value for physical and mental health. To properly inform public health policy, it is crucial to uncover the mechanisms underlying high neuroticism. Many internal and external factors that affect brain development and functioning and therefore might contribute to the variability of neuroticism remain understudied. Among them, the impact of vitamin sufficiency is of great interest, as it is a modifiable factor. This study aimed to evaluate the associations of neuroticism with vitamin D (VD) and vitamin B9 (VB9) using polygenic scores (PGS) in a nonclinical cohort.MethodsWe analyzed data from 348 healthy unrelated individuals, including neuroticism scores on the Eysenck Personality Inventory, VD-PGS, VB9-PGS and PGS for neuroticism-related traits.ResultsThe analysis controlling for demographic and genetic confounders revealed a negative association between VB9-PGS and neuroticism scores in women and a positive association between VD-PGS and neuroticism scores in men. The highest values of the VD-PGS were observed in men, who scored high on both neuroticism and extraversion. In men, unlike women, neuroticism scores were not correlated with PGS for neuroticism but were associated with PGS for bipolar disorder type 1 and alcohol use disorders.ConclusionThe results suggest that the effects on neuroticism of genetic propensity for suboptimal vitamin D and B9 concentrations might differ across the two sexes. The findings are consistent with the idea of the importance of vitamin B9 for emotional stability in women and indicate the involvement of genetic factors predisposing to higher vitamin D levels in excitability-related components of neuroticism in men.

BACKGROUND:Schizotypy (ST) and psychotic-like experiences and negative symptoms (PENS) are commonly used phenotypes in high-risk and early intervention research for schizophrenia and other non-affective psychoses. However, the origin of these phenotypes in the general population is poorly understood and their association with the genetic predisposition to psychoses has not yet been proven. AIM:The aim of this study is to answer the question of whether data on the relations of ST and PENS with polygenic risk scores for schizophrenia (SZ-PRS) support the hypothesis that these phenotypes are subclinical manifestations of genetic liability for schizophrenia. METHODS:Literature describing these relations in the general population was analyzed. The literature search was performed in the PubMed database using the following keywords in English: (("schizotyp*" OR "psychotic-like experiences" OR "psychosis proneness" OR "psychotic experiences") AND ("polygenic risk" OR "genetic liability" OR "polygenic score")); the search in eLIBRARY.RU was conducted using the Russian words for "schizotypy", "schizotypal features", "psychotic experiences", "psychotic experience", "psychotic symptoms", and "polygenic risk", covering publications from 2009 to 2024. RESULTS:Of the identified records, 45 publications were found eligible. No expected positive correlations of SZ-PRS with common ST measures have been observed. For PENS, the results are inconsistent. Overall, SZ-PRS correlate more often with the PENS general factor and negative symptoms than with psychotic experiences per se. CONCLUSION:The literature does not provide convincing evidence of the association between SZ-PRS and ST/PENS. The search for the substantive psychological meaning of polygenic vulnerability to psychosis captured by SZ-PRS should be expanded to other personality processes and traits.

Background/Objectives: Schizophrenia is a clinically heterogeneous complex disorder with a substantial polygenic basis. The discovery of phenotypes indexing genetic differences advances research into the schizophrenia etiology but has proven to be challenging. The study aimed to further clarify the relationships of schizophrenia polygenic risk scores (SZ-PRSs) with a comprehensive array of schizophrenia antecedents and presentations using a culturally and ethnically homogeneous sample of schizophrenia spectrum patients. Methods: The top and bottom deciles (n = 172) of the SZ-PRS distribution in a group of 861 patients were compared on information derived from medical records using logistic regression. Results: High SZ-PRSs were associated with female sex, family history of a wide range of neuropsychiatric conditions, moderately poor premorbid social and cognitive adjustment in childhood, the schizophrenia diagnosis, and positive and “abnormal” psychomotor symptoms. The low-SZ-PRS group demonstrated an accumulation of both individuals with milder forms of SZ spectrum disorders and those with severe premorbid abnormalities in the social, cognitive, and neurological domains. Conclusions: The results highlight moderately poor premorbid social and cognitive adjustment as characteristic manifestations of the polygenic component of the schizophrenia etiology and provide the first piece of PRS-based evidence for the long-standing idea of a higher liability threshold in women. The presence of milder and severe cases in the bottom SZ-PRS decile, suggesting its etiological heterogeneity, might be an important source of the inconsistency in the previous research on SZ-PRSs’ relationship with schizophrenia phenotypes and should be considered in future studies.

The study aimed to analyze the associations between cognitive domains impaired in schizophrenia and the rs58335419 polymorphism located within the schizophrenia GWAS-significant locus, in the gene MIR137 encoding miR-137. Schizophrenia spectrum patients (n = 787) and healthy volunteers without a family history of psychosis (n = 622) completed tests of semantic verbal fluency (VF), attention/working memory, verbal episodic memory, and executive functions. After correction for multiple testing, VF abnormalities were associated with homozygosity for the common allele (with three repeats) in male patients. Similar trends occurred in the pooled sample for attention/working memory and the general index of cognitive functioning. The four-repeat allele was not associated with variance in cognitive performance. The results obtained indicate an association between homozygosity for the common allele at rs58335419 and lower levels of cognitive functions, which is opposite to the effect of this polymorphism on the risk of developing schizophrenia.

Objective. To assess associations between polymorphic sites in the TAAR1–9 gene cluster on chromosome 6 and cognitive functions in patients with schizophrenia spectrum disorders and healthy controls. Materials and methods. Patients with schizophrenia spectrum disorders (n = 216) and healthy controls without any family history of mental disorders (n = 240) completed a battery of cognitive tests, which were used to calculate individual indexes of cognitive functioning. Associations between the cognitive index and 22 polymorphic sites in the TAAR genes were assessed by analysis of covariance, controlling for gender, age, the genetic structure of the sample, and polygenic risk scores for schizophrenia and intelligence. Results. A group/genotype interaction at the rs3813355 site in the TAAR5 gene was found to influence the cognitive index (F = 6.68; p = 0.010; η_p^2 = 0.02). Post hoc analysis revealed genotype-related differences in the patients group. Homozygotes for the common A allele had less 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 the cognitive index remained significant when additionally controlling for disease duration and negative symptoms (F = 7.99; p = 0.005; η_p^2 = 0.04). Of the individual cognitive indexes, associations with genotype were found for working memory and attention (F = 8.25; p = 0.005; η_p^2 = 0.05), cognitive flexibility (F = 5.82; p = 0.017; η_p^2 = 0.05), and auditory verbal episodic memory (F = 6.75; p = 0.011; η_p^2 = 0.05). Conclusions. The results obtained here are consistent with the hypothesis that genetic polymorphism of the TAAR5 gene has a role in the variability of cognitive deficit in patients with schizophrenia.

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 The main finding of a large-scale collaborative study (Rees et al. Nat Neurosci 2020;23(2) 179-184), which focused on de novo mutations in schizophrenia, was the discovery of an enrichment of these mutations in the SLC6A1 gene. This gene encodes the gamma-aminobutyric acid (GABA) transporter GAT1, thereby encouraging further research into novel schizophrenia targets within the GABA pathway. However, the gene was not highlighted in recent schizophrenia genetic studies, while typically pathogenic SLC6A1 mutations result in epilepsy, motor dysfunction, autistic spectrum disorder (ASD) and developmental delay. The absence of genetic replication for SLC6A1’s involvement in schizophrenia and the differing clinical spectrum for SLC6A1 mutations led us to study in depth one of the only three original probands from the Rees et al. 2020 study. Objectives In our comprehensive case study, we delved deep into the relationship between the SLC6A1 mutation and schizophrenia. Methods Our subject, a patient who first presented with acute mania symptoms at age 15 and was later diagnosed with schizophrenia, carried the SLC6A1 Arg211Cys mutation. Over a detailed 25-year follow-up, we conducted an array of assessments and tests, including cognitive testing, personality assessments, EEG, and 1H-MRS. Results Notably, we discovered abnormal GABA levels, potentially indicating a dysfunction in GABA reuptake, adding a new layer of complexity to our understanding. Further analysis revealed a significant correlation between the patient’s clinical picture and a polygenic background, rather than the SLC6A1 mutation. Despite having a high polygenic risk score for bipolar disorder, the dominant features of his condition were more representative of schizophrenia. Interestingly, neither the patient nor his father, who also showed a higher BP PRS, had a diagnosis of bipolar disorder. The pathogenic significance of the mutation warrants investigation in cells of neuronal origin. We generated induced pluripotent stem cells (iPSC) from the patient and his parents. This approach provides us with a platform for future investigations into the pathogenic significance of the mutation in neuronal cells. The Human Pluripotent Stem Cell Registry accession numbers of those cells are MHRCCGi001-A (patient), MHRCCGi005-A (mother) and MHRCCGi004-A (father). Conclusions In the presented case the clinical picture is rather explained by the polygenic background than by the SLC6A1 Arg211Cys mutation. The study is supported by Russian Science Foundation, grant 21-15-00124 (https://rscf.ru/project/21-15-00124) Disclosure of Interest None Declared

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.

Impairments of verbal episodic memory are a central component of cognitive deficits in schizophrenia, and their investigation is important for solving diagnostic, expert and rehabilitation tasks. The study aimed to test the ability of learning slope and serial position effects to differentiate schizophrenia patients from non-psychiatric controls. Schizophrenia patients (n=618; mean age 30.31±7.46 years; 54% female) were compared to 425 healthy people (24.15±5.44 years; 60% female) and 121 individuals with the postoperative fatigue (31.56±6.20 years; 42% female) on the performance of the Rey Auditory Verbal Learning Test (RAVLT). The participants’ age range was 18–45 years. Covariate analysis adjusted for sex and age showed a decrease in all four studied learning slope measures (all p<0.001) and an increase in the recency effect (F=35.26; p<0.001; η²p=0.06) in schizophrenia patients compared to both control groups. Logistic regression differentiating patients and controls demonstrated that only the recency measure explained more variance above and beyond the total recall (p<0.001). In the schizophrenia group, a correlation analysis conditioned on total recall revealed an association between the recency and the RAVLT retroactive interference indicator (ρ=0.13; p=0.001), but not with symptoms, processing speed, or executive functions. Thus, an increased recency effect, which is likely arises, in part, due to a heightened retroactive interference, may have diagnostic significance for schizophrenia, in addition to the overall poor learning efficiency.

OBJECTIVE:To evaluate the associations between peripheral levels of inflammatory markers and willingness to exert effort in individuals at clinical high risk for psychosis (CHR-P) and a role of fatigue as a mediator of these associations. MATERIAL AND METHODS:Forty-nine young men admitted for a depressive episode, who met the criteria for CHR-P, had pre-treatment blood tests to determine levels of C-reactive protein (CRP), tumor necrosis factor-α (TNF-α), and interleukins IL-6, IL-8 and IL-10. After treatment and normalization of their condition, they completed the EEfRT task of willingness to exert physical effort to receive monetary reward and filled out the Fatigue Assessment Scale (FAS-10). The association between EEfRT scores, fatigue and inflammatory markers was assessed using regression analysis, controlling for residual clinical symptoms. RESULTS:Independent significant predictors of difficult task choices were the levels of CRP (b=-0.14; 95% CI: -0.30 - -0.07; p<0.001), IL-8 (b=-0.05; 95% CI: -0.09 - -0.002; p=0.043) and fatigue (b=0.07; 95% CI: 0.05 - 0.09; p<0.001). These indicators were not associated with the slope of the curve reflecting the dependence of the choice of difficult tasks on the probability and magnitude of reward. CONCLUSION:In CHR-P, an increase in the levels of CRP and IL-8 before treatment may have prognostic significance regarding the persistence of motivational deficits in the form of a decrease in the willingness to exert efforts after relief of depressive symptoms. Fatigue is not a mediator of the identified relationship.

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.

For a long time, schizotypy was regarded as a manifestation of a genetic predisposition to schizophrenia. However, accumulated data suggest a complex, heterogeneous genetic etio­logy of schizotypal traits. This study is intended to answer the question of whether psychometric schizotypy should be further applied to the study and prevention of schizophrenia and to help provide care for individuals with high schizotypal severity, as the latter is often coupled with various signs of maladaptation. To explore the etiology of schizotypy, in this study the authors assessed the relations between cognitive & perceptual, paranoid, interpersonal and disorganizational factors in schizotypy and personality (n = 1,115), motivational (n = 645), cognitive processes (n = 557) and polygenic risk scores (PRS) of schizophrenia and schizotypy-related psychological traits (n = 417). The researchers used regression and network analyses. The study demonstrated that the severity of schizotypal traits does not correlate with the genetic burden of schizophrenia, but to a certain extent is associated to the polygenic predisposition to neuroticism. The latter could apparently influence schizotypal traits both directly and through the response set. However, the anxiety traits themselves do not mediate the relation between polygenic scores of neuroticism and schizotypal traits. Together with the source data, findings of this study point to the need to improve schizotypy assessment tools by introducing validity scales, and to adopt a genetically determined tendency to high neuroticism as a source of schizotypy in the general population, which requires further in-depth investigation.

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

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.

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 ( p FDR < 0.018; _p^2 = 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; _p^3 = 0.03). Stereotyped thinking and volitional disorder identified on the PANSS showed the strongest correlations with the cognitive disorganization factor ( r o = 0.84 and r o = 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.

Introduction Schizophrenia is a severe mental disorder mainly caused by genetic risk factors. Many studies have demonstrated that both multiple genetic variants and rare mutations are associated with schizophrenia risk. The next step is to study the causal effect of the gene on the phenotype. Recently, a large family-based study identified de novo mutations, which may increase liability to schizophrenia (Rees et al 2020). In particular, a mutation in the GABA transporter (SLC6A1) gene (rs756927822 C/T) was identified in one patient from our subsample. Objectives Here, we present a case report of this patient and describe the procedure of derivation of induced pluripotent stem cells (iPSCs) from fibroblast cultures. Methods Clinical, psychometric and neuropsychological methods were used. iPSCs were derived from patients’ and both unaffected parents’ fibroblasts. Human fibroblasts, cultured in fibroblast medium, are infected with lentivirus vectors expressing the transcription factors Oct4, Sox2, c-Myc, and KLF4. All iPSCs were immunocytochemical stained for intracellular (Oct4, Sox2) and extracellular (SSEA4, Tra-1-81, Tra-1-60) pluripotency markers. An qPCR analysis for pluripotency markers (TDGF1, Sox2, Oct4, REX1, LIN28, NANOG, KLF4, GDF3, DPPA4, DNMT3) was performed. All four iPSC lines formed embryoid bodies before the differentiating into three germ layers. Differentiation was confirmed by immunostaining for mesoderm (aSMA), ectoderm (Nestin, Desmin) andendoderm (FoxA2, Pax6) markers. Results A 47-year-old male patient was presented to psychiatry at the age of 16. There was no personal or family history of psychiatric disorder, the premorbid functioning was normal, the patient had no somatic diseases, showed high performance in sport (mountain skiing). On his first admission, he was diagnosed with schizoaffective psychosis. The patient showed signs of mania and catatonia. Neuropsychological testing revealed a decrease of cognitive functioning (short-term and associative memory). The patient was followed up for more than 20 years. The diagnosis was changed for schizophrenia at the age of 43 years. There was a deterioration in cognitive function (the apparent decrease in performance on neurocognitive tests (attention, memory, executive functions) from the first examination (1997) till last one (2019). The patient refused or was not able to perform most of the tasks. During follow-up, the patient shows good adherence to treatment. Conclusions For this patient, obtained lines might be valuable for investigating the disease mechanisms and screening candidate drugs. Disclosure of Interest None Declared

• The patient with an SLC6A1 mutation, typically linked to disorders like epilepsy and autism , exhibited symptoms consistent with schizophrenia and bipolar disorder . • The patient's polygenic risk score was aligned with both schizophrenia and bipolar disorder, despite no family history of psychiatric disorders. • The study contributed to ongoing discussion of the importance of GABAergic processes in schizophrenia's etiology.

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.

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.