A Role of DNA Methylation within the CYP17A1 Gene in the Association of Genetic and Environmental Risk Factors with Stress-Related Manifestations of Schizophrenia.

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.

A study of the association between polymorphisms in the genes for interleukins IL-6 and IL-10 and negative symptoms subdomains in schizophrenia.

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.

The 844ins68 polymorphism of the cystathionine beta-synthase gene is associated with schizophrenia.

A subtle genetic defect in homocysteine metabolism is thought to play an etiologic role in schizophrenia. Cystathionine-beta-synthase (CBS) is a key enzyme related to homocysteine levels. The aim of the present study was to search for association between the 844ins68 polymorphism of the CBS gene and schizophrenia in a large Russian sample using case-control and family-based designs. The sample comprised 1135 patients, 626 controls and 172 families. There was a trend for association between the 844ins68 polymorphism and schizophrenia in the case-control study, with higher frequency of the insertion in the control group. The FBAT revealed a statistically significant difference in transmission of alleles from parents to the affected proband, with preferential transmission of the variant without insertion. When the sample of patients was stratified by sex and forms of schizophrenia, the significantly lower frequency of insertion was observed in the group of female patients with chronic schizophrenia (n=180) as compared to psychiatrically well women. The insertion variant has been reported earlier to be related to decreased levels of homocysteine and thus thought to play a protective role. In conclusion, our study revealed a possible relation of the CBS 844ins68 polymorphism to schizophrenia.

Emotional distress in parents of psychotic patients is modified by serotonin transporter gene (5-HTTLPR)--brain-derived neurotrophic factor gene interactions.

Caregiving of a family member with psychotic disorder is considered among the most significant stressors and relatives of a sufferer experienced psychological and physical burden that may be the cause of neurotic states. There is growing evidence that sensitivity of individuals to depressogenic effects of stressful factor is moderated by genetic variants of serotonin transporter (SERT) and brain-derived neurotrophic factors (BDNF). We examined the association of the 5-HTTLPR SERT and Val66Met BDNF polymorphisms with signs of depression and anxiety measured with the Minnesota Multiphasic Personality Inventory (MMPI) in 235 unaffected parents of patients with major psychosis and 102 age-matched controls. A significant effect of the SERT-BDNF interaction on Depression and Psychasthenia scales was found in the group of parents, but not in the control group. Carriers of the Val/Val x SS variant scored higher as compared to other allelic combinations. The results obtained revealed that the SERT-BDNF interactions might moderate the level of anxiety and depression caused by caregiving status in parents of psychotic patients.

A Potential Role of the 5-HTTLPR Polymorphism in Self-Reported Executive Functioning.

Intense effort is directed toward searching for associations between genes and neuropsychological measures of executive functions. In contrast, the impact of genetic polymorphisms on self-rating of everyday executive functioning has not been investigated so far. This study was designed to test associations of self-reported executive functioning, measured with the Behavior Rating Inventory of Executive Function (BRIEF-A), with dopaminergic and serotoninergic genes in non-clinical population and to assess impact of neuropsychological and personality characteristics on these associations. One hundred healthy adults completed the BRIEF-A, personality inventories SPQ-74, STAI, MMPI, and neuropsychological tests for executive functions. Polymorphisms in the DRD4, COMT, DRD2, HTR2A, and SLC6A4 genes were genotyped. We revealed a significant main effect of the SLC6A4's 5-HTTLPR polymorphism on BRIEF-A scores (F = 2.21, P = .018, η2 = .24). Among the BRIEF-A measures, the genotype effect was significant for the Plan/Organize (F = 7.34, P = .008, η2 = .07) and Task Monitor scales (F = 4.33, P = .04, η2 = .04), and the Metacognition index (F = 4.21, P = .043, η2 = .04). Carriers of the short allele reported fewer problems than homozygotes for the long allele. Correlations of the BRIEF-A measures with neuropsychological variables were weak, while those with personality characteristics were strong, with trait anxiety being the most powerful predictor of the BRIEF-A scores. However, the relationship between the 5-HTTLPR and BRIEF-A scores remained significant when trait anxiety was controlled for. The results suggest a potential role of the 5-HTTLPR in self-reported everyday task planning and monitoring.

Interaction Effects of Season of Birth and Cytokine Genes on Schizotypal Traits in the General Population.

Literature suggests that the effect of winter birth on vulnerability to schizophrenia might be mediated by increased expression of proinflammatory cytokines due to prenatal infection and its inadequate regulation by anti-inflammatory factors. As the response of the immune system depends on genotype, this study assessed the interaction effects of cytokine genes and season of birth (SOB) on schizotypy measured with the Schizotypal Personality Questionnaire (SPQ-74). We searched for associations of IL1B rs16944, IL4 rs2243250, and IL-1RN VNTR polymorphisms, SOB, and their interactions with the SPQ-74 total score in a sample of 278 healthy individuals. A significant effect of the IL4 X SOB interaction was found, p = 0.007 and η2 = 0.028. We confirmed this effect using an extended sample of 373 individuals. Homozygotes CC born in winter showed the highest SPQ total score and differed significantly from winter-born T allele carriers, p = 0.049. This difference was demonstrated for cognitive-perceptual and disorganized but not interpersonal dimensions. The findings are consistent with the hypothesis that the cytokine genes by SOB interaction can influence variability of schizotypal traits in the general population. The IL4 T allele appeared to have a protective effect against the development of positive and disorganized schizotypal traits in winter-born individuals.

The serotonin transporter gene 5-HTTLPR polymorphism is associated with affective psychoses but not with schizophrenia: A large-scale study in the Russian population.

BACKGROUND: Affective syndrome is thought to be a key feature that differentiates schizophrenia from schizoaffective disorder (SA) and bipolar disorder with psychotic features (BDP). However genetic underpinnings of these differences remain unresolved. OBJECTIVES: We compared clinical variables of affective psychoses (SA, BDP and schizophrenia with affective symptoms (AFF SCZ)) and schizophrenia without affective symptoms (non-AFF SCZ) and searched for a genetic variant that may differentiate affective psychosis from non-AFF SCZ. METHODS: A total of 2677 subjects, including 831 patients with affective psychosis, 785 patients with non-AFF SCZ and 1061 healthy controls, were used. Clinical symptoms were assessed with the PANSS. The sample was genotyped for 5-HTTLPR polymorphism of the serotonin transporter gene. RESULTS: The diagnostic groups differed significantly on demographic and clinical variables. The percentage of men was higher, the current age and age at illness onset were lower in non-AFF SCZ and SA compared to AFF SCZ and BDP. The severity of positive and negative symptoms decreased significantly from group to group in the following manner: non-AFF SCZ>AFF SCZ>SA>BDP. There was the association between 5-HTTLPR polymorphism and affective psychosis (p=0.01). The frequency of the SS genotype was higher in the affective psychosis group compared to non-AFF SCZ and controls. No differences in the genotype distribution were identified between the non-AFF SCZ group and controls. LIMITATIONS: Difficulties in the differentiation between non-AFF SCZ and AFF SCZ or SA and between AFF SCZ and SA due to uncertain diagnostic boundaries between these conditions. CONCLUSIONS: SA is intermediate between non-AFF SCZ and BDP in the severity of positive and negative symptoms. The first episode patients, carriers of the SS genotype have a higher risk of developing affective psychosis than non-AFF SCZ. This finding carries implications for the prognosis of psychosis outcomes in the first-episode patients.

Interaction effects of the COMT and DRD4 genes with anxiety-related traits on selective attention.

The study investigated whether the DRD4 and COMT genes can modify relations between trait anxiety and selective attention. Two hundreds and sixty-six subjects performed a visual search task in which they had to find words looking through a sheet with rows of letters. After finishing the first sheet the subject was presented the second one, this time with an instruction to perform the task as quickly and accurate as possible. To study top-down attention, the number of correctly identified words (accuracy) and the time for completion of each trial were analyzed. To study bottom-up attention, the letters 'o' and 'n' were written in green, whilst the others were in black, and subjects were asked whether they had noticed that 2-3 minutes after the task completion. Genotypes for the COMT Val158Met and DRD4 VNTR-48 polymorphisms and TCI Harm Avoidance and MMPI Depression scales' scores were obtained as well. High anxious individuals showed a more pronounced increase in accuracy in the second trial and more profound processing of irrelevant stimuli (colored letters). There was a significant interaction effect of DRD4 and Harm avoidance on the accuracy dynamics F(1, 210), = 7.65, p = .006, η2 = .04. Among DRD4 long allele carriers, high anxious subjects significantly improved accuracy (p = .013) and tended to slow speed, while those with lower Harm avoidance demonstrated the opposite trend. These effects were more robust in less educated individuals. It was concluded that the DRD4 polymorphism may modify the influence of trait anxiety on the speed-accuracy tradeoff.