ZNF804A Rs1344706 Research Articles

The polymorphism ZNF804A rs1344706 is differentially associated with negative symptoms domains in schizophrenia

IntroductionNegative symptoms (NS) are an important clinical characteristic of schizophrenia. In recent years, clinical research on NS has focused on their clinical heterogeneity. Based on two-factor analysis, it has been proposed to divide NS into abulia-apathy (AA) and expressive deficit (ED) domains. A number of studies have shown that these domains have different effects on the clinical features of schizophrenia, which suggests different pathophysiological mechanisms of their development. Neurobiological differences between AA and DE have been identified in neuroimaging and immunological studies but there is less research on the genetic background of NS.ObjectivesTo search for an association between the rs1344706 polymorphism of the zinc finger protein gene (ZNF804A) and the AA and ED subdomains. The rs1344706 polymorphism is one of the best-supported risk variants for schizophrenia. The risk genotype AA has been shown to be associated with clinical presentations of the disease.MethodsThe study included 1116 (741 (66.3% women) patients with schizophrenia. The diagnosis was made according to ICD-10 criteria (item F20). The average age of the patients was 38.4 (13.6) years, age at disease onset was 26.1 (10.6) years. NS were assessed with the PANSS. The PANSS-derived AA domain consisted of Emotional withdrawal (PANSS item N2), Apathetic social withdrawal (N4), Active social avoidance (G16). The DE domain included Blunted affect (N1), Poor rapport (N3), Lack of spontaneity (N6), Mannerism and posturing (G5), Motor retardation (G7), Disturbance of volition (G13). Genotyping of the ZNF804A rs1344706 polymorphism was carried out using HRM-PCR. ANOVA with genotype and sex as independent variables, and age at the time of disease manifestation and its duration as covariates was used. Post hoc tests were performed using Bonferroni correction.ResultsA significant effect of the rs1344706 polymorphism on the severity of symptoms in the AA domain was revealed (F=5.88, df=2, p=0.002). In carriers of the CC genotype, the severity of symptoms was significantly lower than in carriers of the AA genotype and the AC genotype (8.4(3.5), 9.4(7.4) and 8.8(3.5) points, respectively). This effect was independent of sex and was not mediated by age at onset or duration of disease. There was no effect of the rs1344706 polymorphism on the severity of symptoms in the ED domain.ConclusionsThe association of the ZNF804A rs1344706 (A/C) polymorphism with NS of schizophrenia has not been reported so far though some studies have found the effect of this polymorphism on PANSS positive symptoms and PANSS total score. The finding of the association with NS can be explained by the fact that the NS heterogeneity was taken into account in the present study.Disclosure of InterestNone Declared

Impulsivity and aggression in alcohol withdrawal syndrome is modulated by the interaction of ZNF804A and mTOR polymorphism

Alcohol withdrawal syndrome (AWS) is a poorly studied phenotype of alcohol use disorder. Understanding the relationship between allelic interactions and AWS-related impulsivity and aggression could have significant implications. This study aimed to investigate the main and interacting effects of ZNF804A and mTOR on impulsivity and aggression during alcohol withdrawal. 446 Chinese Han adult males with alcohol dependence were included in the study. Impulsivity and aggression were assessed, and genomic DNA was genotyped. Single gene analysis showed that ZNF804A rs1344706 (A allele/CC homozygote) and mTOR rs1057079 (C allele/TT homozygote) were strongly associated with AWS-related impulsivity and aggression. In the allelic group, MANOVA revealed a significant gene x gene interaction, suggesting that risk varied systematically depending on both ZNF804A and mTOR alleles. Additionally, a significant interactive effect of ZNF804A rs1344706 and mTOR rs7525957 was found on motor impulsivity and physical aggression, and the ZNF804A rs1344706 gene variant had significant effects on motor impulsivity and physical aggression only in mTOR rs7525957 TT homozygous carriers. The study showed that specific allelic combinations of ZNF804A and mTOR may have protective or risk-enhancing effects on AWS-related impulsivity and aggression.

ZNF804A intronic variant rs1344706 and NGRN rs12807809 genetic polymorphisms and risk of schizophrenia in Bangladesh

BackgroundGenetic polymorphism exerts an undeniable impact on schizophrenia (SCZ) pathogenesis. Two polymorphisms, including rs1344806 of ZNF804A and rs12807809 of NRGN gene have been identified as susceptible candidates bearing the risk of SCZ. The target of this experimental study is to investigate the role of these polymorphisms with SCZ in native Bangladeshi people. MethodsFor this study, 220 schizophrenic patients and 204 non-schizophrenic controls were recruited to perform this investigation. For genotyping, tetra-primer ARMS-PCR technique was applied. The Agarose gel electrophoresis system visualized the final genomic products of the desired size. ResultsFrom the genotypic analysis of ZNF804A rs1344706 polymorphism, it was revealed that the minor allele frequency was noticeably increased in the patients than in the healthy population (42.27% vs. 29.17%). Five genetic models showed significantly increased risk of SCZ, including codominant model 1 (1.56-times), codominant model 2 (3.02-times), dominant model (1.86-times), recessive model (2.43-times), and allele model (1.78-times) (p < 0.05). The over-dominant model also had 1.18 times higher risk for SCZ, although the result could not meet the significance level (p > 0.05). Genotyping of rs12807809 unveiled the presence of a comparatively higher genotypic frequency of the minor allele among the patients than in controls (39.09% vs. 17.65%). Every genetic model under investigation showed significantly increased risk for SCZ– codominant model 1 (2.85-times), codominant model 2 (6.45-times), dominant model (3.44-times), recessive model (4.31-times), over-dominant model (2.10-times), and allele model (3.00-times) (p < 0.05). ConclusionThis experimental study concluded that rs1344806 of ZNF804A and rs12807809 of NRGN SNPs are significantly associated with SCZ in the Bangladeshi population.

ASSOCIATION OF THE &lt;i&gt;ZNF804A rs1344706&lt;/i&gt; GENE POLYMORPHISM WITH THE INDUCED EEG RHYTHMS IN VISUAL PERCEPTION OF THE VERBAL STIMULI IN HEALTHY SUBJECTS AND IN SCHIZOPHRENIA

We studied the relationship between the ZNF804A rs1344706 gene polymorphism and the parameters of event-related synchronization/desynchronization of EEG rhythms in visual perception of semantic and meaningless verbal information in patients with schizophrenia and schizophrenia spectrum disorders (n = 93) and mentally healthy subjects (n = 93). When reading verbal information regardless of psychiatric status, the theta rhythm synchronization was less pronounced in subjects with the AA genotype than in carriers of allele C. In healthy subjects, the carriers of the AA genotype, in comparison with carriers of allele C, the synchronization of theta rhythm in the posterior cortical areas of the left hemisphere was reduced, and there were no differences in the synchronization of gamma and desynchronization of mu rhythms when perceiving semantic and nonsensical verbal information. In patients with genotype AA, compared with carriers of allele C, the desynchronization of mu rhythm was smaller, which correlated with the severity of poverty of speech on the PANSS scale. The study results indicate a modulating effect of the rs1344706 polymorphism of the ZNF804A gene on the neurophysiological characteristics of the reading process and its contribution to the variability of clinically expressed language disorders.

The Interaction Between Genetic Variant ZNF804A rs1344706 and Alcohol Withdrawal on Impulsivity: Evidence for the Diathesis-Stress Model.

Objective: Alcohol use disorder (AUD) is the most common substance use disorder, which may relate to increased impulsivity. A more detailed understanding of the potential moderating factor on association between AUD and impulsivity is likely to have far-reaching effects. This study aims to examine whether the interaction between a genetic variant ZNF804A rs1344706 and alcohol use is related to impulsivity in Chinese Han adult males diagnosed with AUD.Methods: A total of 455 Chinese Han adult males diagnosed with AUD were included in this study. Impulsivity was assessed using Barratt Impulsiveness Scale. Alcohol dependence was measured by Michigan Alcoholism Screening Test. Genomic DNA was extracted from peripheral blood of participants and genotyped.Results: Hierarchical multiple regression yielded a significant interaction between ZNF804A rs1344706 and alcohol use (β = 0.20, p = 0.0237). Then, A region of significance (RoS) test was performed to interpret the interaction effect. Re-parameterized regression models revealed that the interaction between ZNF804A rs1344706 and alcohol problem severity fit to the weak diathesis-stress model (R2 = 0.15, p < 0.0010), indicating that the T allele carriers are more susceptible to alcohol problem severity, jointly contributing to impulsivity.Conclusions: This study, which analyzed a specific gene-environment interaction, demonstrated that carriers of the T allele of ZNF804A rs1344706 may be more susceptible to alcohol problem severity, correlated with higher levels of impulsivity during withdrawal.

Impact on the Risk and Severity of Childhood Onset Schizophrenia of Schizophrenia Risk Genetic Variants at the DRD2 and ZNF804A Loci.

The study explored whether schizophrenia risk alleles of the DRD2 rs2514218 and ZNF804A rs1344706 polymorphisms also influenced the risk and severity of childhood-onset schizophrenia (COS) and differentiated it from autism spectrum disorders (ASD). We compared 75 children with COS to 75 children with ASD, 150 patients with adult-onset schizophrenia and 150 healthy individuals. Frequency of the DRD2 T-allele, assumed to be protective against schizophrenia overall, was higher in COS compared to adult-onset schizophrenia and healthy controls. The risk allele A of ZNF804A was associated with greater severity of negative symptoms in COS. The latter result is consistent with the involvement of ZNF804A in the development of severe forms of schizophrenia. The findings regarding DRD2 suggest that the same genetic variants may play different roles in schizophrenia with childhood and adult onset. This warrants further research, since D2 receptor blockade is a general pharmacodynamic property of antipsychotics.

Analysis of associations between pharmacodynamic genetic factors and antipsychotics’ effectiveness and safety in adolescents with acute psychotic episodes taking antipsychotics during a 28-day follow-up

Introduction. Antipsychotics are the main drugs for treatment of schizophrenia spectrum disorders. Pharmacodynamic genetic factors are being actively studied to improve the accuracy of antipsychotic selection based on pharmacogenetic testing.Purpose of this study: to establish associations of genetic polymorphisms of the DRD2, DRD3, DRD4, HTR2A, COMT, ZNF804A, and ANKS1B genes with the efficacy and safety of antipsychotics in adolescents with an acute psychotic episode during a 28-day follow-up.Materials and methods. The study included 68 adolescents with an established diagnosis of acute polymorphic psychotic disorder at the time of admission (F23.0-9 according to ICD-10). All patients received an antipsychotic as their main therapy. Patients were monitored for 28 days. The effectiveness of antipsychotics was assessed using the Children’s Global Assessment Scale (CGAS), Positive and Negative Symptoms Scale (PANSS), Clinical Global Impression Severity (CGI-S) and Improvement (CGI-I). The safety of pharmacotherapy was assessed using the UKU Side Effects Rating Scale (UKU SERS), Sympson-Angus Scale (SAS), Barnes Akathisia rating scale (BARS). From each patient we obtained a buccal scraped epithelium, extracted DNA from it by sorbent method and detected carriage of genetic polymorphisms DRD2 rs1800497 (C&gt;T), DRD3 rs6280 (C&gt;T), DRD3 rs324026 (C&gt;T), DRD4 rs1800955 (C&gt;T), HTR2A rs6313 (T&gt;C), COMT rs4680 (Val158Met, G&gt;A), ZNF804A rs1344706 (A&gt;C), ANKS1B rs7968606 (C&gt;T) by real-time PCR.Results. DRD2 rs1800497 T allele carriers had a stronger reduction in the PANSS subscore «Productive Symptomatics» on day 14 (Me=-7.0 [-9.0;-5.0] vs Me=-7.0 [-8.0;-2.0]; p=0.018) and day 28 of follow-up (Me=-11.0 [-9.0;-5.5] vs Me=-8.0 [-8.0;-2.0]; p=0.019). Also, greater improvement on the CGAS scale on day 14 of follow-up was seen in TC+CC HTR2A rs6313 carriers (Me=2.0 [1.0;3.0] vs. Me=2.0 [1.0;2.0]; p=0.029). DRD3 rs324026 homozygous carriers (TT) had a significantly lower SAS score (Me=0.5 [0.0; 1.0] vs. Me=1.0 [0.0; 5.0]; p=0.016) and UKU subscore «Neurological Disorders» on 28 days of antipsychotic therapy (Me=0.0 [0.0; 0.0] vs. Me=1.0 [0.0; 3.8]; p=0.005). DRD3 rs324026 TT carriers also had lower severity of akathisia according to the BARS scale. Carriers of the T DRD4 rs1800955 allele had a higher SAS scale score on day 28 of therapy compared with CC homozygotes (Me=1.0 [0.0;4.0] vs Me=0.0 [0.0;1.0]; p=0.036).Conclusion. The DRD2 rs1800497 was a predictor of better reduction of productive symptoms; HTR2A rs6313 demonstrated a similar association. The DRD2 rs1800497 polymorphic variant was a predictor of better reduction of productive symptomatology; HTR2A rs6313 demonstrated a similar association. DRD3 rs324026 and HTR2A rs6313 were associated with a lower frequency of neurological adverse reactions and akathisia. In contrast, carriers of the DRD4 rs1800955 were more prone to adverse reactions on pharmacotherapy.

Полиморфизм гена ZNF804A rs1344706 и клиническая гетерогенность шизофрении

Полиморфизм гена ZNF804A rs1344706 и клиническая гетерогенность шизофрении

Proof-of-concept study of a multi-gene risk score in adolescent bipolar disorder

BackgroundFew studies have examined multiple genetic variants concurrently for the purpose of classifying bipolar disorder (BD); the literature among youth is particularly sparse. We selected 35 genetic variants, previously implicated in BD or associated characteristics, from which to identify the most robustly predictive group of genes. Methods215 Caucasian adolescents (114 BD and 101 healthy controls (HC), ages 13–20 years) were included. Psychiatric diagnoses were determined based on semi-structured diagnostic interviews. Genomic DNA was extracted from saliva for genotyping. Two models were used to calculate a multi-gene risk score (MGRS). Model 1 used forward and backward regressions, and model 2 used a PLINK generated method. ResultsIn model 1, GPX3 rs3792797 was significant in the forward regression, DRD4 exonIII was significant in the backward regression; IL1β rs16944 and DISC1 rs821577 were significant in both the forward and backward regressions. These variants are involved in dopamine neurotransmission; inflammation and oxidative stress; and neuronal development. Model 1 MGRS did not significantly discriminate between BD and HC. In model 2, ZNF804A rs1344706 was significantly associated with BD; however, this association did not predict diagnosis when entered into the weighted model. LimitationsThis study was limited by the number of genetic variants examined and the modest sample size. ConclusionsWhereas regression approaches identified four genetic variants that significantly discriminated between BD and HC, those same variants no longer discriminated between BD and HC when computed as a MGRS. Future larger studies are needed evaluating intermediate phenotypes such as neuroimaging and blood-based biomarkers.

Effect of the ZNF804A Gene and Obstetrical Complications on Clinical Characteristics of Schizophrenia

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

Associations of schizophrenia risk genes ZNF804A and CACNA1C with schizotypy and modulation of attention in healthy subjects

Schizotypy is a multidimensional risk phenotype distributed in the general population, constituting of subclinical, psychotic-like symptoms. It is associated with psychosis proneness, and several risk genes for psychosis are associated with schizotypy in non-clinical populations. Schizotypy might also modulate cognitive abilities as it is associated with attentional deficits in healthy subjects. In this study, we tested the hypothesis that established genetic risk variants ZNF804A rs1344706 and CACNA1C rs1006737 are associated with psychometric schizotypy and that schizotypy mediates their effect on attention or vice versa. In 615 healthy subjects from the FOR2107 cohort study, we analysed the genetic risk variants ZNF804A rs1344706 and CACNA1C rs1006737, psychometric schizotypy (schizotypal personality questionnaire-brief SPQB), and a neuropsychological measure of sustained and selective attention (d2 test). ZNF804A rs1344706 C (non-risk) alleles were significantly associated with higher SPQ-B Cognitive-Perceptual subscores in women and with attention deficits in both sexes. This schizotypy dimension also mediated the effect of ZNF804A on attention in women, but not in men. CACNA1C rs1006737-A showed a significant sex-modulated negative association with Interpersonal schizotypy only in men, and no effect on attention. Our multivariate model demonstrates differential genetic contributions of two psychosis risk genes to dimensions of schizotypy and, partly, to attention. This supports a model of shared genetic influence between schizotypy and cognitive functions impaired in schizophrenia.

Spontaneous Regional Brain Activity in Healthy Individuals is Nonlinearly Modulated by the Interaction of ZNF804A rs1344706 and COMT rs4680 Polymorphisms.

ZNF804A rs1344706 has been identified as one of the risk genes for schizophrenia. However, the neural mechanisms underlying this association are unknown. Given that ZNF804A upregulates the expression of COMT, we hypothesized that ZNF804A may influence brain activity by interacting with COMT. Here, we genotyped ZNF804A rs1344706 and COMT rs4680 in 218 healthy Chinese participants. Amplitudes of low-frequency fluctuations (ALFFs) were applied to analyze the main and interaction effects of ZNF804A rs1344706 and COMT rs4680. The ALFFs of the bilateral dorsolateral prefrontal cortex showed a significant ZNF804A rs1344706 × COMT rs4680 interaction, manifesting as a U-shaped modulation, presumably by dopamine signaling. Significant main effects were also found. These findings suggest that ZNF804A affects the resting-state functional activation by interacting with COMT, and may improve our understanding of the neurobiological effects of ZNF804A and its association with schizophrenia.

The interaction between the ZNF804A gene and cannabis use on the risk of psychosis in a non-clinical sample

The ZNF804A gene and cannabis use are risk factors for psychosis and both have also been associated with schizotypal traits. This study aimed to investigate: i) the association of lifetime cannabis use (and its dose effect) with schizotypal personality traits, and ii) whether the genetic variability at ZNF804A gene modulates that association.Our sample consisted of 385 Spanish non-clinical subjects (43.1% males, mean age = 21.11(2.19)). Schizotypy was evaluated using the three factors of the Schizotypal Personality Questionnaire-Brief (SPQ-B): Cognitive-Perceptual (SPQ-CP), Interpersonal (SPQ-I) and Disorganized (SPQ-D). Subjects were classified according to their frequency of cannabis consumption, and dichotomized as users or non-users. The effects of a genetic variant of ZNF804A (rs1344706) and cannabis use, as well as their interaction, on each of the three SPQ-B factors were assessed using linear models and permutation tests. Sex, SCL anxiety scores and use of other drugs were included as covariates.Our analysis showed a significant relationship between ZNF804A and SPQ-I: AA genotype was associated with higher scores (β = 0.885 pFDR = .018). An interaction between the AA genotype and lifetime cannabis use was found in SPQ-CP (β = 1.297 pFDR = 0.018). This interaction showed a dose–effect pattern among AA subjects: schizotypy scores increased with increasing frequency of cannabis use (sporadic users: β = 0.746 pFDR = 0.208; monthly users: β = 1.688 pFDR = 0.091; intense users: β = 1.623 pFDR = 0.038).These results add evidence on that the ZNF804A gene is associated with schizotypy and suggest that the interaction between cannabis use and ZNF804A genotype could modulate psychosis proneness.

ZNF804A Variation May Affect Hippocampal-Prefrontal Resting-State Functional Connectivity in Schizophrenic and Healthy Individuals.

The ZNF804A variant rs1344706 has consistently been associated with schizophrenia and plays a role in hippocampal-prefrontal functional connectivity during working memory. Whether the effect exists in the resting state and in patients with schizophrenia remains unclear. In this study, we investigated the ZNF804A polymorphism at rs1344706 in 92 schizophrenic patients and 99 healthy controls of Han Chinese descent, and used resting-state functional magnetic resonance imaging to explore the functional connectivity in the participants. We found a significant main effect of genotype on the resting-state functional connectivity (RSFC) between the hippocampus and the dorsolateral prefrontal cortex (DLPFC) in both schizophrenic patients and healthy controls. The homozygous ZNF804A rs1344706 genotype (AA) conferred a high risk of schizophrenia, and also exhibited significantly decreased resting functional coupling between the left hippocampus and right DLPFC (F(2,165) = 13.43, P < 0.001). The RSFC strength was also correlated with cognitive performance and the severity of psychosis in schizophrenia. The current findings identified the neural impact of the ZNF804A rs1344706 on hippocampal-prefrontal RSFC associated with schizophrenia.

S17. ZNF804A GENE AND CANNABIS USE: INTERACTION ON THE RISK FOR PSYCHOSIS IN A NON-CLINICAL SAMPLE

BackgroundThe ZNF804A gene and cannabis use are risk factors for psychosis, both of which have also been associated with schizotypic traits. This study aimed to test whether ZNF804A (rs1344706) modulates the relation between cannabis use and schizotypy levels in a general population sample.MethodsThe sample consisted of 389 Spanish non-clinical subjects (43% males, mean age=21.1(2.19)). Schizotypy was evaluated with the three factors of the Schizotypal Personality Questionnaire-Brief (SPQ-B): Cognitive-Perceptual (CP), Interpersonal (I) and Disorganized (D). Subjects were classified as cannabis users or non-users. Multiple linear regressions were conducted to test the effect of genetic and environment factors and their interaction on SPQ-B scores. Sex and anxiety scores (evaluated with SCL) were included as covariates.ResultsThe analyses showed a significant linear relationship between the ZNF804A and SPQ-I: homozygotes AA showed higher scores (p=0.001). An interaction between cannabis use and rs1344706 on SPQ-CP was observed: among individuals AA, cannabis users presented higher scores than non-users, while among individuals CC, cannabis users presented lower scores compared to non-users (p=0.005).DiscussionThese results add evidence on that the ZNF804A modulates schizotypy and suggest that schizotypy levels are influenced by an interaction between the exposure to cannabis and the ZNF804A genotype.

Effect of rs1344706 in the ZNF804A gene on the brain network.

ZNF804A rs1344706 (A/C) was the first SNP that reached genome-wide significance for schizophrenia. Recent studies have linked rs1344706 to functional connectivity among specific brain regions. However, no study thus far has examined the role of this SNP in the entire functional connectome. In this study, we used degree centrality to test the role of rs1344706 in the whole-brain voxel-wise functional connectome during the resting state. 52 schizophrenia patients and 128 healthy controls were included in the final analysis. In our whole-brain analysis, we found a significant interaction effect of genotype × diagnosis at the precuneus (PCU) (cluster size = 52 voxels, peak voxel MNI coordinates: x = 9, y = − 69, z = 63, F = 32.57, FWE corrected P < 0.001). When we subdivided the degree centrality network according to anatomical distance, the whole-brain analysis also found a significant interaction effect of genotype × diagnosis at the PCU with the same peak in the short-range degree centrality network (cluster size = 72 voxels, F = 37.29, FWE corrected P < 0.001). No significant result was found in the long-range degree centrality network. Our results elucidated the contribution of rs1344706 to functional connectivity within the brain network, and may have important implications for our understanding of this risk gene's role in functional dysconnectivity in schizophrenia.

Common variation in ZNF804A (rs1344706) is not associated with brain morphometry in schizophrenia or healthy participants

BackgroundThe single nucleotide polymorphism (SNP) rs1344706 [A>C] within intron 2 of the zinc finger protein 804A gene (ZNF804A) is associated with schizophrenia at the genome-wide level, but its function in relation to the development of psychotic disorders, including its influence on brain morphology remains unclear. MethodsUsing both univariate (voxel-based morphometry, VBM; cortical thickness) and multivariate (source-based morphometry, SBM) approaches, we examined the effects of variation of the rs1344706 polymorphism on grey matter integrity in 214 Caucasian schizophrenia cases and 94 Caucasian healthy individuals selected from the Australian Schizophrenia Research Bank. ResultsNeither univariate nor multivariate analyses showed any associations between indices of grey matter and rs1344706 variation in schizophrenia or healthy participants. This was revealed in the context of the typical pattern of decreased grey matter integrity in schizophrenia compared to healthy individuals, including: (1) large grey matter volume reductions in the orbitofrontal and anterior cingulate cortices and the left fusiform/inferior temporal gyri; (2) decreased cortical thickness in the left inferior temporal and fusiform gyri, the left orbitofrontal gyrus, as well as in the right pars opercularis/precentral gyrus; and (3) decreased covariation of grey matter concentration in frontal and limbic brain regions emerging from the SBM analyses. ConclusionsContrary to some – but not all – previous findings, this study of a large sample of schizophrenia cases and healthy controls reveals no evidence for association between grey matter alterations and variation in rs1344706 (ZNF804A). Differences in sample sizes and ethnicities may account for discrepant findings between the present and previous studies.

SA3. Association of ZNF804A rs1344706 Genotype and Impulsivity in Patients With Chronic Schizophrenia

SA3. Association of ZNF804A rs1344706 Genotype and Impulsivity in Patients With Chronic Schizophrenia

ZNF804A rs1344706 interacts with COMT rs4680 to affect prefrontal volume in healthy adults.

The biological function of ZNF804A rs1344706, the first genome-wide supported risk variant of schizophrenia, remains largely unknown. Based on the upregulating effect of ZNF804A on the expression of COMT, we hypothesize that ZNF804A may affect grey matter volume (GMV) by interacting with COMT. Voxel-based morphometry was applied to analyze the main and interaction effects of ZNF804A rs1344706 and COMT rs4680 on brain GMV in 274 healthy young human subjects. The GMV of the left dorsolateral prefrontal cortex (DLPFC) showed a significant COMT rs4680×ZNF804A rs1344706 interaction, manifesting as an inverted U-shape modulation by the presumed dopamine signaling. In COMT Met-allele carriers, the ZNF804A TG heterozygotes showed greater GMV in the left DLPFC than both GG and TT homozygotes. In COMT Val/Val homozygotes, however, the ZNF804A TG heterozygotes exhibited smaller GMV in the left DLPFC than GG homozygotes and comparable GMV with TT homozygotes. These findings suggest that ZNF804A affects the GMV of the prefrontal cortex by interacting with COMT, which may improve our understanding of neurobiological effect of ZNF804A and its association with schizophrenia.

The impact of CACNA1C gene, and its epistasis with ZNF804A, on white matter microstructure in health, schizophrenia and bipolar disorder1.

Genome-wide studies have identified allele A (adenine) of single nucleotide polymorphism (SNP) rs1006737 of the calcium-channel CACNA1C gene as a risk factor for both schizophrenia (SZ) and bipolar disorder (BD) as well as allele A for rs1344706 in the ZNF804A gene. These illnesses have also been associated with white matter abnormalities, reflected by reductions in fractional anisotropy (FA), measured using diffusion tensor imaging (DTI). We assessed the impact of the CACNA1C psychosis risk variant on FA in SZ, BD and health. 230 individuals (with existing ZNF804A rs1344706 genotype data) were genotyped for CACNA1C rs1006737 and underwent DTI. FA data was analysed with tract-based spatial statistics and threshold-free cluster enhancement significance correction (P < 0.05) to detect effects of CACNA1C genotype on FA, and its potential interaction with ZNF804A genotype and with diagnosis, on FA. There was no significant main effect of the CACNA1C genotype on FA, nor diagnosis by genotype(s) interactions. Nevertheless, when inspecting SZ in particular, risk allele carriers had significantly lower FA than the protective genotype individuals, in portions of the left middle occipital and parahippocampal gyri, right cerebellum, left optic radiation and left inferior and superior temporal gyri. Our data suggests a minor involvement of CACNA1C rs1006737 in psychosis via conferring susceptibility to white matter microstructural abnormalities in SZ. Put in perspective, ZNF804A rs1344706, not only had a significant main effect, but its SZ-specific effects were two orders of magnitude more widespread than that of CACNA1C rs1006737.