Association Between ZNF804A Gene rs1344706 Polymorphism and Brain Functions in Healthy Individuals: A Systematic Review and Voxel-Based Meta-Analysis.

OBJECTIVE: Zinc finger protein 804A (ZNF804A) protein participates in embryonic neural repair and development. The single nucleotide polymorphism rs1344706 in ZNF804A gene is closely related to functional abnormalities of the human brain. However, these results are inconsistent. This association was verified by meta-analysis in this study. METHODS: Fifteen studies on functional magnetic resonance imaging involving 1710 healthy individuals were included in the systematic review and meta-analysis used by Anisotropic Effect-Size Signed Differential Mapping software. RESULTS: Functional connectivity of the right dorsolateral prefrontal cortex (rDLPFC)-left hippocampus in the rs1344706 risk allele carrier was significantly increased (z = 2.066, p < 0.001), while those in the rDLPFC-left middle frontal gyrus (z = -1.420, p < 0.001) and rDLPFC-right middle frontal gyrus (z = -1.298, p < 0.001) were significantly decreased. Neural activity of the left anterior cingulate gyrus in the rs1344706 risk allele carrier was significantly decreased (z = -2.525, p < 0.001). Sensitivity analysis was almost stable, and no publication bias was found. CONCLUSION: The changes in brain function have a clear correlation with ZNF804A gene in healthy individuals, which indicate the contribution of genetic variants on brain dysfunction. REGISTRATION NUMBER: This meta-analysis is registered in PROSPERO (No. CRD42016051331).

Schizophrenia­associated microRNA­148b­3p regulates COMT and PRSS16 expression by targeting the ZNF804A gene in human neuroblastoma cells.

Zinc finger protein 804A (ZNF804A) has been identified by genome­wide association studies as a robust risk gene in schizophrenia, but how ZNF804A contributes to schizophrenia and its upstream regulation remains unknown. Previous studies have indicated that microRNAs (miRs) are key factors that regulate the expression levels of their target genes. The present study revealed significantly increased expression of miR­148b­3p in the peripheral blood of patients with first­onset schizophrenia compared with healthy controls, and bioinformatics analysis predicted that the ZNF804A gene is a target of miR­148b­3p. Therefore, the present study investigated the possible upstream regulation of ZNF804A by miR­148b­3p in the human neuroblastoma SH­SY5Y cell line, and assessed the implications for schizophrenia. The results revealed significantly reversed expression levels of miR­148b­3p (P=0.0051) and ZNF804A (P=0.0218) in the peripheral blood of patients with first­onset schizophrenia compared with healthy individuals. Furthermore, it was demonstrated that miR­148b­3p directly targeted ZNF804A via binding to conserved target sites in the 3'­untranslated region of ZNF804A mRNA, where it inhibited the endogenous expression of ZNF804A at both the mRNA (P=0.048) and protein levels (P=0.013) in SH­SY5Y cells. Furthermore, miR­148b­3p was revealed to regulate the expression levels of catechol­O­methyltransferase (COMT) and serine protease 16 (PRSS16) by targeting ZNF804A in SH­SY5Y cells. Collectively, the present results indicated that there was a direct upstream regulation of the schizophrenia risk gene ZNF804A by miR­148b­3p, which contributed to the regulation of the downstream genes COMT and PRSS16. Thus, the miR­148b­3p/ZNF804A/COMT/PRSS16 pathway may play an important role in the pathophysiology of schizophrenia, and may serve as a potential target in drug discovery and gene therapy for this disorder.

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.

Association between ZNF804A gene polymorphism and cognitive dysfunction in patients with schizophrenia / 中华行为医学与脑科学杂志

Objective To investigate the relationship between three polymorphic sites of ZNF804A gene and cognitive dysfunction in schizophrenia.Methods Polymerase Chain Reaction (PCR) was used to determine the genotypes and allele frequencies of the three sites (rs1344706,rs12613195 and rs1583048) of ZNF804A gene in 320 patients with schizophrenia (case group) and 324 normal people (control group).The Montreal Cognitive Assessment (MoCA) was used to assess cognitive function.Results (1) The allelic and genotypic distributions in rs1344706 between patients with schizophrenia (T/T,T/G,G/G genotypes:20.3％,50.0％,29.7％),and healthy controls(T/T,T/G,G/G genotypes:13.7％,51.2％,35.1％)had statistically significance(P＞0.05).There was a statistically significant difference in the allele and genotype distribution of rs1344706 between the case group and the control group (P＜0.05),and the family transmission disequilibrium existed in rs1344706 and rs12613195.(2) The MoCA scores in the case group(＜26 points) were lower than those of the control group (P＜0.05).(3)There was a statistically significant difference between the total scores of MoCA (F=202.49,P＜0.05) and scores assessed in different time (F=53.34,P＜ 0.05) in patients with three genotypes of rs1344706.Moreover,the interaction between genotype and time was also statistically significant (F=3.88,P＜0.05),in which the patients with T/T genotype had the lowest total score.(4)There was a statistically significant difference between the total score of MoCA(F=367.78,P ＜0.05) and scores assessed in different time (F=27.35,P＜0.05) in patients with three genotypes of rs12613195,in which the patients with C/C genotype had the lowest total score.However,the interaction between genotype and time was not statistically significant(P＞0.05).(5)The effect of rs1344706 on cognitive function was slightly larger than that of rs12613195.(6)The cognitive function scores of patients carrying rs1344706 and rs12613195 sites decreased year by year.Conclusion ZNF804A gene rs1344706 and rs12613195 may be associated with cognitive dysfunction of schizophrenia,and rs1344706T and rs12613195C may be risk factors for schizophrenia and cognitive impairment.Furthermore,cognitive impairment in patients with rs1344706 is more pronounced and worsened with prolonged condition.rs1583048 may not be associated with cognitive function of schizophrenia.

Spontaneous Regional Brain Activity in Healthy Individuals is Nonlinearly Modulated by the Interaction of ZNF804A rs1344706 and COMT rs4680 Polymorphisms / 神经科学通报·英文版

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.

Pleiotropic action of genetic variation rs1344706 in ZNF804A on brain structure and function in pa-tients with schizophrenia / 中华行为医学与脑科学杂志

Objective To explore the association between the ZNF804A gene genetic variation poly-morphism rs1344706 and brain structure and function in patients with schizophrenia. Methods Literature search was conducted in Pubmed and other databases,the processes were performed in strict accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines,then the Comprehensive Meta-Analysis software was used for meta-analysis. Results Schizophrenia patients with rs1344706 risk al-lele had lager gray matter in the amount of brain regions including frontal lobe (z＝3.445,P＝0.001),tempo-ral lobe (z＝2.140,P＝0.032) and other brain regions; healthy controls with the risk allele had smaller gray matter and regional activity in the frontal lobe ( gray matter: z＝－2.008, P＝0.045, regional activity: z＝－4.036,P＜0.01) and other regions. Sensitivity analysis was stable,but publication bias existed in a few ana-lyses of indexes. Conclusion The risk allele in ZNF804A gene rs1344706 has positive effects on the brain structure in patients with schizophrenia,but negative effects on the brain structure and function in the healthy individuals.

Association between the zinc finger protein 804A (ZNF804A) gene and the risk of schizophrenia and bipolar I disorder across diagnostic boundaries.

OBJECTIVES: In this study, we aimed to determine the role of genetic variations within the zinc finger protein 804A (ZNF804A) gene, a candidate for a psychosis risk-conferring gene, in the development of schizophrenia (SZ) and bipolar disorder (BP) in the Korean population. METHODS: A total of 921 patients with SZ, bipolar I (BP-I) and II (BP-II) disorder, and 502 control subjects participated in the study. Twenty-one tag single nucleotide polymorphisms (SNPs) across the genomic region of ZNF804A and seven reference SNPs based on previous reports were genotyped. We applied logistic regression analyses under additive, dominant and recessive models. RESULTS: Fifteen of the 28 SNPs showed a nominally significant association with at least one diagnostic group. However, none of these associations remained significant after false discovery rate (FDR) correction. As the trend of association was observed mostly in SZ and BP-I with similar patterns, we performed a post hoc analysis for the combined SZ and BP-I group. Five SNPs (rs2369595, rs6755404, rs10931156, rs12476147 and rs1366842) showed a significant association with an FDR-corrected P of <.05. CONCLUSIONS: This study supports a possible role of ZNF804A in the common susceptibility of major psychoses, and identified additional candidate variants of the gene in the Korean population.

No association between ZNF804A rs1344706 and schizophrenia in a case-control study of Han Chinese.

Previous studies indicated that the single nucleotide polymorphism (SNP) rs1344706 within the gene ZNF804A was a promising risk variant for schizophrenia in European populations. However, existing results are inconsistent in Han Chinese. Hoping to validate the association of rs1344706 with schizophrenia susceptibility in Han Chinese, we conducted a case-control study in 1284 cases and 990 healthy controls from Jiangsu Province, China. We did not detect any significant between-group difference (all P>0.05) in either allele or genotype frequency under any genetic model between cases and controls. Stratified analysis by sex also failed to find any significant association. Our results did not support the association of rs1344706 with schizophrenia in Han Chinese, and further association studies with large samples from other ethnic backgrounds and focus on more SNPs of ZNF804A are warranted.

Genetic analysis of common variants in the CMYA5 (cardiomyopathy-associated 5) gene with schizophrenia.

Recently, CMYA5 was suggested as a susceptibility gene for schizophrenia based on two independent studies utilizing different ethnic samples. We designed a case-control study to examine whether 21 SNPs contained within CMYA5 were associated with the disorder in a western Han Chinese sample comprised of 488 schizophrenia patients and 516 healthy control subjects. The allele distribution of SNPs rs7714250, rs16877135 and rs13158477 showed significant association with schizophrenia (Puncorrected=0.008, Puncorrected=0.04, and Puncorrected=0.009, respectively) as well as the genotype distribution in the Cochran-Armitage trend test (Puncorrected=0.008, Puncorrected=0.037 and Puncorrected=0.011, respectively). After Bonferroni correction, rs7714250 showed a trend of association with schizophrenia both in allele distribution (Pcorrected=0.088) and genotype distribution (Pcorrected=0.088). Furthermore, significant associations were found in several two-, three-, four-, and five-SNP tests of haplotype analyses. Replications of the association of CMYA5 with schizophrenia across various studies suggest that it is very likely a potential common schizophrenia-related gene worldwide. Functional studies correlating CMYA5 with DTNBP1 and PKA warrant further investigation of the molecular basis of this gene in relationship to the signal transduction pathway(s) underlying the pathogenesis of schizophrenia.