The Impact of a Genome-Wide Supported Psychosis Variant in the ZNF804A Gene on Memory Function in Schizophrenia
A recent genome-wide association study showed that a variant (rs1344706) in the ZNF804A gene was associated with schizophrenia and bipolar disorder. Replication studies supported the evidence for association between this variant in the ZNF804A gene and schizophrenia and that this variant is the most likely susceptibility variant. Subsequent functional magnetic resonance imaging studies in healthy subjects demonstrated the association of the high-risk ZNF804A variant with neural activation during a memory task and a theory of mind task. As these cognitive performances are disturbed in patients with schizophrenia, this gene may play a role in cognitive dysfunction in schizophrenia. The aim of the current study was to investigate the potential relationship between this ZNF804A polymorphism and memory function. The effects of the high-risk ZNF804A genotype, diagnosis, and genotype-diagnosis interaction on verbal memory, visual memory (VisM), attention/concentration, and delayed recall (measured by the Wechsler Memory Scale-Revised) were analyzed by two-way analysis of covariance in 113 patients with schizophrenia and 184 healthy subjects. Consistent with previous studies, patients with schizophrenia exhibited poorer performance on all indices as compared to healthy control subjects (P < 0.001). A significant ZNF804A genotype-diagnosis interaction was found for VisM performance (P = 0.0012). Patients with the high-risk T/T genotype scored significantly lower on VisM than G carriers did (P = 0.018). In contrast, there was no genotype effect for any index in the healthy control subjects (P > 0.05). Our data suggest that rs1344706 may be related to memory dysfunction in schizophrenia. © 2010 Wiley-Liss, Inc.
Available from: Eric H Chang
- "It was the first gene to reach genome-wide significance for psychosis (O'Donovan et al., 2008), and its association with both schizophrenia and bipolar disorder has been subsequently confirmed in multiple genome-wide association studies (GWASs; Riley et al., 2010; Williams et al., 2011; Zhang et al., 2011). Studies of the single nucleotide polymorphism (SNP) rs1344706 in both psychiatric patients and healthy risk allele carriers have demonstrated effects on white and gray matter volume, white matter tract integrity, functional connectivity (Esslinger et al., 2009; Lencz et al., 2010; Voineskos et al., 2011; Ikuta et al., 2014; Wei et al., 2015), and cognition (Hashimoto et al., 2010; Walters et al., 2010; Esslinger et al., 2011; Walter et al., 2011; Chen et al., 2012), indicating potential functional consequences of this gene variant. While these findings illustrate the potential wide-ranging effects of a ZNF804A polymorphism, little is known about the biological functions of the gene itself. "
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ABSTRACT: The zinc finger protein ZNF804A rs1344706 variant is a replicated genome-wide significant risk variant for schizophrenia and bipolar disorder. While its association with altered brain structure and cognition in patients and healthy risk allele carriers is well documented, the characteristics and function of the gene in the brain remains poorly understood. Here, we used in situ hybridization to determine mRNA expression levels of the ZNF804A rodent homologue, Zfp804a, across multiple postnatal neurodevelopmental time points in the rat brain. We found changes in Zfp804a expression in the rat hippocampus, frontal cortex, and thalamus across postnatal neurodevelopment. Zfp804a mRNA peaked at postnatal day (P) 21 in hippocampal CA1 and DG regions and was highest in the lower cortical layers of frontal cortex at P1, possibly highlighting a role in developmental migration. Using immunofluorescence, we found that Zfp804a mRNA and ZFP804A co-localized with neurons and not astrocytes. In primary cultured cortical neurons, we found that Zfp804a expression was significantly increased when neurons were exposed to glutamate [20μM], but this increase was blocked by the N-methyl-d-aspartate receptor (NMDAR) antagonist MK-801. Expression of Comt, Pde4b, and Drd2, genes previously shown to be regulated by ZNF804A overexpression, was also significantly changed in an NMDA-dependent manner. Our results describe, for the first time, the unique postnatal neurodevelopmental expression of Zfp804a in the rodent brain and demonstrate that glutamate potentially plays an important role in the regulation of this psychiatric susceptibility gene. These are critical steps toward understanding the biological function of ZNF804A in the mammalian brain.
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Available from: Stephen J Glatt
- "Such an approach has been useful thus far for the identification of zinc finger protein 804A (ZNF804A), a genome-wide significant candidate gene associated with SZ and BD. Investigation of this gene has moved from its initial genetic association [O'Donovan et al., 2008] to neurophysiological and structural examination [Hashimoto et al., 2010; Walters et al., 2010; Donohoe et al., 2011; Esslinger et al., 2011; Rasetti et al., 2011; Voineskos et al., 2011; Chen et al., 2012; Cousijn et al., 2012; Wassink et al., 2012] to recent scrutiny of its biological impact [Hill and Bray, 2012; Hill et al., 2012; Umeda-Yano et al., 2013]. ZNF804A exemplifies the ability of one gene to effectively challenge the Kraepelinian dichotomy through a preponderance of evidence at multiple levels of analysis. "
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ABSTRACT: The gene that encodes zinc finger protein 804A (ZNF804A) became a candidate risk gene for schizophrenia (SZ) after surpassing genome-wide significance thresholds in replicated genome-wide association scans and meta-analyses. Much remains unknown about this reported gene expression regulator; however, preliminary work has yielded insights into functional and biological effects of ZNF804A by targeting its regulatory activities in vitro and by characterizing allele-specific interactions with its risk-conferring single nucleotide polymorphisms (SNPs). There is now strong epidemiologic evidence for a role of ZNF804A polymorphisms in both SZ and bipolar disorder (BD); however, functional links between implicated variants and susceptible biological states have not been solidified. Here we briefly review the genetic evidence implicating ZNF804A polymorphisms as genetic risk factors for both SZ and BD, and discuss the potential functional consequences of these variants on the regulation of ZNF804A and its downstream targets. Empirical work and predictive bioinformatic analyses of the alternate alleles of the two most strongly implicated ZNF804A polymorphisms suggest they might alter the affinity of the gene sequence for DNA- and/or RNA-binding proteins, which might in turn alter expression levels of the gene or particular ZNF804A isoforms. Future work should focus on clarifying the critical periods and cofactors regulating these genetic influences on ZNF804A expression, as well as the downstream biological consequences of an imbalance in the expression of ZNF804A and its various mRNA isoforms. © 2013 Wiley Periodicals, Inc.
Available from: Kazutaka Ohi
- "males, 102 males and 71 females, mean age ± SD, range 36.0 ± 12.3 years) and 449 healthy subjects (47.7% males, 214 males and 235 females, mean age ± SD, range 35.4 ± 12.8 years). All subjects were biologically unrelated within the second-degree of relationship and were of Japanese descent [25,26]. The subjects were excluded if they had neurological or medical conditions that could potentially affect the central nervous system, such as atypical headache, head trauma with loss of consciousness, chronic lung disease, kidney disease, chronic hepatic disease, thyroid disease, active cancer, cerebrovascular disease, epilepsy, seizures, substance-related disorders or mental retardation. "
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ABSTRACT: Genome-wide significant associations of schizophrenia with eight SNPs in the CNNM2, MIR137, PCGEM1, TRIM26, CSMD1, MMP16, NT5C2 and CCDC68 genes have been identified in a recent mega-analysis of genome-wide association studies. To date, the role of these SNPs on gray matter (GM) volumes remains unclear.
After performing quality control for minor-allele frequency > 5% using a JPT HapMap sample and our sample, a genotyping call rate > 95% and Hardy-Weinberg equilibrium testing (p > 0.01), five of eight SNPs were eligible for analysis. We used a comprehensive voxel-based morphometry (VBM) technique to investigate the effects of these five SNPs on GM volumes between major-allele homozygotes and minor-allele carriers in Japanese patients with schizophrenia (n = 173) and healthy subjects (n = 449).
The rs7914558 risk variant at CNNM2 was associated with voxel-based GM volumes in the bilateral inferior frontal gyri (right T = 4.96, p = 0.0088, left T = 4.66, p = 0.031). These peak voxels, which were affected by the variant, existed in the orbital region of the inferior frontal gyri. Individuals with the risk G/G genotype of rs7914558 had smaller GM volumes in the bilateral inferior frontal gyri than carriers of the non-risk A-allele. Although several effects of the genotype and the genotype-diagnosis interaction of other SNPs on GM volumes were observed in the exploratory VBM analyses, these effects did not remain after the FWE-correction for multiple tests (p > 0.05).
Our findings suggest that the genetic variant in the CNNM2 gene could be implicated in the pathogenesis of schizophrenia through the GM volumetric vulnerability of the orbital regions in the inferior frontal gyri.
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