Psychosis Susceptibility Gene ZNF804A and Cognitive Performance in Schizophrenia

Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Department of Psychological Medicine and Neurology, School of Medicine, Cardiff University, Cardiff, Wales.
Archives of general psychiatry (Impact Factor: 14.48). 07/2010; 67(7):692-700. DOI: 10.1001/archgenpsychiatry.2010.81
Source: PubMed


The Zinc Finger Protein 804A gene (ZNF804A) has been implicated in schizophrenia susceptibility by several genome-wide association studies. ZNF804A is brain expressed but of unknown function.
To investigate whether the identified risk allele at the disease-associated single nucleotide polymorphism rs1344706 is associated with variation in neuropsychological performance in patients and controls.
Comparison of cases and controls grouped according to ZNF804A genotype (AA vs AC vs CC) on selected measures of cognition in 2 independent samples.
Unrelated patients from general adult psychiatric inpatient and outpatient services and unrelated healthy participants from the general population were ascertained.
Patients with DSM-IV-diagnosed schizophrenia and healthy participants from independent samples of Irish (297 cases and 165 controls) and German (251 cases and 1472 controls) nationality.
In this 2-stage study, we tested for an association between ZNF804A rs1344706 and cognitive functions known to be impaired in schizophrenia (IQ, episodic memory, working memory, and attention) in an Irish discovery sample. We then tested significant results in a German replication sample.
In the Irish samples, the ZNF804A genotype was associated with differences in episodic and working memory in patients but not in controls. These findings replicated in the same direction in the German samples. Furthermore, in both samples, when patients with a lower IQ were excluded, the association between ZNF804A and schizophrenia strengthened.
In a disorder characterized by heterogeneity, a risk variant at ZNF804A seems to delineate a patient subgroup characterized by relatively spared cognitive ability. Further work is required to establish whether this represents a discrete molecular pathogenesis that differs from that of other patient groups and whether this also has consequences for nosologic classification, illness course, or treatment.

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    • "It would be interesting to investigate whether rs1344706 carriers have altered ZNF804A expression selectively in the CA1 region of the hippocampus during adolescence, as our results suggest that there is a transient upregulation of Zfp804a at this neurodevelopmental stage. If there was dysregulation of Zfp804a in this region, at this stage, then it could potentially contribute to cognition impairment in individuals with schizophrenia (Walters et al., 2010). rs1344706 risk allele carriers have been shown to have larger hippocampal volumes than non-carriers (Donohoe et al., 2011), suggesting a specific effect on hippocampal structure. "
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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. Copyright © 2015 Elsevier B.V. All rights reserved.
    Full-text · Article · Jul 2015 · Schizophrenia Research
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    • "The earlier work by Walters et al. [2010] provided a thorough surveying of rs1344706 genotypic consequences in the context of neurocognitive performance. From their examination of ZNF804A on the effects of cognitive functions in an Irish case–control sample, the authors reported reliable associations of the risk SNP with aspects of verbal and spatial working memory which they replicated in a separate analysis of German subjects [Walters et al., 2010]. Contrary to the reports by Walters et al., Voineskos et al. [2011] did not observe a significant association of rs1344706 in the context of working memory; however, they found that presence of the risk allele accompanies the reduced cortical thickness exhibited in multiple brain regions (e. g., anterior cingulated cortex, posterior cingulated cortex, and superior temporal gyrus) in their healthy adult samples. "
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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.
    Full-text · Article · Jan 2014 · American Journal of Medical Genetics Part B Neuropsychiatric Genetics
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    • "Diagnosis was confirmed by trained psychiatrists using the Structured Clinical Interview for DSM-IV Axis I Diagnoses (SCID; First et al. 1995). Additional diagnostic and clinical information ascertained at time of interview, including symptom severity (SAPS/SANS; Andreasen 1984a,b) and medication dosage are detailed elsewhere (Walters et al. 2010). The healthy control sample was recruited on the basis of response to local media advertisements. "
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    ABSTRACT: The single nucleotide polymorphism rs10503253, located within the CUB and Sushi multiple domains-1 (CSMD1) gene on 8p23.2, was recently identified as genome wide significant for schizophrenia, but is of unknown function. We investigated the neurocognitive effects of this CSMD1 variant in vivo in patients and healthy participants using behavioral and imaging measures of brain structure and function. We compared carriers and non-carriers of the risk 'A' allele on measures of neuropsychological performance typically impaired in schizophrenia (General cognitive ability, episodic and working memory, and attentional control) in independent samples of Irish patients (n=387) and controls (n=171) and German patients (205) and controls (n=533). Across these groups, the risk 'A' allele at CSMD1 was associated with deleterious effects across a number of neurocognitive phenotypes. Specifically, the risk allele was associated with poorer performance on neuropsychological measures of general cognitive ability and memory function but not attentional control. These effects, while significant, were subtle, and varied between samples. Consistent with previous evidence suggesting that CSMD1 may be involved in brain mechanisms related to memory and learning, these data appear to reflect the deleterious effects of the identified 'A' risk allele on neurocognitive function, possibly as part of the mechanism by which CSMD1 is associated with schizophrenia risk.
    Full-text · Article · Jan 2013 · Genes Brain and Behavior
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