Replication of association between schizophrenia and ZNF804A in the Irish Case Control Study of Schizophrenia (ICCSS) sample

Department of Psychiatry, Virginia Commonwealth University, Richmond, VA 23298-0424, USA.
Molecular Psychiatry (Impact Factor: 14.5). 10/2009; 15(1):29-37. DOI: 10.1038/mp.2009.109
Source: PubMed


A recent genome-wide association study reported association between schizophrenia and the ZNF804A gene on chromosome 2q32.1. We attempted to replicate these findings in our Irish Case-Control Study of Schizophrenia (ICCSS) sample (N=1021 cases, 626 controls). Following consultation with the original investigators, we genotyped three of the most promising single-nucleotide polymorphisms (SNPs) from the Cardiff study. We replicate association with rs1344706 (trend test one-tailed P=0.0113 with the previously associated A allele) in ZNF804A. We detect no evidence of association with rs6490121 in NOS1 (one-tailed P=0.21), and only a trend with rs9922369 in RGRIP1L (one-tailed P=0.0515). On the basis of these results, we completed genotyping of 11 additional linkage disequilibrium-tagging SNPs in ZNF804A. Of 12 SNPs genotyped, 11 pass quality control criteria and 4 are nominally associated, with our most significant evidence of association at rs7597593 (P=0.0013) followed by rs1344706. We observe no evidence of differential association in ZNF804A on the basis of family history or sex of case. The associated SNP rs1344706 lies in approximately 30 bp of conserved mammalian sequence, and the associated A allele is predicted to maintain binding sites for the brain-expressed transcription factors MYT1l and POU3F1/OCT-6. In controls, expression is significantly increased from the A allele of rs1344706 compared with the C allele. Expression is increased in schizophrenic cases compared with controls, but this difference does not achieve statistical significance. This study replicates the original reported association of ZNF804A with schizophrenia and suggests that there is a consistent link between the A allele of rs1344706, increased expression of ZNF804A and risk for schizophrenia.

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Available from: Brien Patrick Riley
    • "(O'Donovan et al., 2008; Riley et al., 2010; Williams et al., 2011; Zhu et al., 2014; in the yet largest genome-wide association study on schizophrenia investigating 36.989 patients and 113.075 controls another single nucleotide polymorphism within ZNF804A, rs11693094, in high LD with rs1344706 (R²=.84) "
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    ABSTRACT: As evidenced by a multitude of studies, abnormalities in Theory of Mind (ToM) and its neural processing might constitute an intermediate phenotype of schizophrenia. If so, neural alterations during ToM should be observable in unaffected relatives of patients as well, since they share a considerable amount of genetic risk. While behaviorally, impaired ToM function is confirmed meta-analytically in relatives, evidence on aberrant function of the neural ToM network is sparse and inconclusive. The present study therefore aimed to further explore the neural correlates of ToM in relatives of schizophrenia. 297 controls and 63 unaffected first-degree relatives of patients with schizophrenia performed a ToM task during functional magnetic resonance imaging. Consistent with the literature relatives exhibited decreased activity of the medial prefrontal cortex. Additionally, increased recruitment of the right middle temporal gyrus and posterior cingulate cortex was found, which was related to subclinical paranoid symptoms in relatives. These results further support decreased medial prefrontal activation during ToM as an intermediate phenotype of genetic risk for schizophrenia. Enhanced recruitment of posterior ToM areas in relatives might indicate inefficiency mechanisms in the presence of genetic risk. © The Author (2015). Published by Oxford University Press. For Permissions, please email:
    No preview · Article · Sep 2015 · Social Cognitive and Affective Neuroscience
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    • "The gene that encodes ZNF804A is a widely studied susceptibility gene for schizophrenia and bipolar disorder. 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. "
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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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    • "(2003)havealsopublisheddataontheabsenceofanassociation betweenCArepeatpolymorphismandschizophrenia(Liouetal., 2003).PositiveresultsfortheJapanesepopulationhavebeen presentedinanalysisbyCuietal.(2010),whohaverevealed anassociationofpolymorphismrs41279104withschizophrenia development.Further,itisestablishedthatcarriersofallele Ahavereliablyearlierageofmanifestationofthediseaseas comparedwithGG-homozygotes.Inwomen,theinfluenceof genotypeontendencytodiseasewasexpressedmorestrongly (Cuietal.,2010).Polymorphismrs6490121hasshownapossible associationwithschizophreniaonsetinGWAS,whichwas confirmedbyRileyetal.(2010).Functionalpolymorphisms "NOS1_1d"and"NOS1_1f"havealsobeenstudied,buton smallsamplesofassaysofbraintissue,havingshownareliable increaseinexpressioninschizophrenia(Silberbergetal.,2010). NOS1genepolymorphismswerecombinedwithdisturbance ofcognitivefunctionsbothinpatientswithschizophrenia (Donohoeetal.,2009;Reifetal.,2011)andinhealthypersons "
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    ABSTRACT: Currently, schizophrenia is considered a multifactorial disease. Over the past 50 years, many investigators have considered the role of toxic free radicals in the etiology of schizophrenia. This is an area of active research which is still evolving. Here, we review the recent data and current concepts on the roles of nitric oxide (NO) and related molecules in the pathogenesis of schizophrenia. NO is involved in storage, uptake and release of mediators and neurotransmitters, including glutamate, acetylcholine, noradrenaline, GABA, taurine and glycine. In addition, NO diffuses across cell membranes and activates its own extrasynaptic receptors. Further, NO is involved in peroxidation and reactive oxidative stress. Investigations reveal significant disturbances in NO levels in the brain structures (cerebellum, hypothalamus, hippocampus, striatum) and fluids of subjects with schizophrenia. Given the roles of NO in central nervous system development, these changes may result in neurodevelopmental changes associated with schizophrenia. We describe here the recent literature on NOS gene polymorphisms on schizophrenia, which all point to consistent results. We also discuss how NO may be a new target for the therapy of mental disorders. Currently there have been 2 randomized double-blind placebo-controlled trials of L-lysine as an NOS inhibitor in the CNS.
    Full-text · Article · May 2015 · Frontiers in Physiology
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