| 1 | Nat. Genet. 2008 Sep 40: 1053-5 |
|---|---|
| PMID | 18677311 |
| Title | Identification of loci associated with schizophrenia by genome-wide association and follow-up. |
| Abstract | We carried out a genome-wide association study of schizophrenia (479 cases, 2,937 controls) and tested loci with P < 10(-5) in up to 16,726 additional subjects. Of 12 loci followed up, 3 had strong independent support (P < 5 x 10(-4)), and the overall pattern of replication was unlikely to occur by chance (P = 9 x 10(-8)). Meta-analysis provided strongest evidence for association around ZNF804A (P = 1.61 x 10(-7)) and this strengthened when the affected phenotype included bipolar disorder (P = 9.96 x 10(-9)). |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizotypal |
| 2 | Nervenarzt 2009 Jan 80: 6, 8, 10-1 |
| PMID | 19132332 |
| Title | [Progress in locating the genetic causes of schizophrenia]. |
| Abstract | Elucidation of the pathogenesis of schizophrenia is progressing rapidly. The importance of the glutamatergic system and the glutamate receptor GRM3 were shown in both genetic and pharmacological studies of the new drug LY2140023. The zinc finger domain-containing gene ZNF804A could be identified as a new schizophrenia susceptibility gene, while large copy number variants at 1q21.1 and 15q13.3 now are seen as monogenic causes of schizophrenia. It is anticipated that the coming years will see further rapid progress in the unraveling of the causes of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizotypal |
| 3 | Curr. Opin. Genet. Dev. 2009 Jun 19: 266-70 |
| PMID | 19345090 |
| Title | Schizophrenia genetics: advancing on two fronts. |
| Abstract | Recent studies have supported the hypothesis that the high heritability of schizophrenia reflects a combination of relatively common alleles of small effect and some rare alleles with relatively large effects. Genome-wide association studies have identified at least one common allele of small effect at ZNF804A, which encodes a putative zinc finger binding protein, as well as possible roles for other loci. The genome-wide studies of at least one class of relatively uncommon variant, submicroscopic chromosomal abnormalities often referred to as copy number variations (CNVs), suggest that these confer high risk of schizophrenia. There is evidence both for an increased burden of CNVs in schizophrenia and that risk is conferred by specific large deletions at 1q21.1 and at 15q13.2 and by deletions of NRXN1 which encodes the synaptic scaffolding protein neurexin 1. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizotypal |
| 4 | Science 2009 May 324: 605 |
| PMID | 19407193 |
| Title | Neural mechanisms of a genome-wide supported psychosis variant. |
| Abstract | schizophrenia is a devastating, highly heritable brain disorder of unknown etiology. Recently, the first common genetic variant associated on a genome-wide level with schizophrenia and possibly bipolar disorder was discovered in ZNF804A (rs1344706). We show, by using an imaging genetics approach, that healthy carriers of rs1344706 risk genotypes exhibit no changes in regional activity but pronounced gene dosage-dependent alterations in functional coupling (correlated activity) of dorsolateral prefrontal cortex (DLPFC) across hemispheres and with hippocampus, mirroring findings in patients, and abnormal coupling of amygdala. Our findings establish disturbed connectivity as a neurogenetic risk mechanism for psychosis supported by genome-wide association, show that rs1344706 or variation in linkage disequilibrium is functional in human brain, and validate the intermediate phenotype strategy in psychiatry. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizotypal |
| 5 | Hum. Genet. 2009 Jul 126: 3-12 |
| PMID | 19521722 |
| Title | Genetics of psychosis; insights from views across the genome. |
| Abstract | The major psychotic illnesses, schizophrenia and bipolar disorder (BD), are among the most heritable common disorders, but finding specific susceptibility genes for them has not been straightforward. The reasons are widely assumed to include lack of valid phenotypic definition, absence of good theories of pathophysiology for candidate gene studies, and the involvement of many genes, each making small contributions to population risk. Within the last year or so, a number of genome wide association (GWAS) of schizophrenia and BD have been published. These have produced stronger evidence for association to specific risk loci than have earlier studies, specifically for the zinc finger binding protein 804A (ZNF804A) locus in schizophrenia and for the calcium channel, voltage-dependent, L type, alpha 1C subunit (CACNA1C) and ankyrin 3, node of Ranvier (ANK3) loci in bipolar disorder. The ZNF804A and CACNA1C loci appear to influence risk for both disorders, a finding that supports the hypothesis that schizophrenia and BD are not aetiologically distinct. In the case of schizophrenia, a number of rare copy number variants have also been detected that have fairly large effect sizes on disease risk, and that additionally influence risk of autism, mental retardation, and other neurodevelopmental disorders. The existing findings point to some likely pathophysiological mechanisms but also challenge current concepts of disease classification. They also provide grounds for optimism that larger studies will reveal more about the origins of these disorders, although currently, very little of the genetic risk of either disorder is explained. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizotypal |
| 6 | Schizophr Bull 2009 May 35: 482-90 |
| PMID | 19329560 |
| Title | Psychosis genetics: modeling the relationship between schizophrenia, bipolar disorder, and mixed (or "schizoaffective") psychoses. |
| Abstract | As a result of improving technologies and greatly increased sample sizes, the last 2 years has seen unprecedented advances in identification of specific genetic risk factors for psychiatric phenotypes. Strong genetic associations have been reported at common polymorphisms within ANK3 and CACNA1C in bipolar disorder and ZNF804A in schizophrenia and a relatively specific association between common variation in GABA(A) receptor genes and cases with features of both bipolar disorder and schizophrenia. Further, the occurrence of rare copy number variants (CNVs) has been shown to be increased in schizophrenia compared with controls. These emerging data provide a powerful resource for exploring the relationship between psychiatric phenotypes and can, and should, be used to inform conceptualization, classification, and diagnosis in psychiatry. It is already clear that, in general, genetic associations are not specific to one of the traditional diagnostic categories. For example, variation at ZNF804A is associated with risk of both bipolar disorder and schizophrenia, and some rare CNVs are associated with risk of autism and epilepsy as well as schizophrenia. These data are not consistent with a simple dichotomous model of functional psychosis and indicate the urgent need for moves toward approaches that (a) better represent the range of phenotypic variation seen in the clinical population and (b) reflect the underlying biological variation that gives rise to the phenotypes. We consider the implications for models of psychosis and the importance of recognizing and studying illness that has prominent affective and psychotic features. We conclude that if psychiatry is to translate the opportunities offered by new research methodologies, we must finally abandon a 19th-century dichotomy and move to a classificatory approach that is worthy of the 21st century. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizotypal |
| 7 | J. Biomed. Biotechnol. 2010 -1 2010: 231708 |
| PMID | 20508826 |
| Title | Mouse Homologue of the Schizophrenia Susceptibility Gene ZNF804A as a Target of Hoxc8. |
| Abstract | Using a ChIP-cloning technique, we identified a Zinc finger protein 804a (Zfp804a) as one of the putative Hoxc8 downstream target genes. We confirmed binding of Hoxc8 to an intronic region of Zfp804a by ChIP-PCR in F9 cells as well as in mouse embryos. Hoxc8 upregulated Zfp804a mRNA levels and augmented minimal promoter activity in vitro. In E11.5 mouse embryos, Zfp804a and Hoxc8 were coexpressed. Recent genome-wide studies identified Zfp804a (or ZNF804A in humans) as a plausible marker for schizophrenia, leading us to hypothesize that this embryogenic regulatory control might also exert influence in development of complex traits such as psychosis. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizotypal |
| 8 | Curr. Opin. Neurobiol. 2010 Dec 20: 810-5 |
| PMID | 20934321 |
| Title | The neurobiology of schizophrenia: new leads and avenues for treatment. |
| Abstract | Recent large-scale genetic studies have provided robust evidence implicating several novel susceptibility genes for schizophrenia. These include ZNF804A, TCF4 and NRGN, which contain common variants that weakly increase schizophrenia susceptibility, and NRXN1, in which rare copy number variants have a greater impact on schizophrenia risk. Investigation of these and other substantiated susceptibility genes are providing valuable insight into the primary neurobiological mechanisms underlying schizophrenia, which may lead to novel therapeutic interventions for the disorder. In the meantime, several novel pharmacological strategies, including activation of mGluRs, elevation of synaptic glycine and inhibition of phosphodiesterase 10A, have recently shown promise for the treatment of schizophrenia in clinical trials. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizotypal |
| 9 | Front Behav Neurosci 2010 -1 4: 23 |
| PMID | 20485477 |
| Title | New Genetic Findings in Schizophrenia: Is there Still Room for the Dopamine Hypothesis of Schizophrenia? |
| Abstract | schizophrenia is a highly heritable disorder, but the identification of specific genes has proven to be a difficult endeavor. Genes involved in the dopaminergic system are considered to be major candidates since the "dopamine hypothesis" of impairment in dopaminergic neurotransmission is one of the most widely accepted hypotheses of the etiology of schizophrenia. The overall findings from candidate studies do provide some support for the "dopamine hypothesis." However, results from the first systematic genome-wide association (GWA) studies have implicated variants within ZNF804A, NRGN, TCF4, and variants in the MHC region on chromosome 6p22.1. Although these genes may not immediately impact on dopaminergic neurotransmission, it remains possible that downstream impairments in dopaminergic function are caused. Furthermore, only a very small fraction of all truly associated genetic variants have been detected and many more associated variants will be identified in the future by GWA studies and alternative approaches. The results of these studies may allow a more comprehensive re-evaluation of the dopamine hypothesis. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizotypal |
| 10 | Schizophr Bull 2010 Sep 36: 904-9 |
| PMID | 20688871 |
| Title | The psychosis susceptibility gene ZNF804A: associations, functions, and phenotypes. |
| Abstract | As the first gene to have achieved genome-wide significance for psychosis, ZNF804A has predictably been a subject of intense research activity. We review the evidence to date for the association between schizophrenia and the original risk variant rs1344706 identified as well as additional common and rare variants at this locus. We describe the still scant literature on the biological function of ZNF804A and discuss the efforts being made to characterize and refine the associated phenotype using imaging and neuropsychological approaches. We conclude that ZNF804A is robustly, if modestly, associated with schizophrenia risk, with much work still remaining to elucidate its role in schizophrenia biology. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizotypal |
| 11 | Hum. Mol. Genet. 2010 Jul 19: 2841-57 |
| PMID | 20457675 |
| Title | SMARCA2 and other genome-wide supported schizophrenia-associated genes: regulation by REST/NRSF, network organization and primate-specific evolution. |
| Abstract | The SMARCA2 gene, which encodes BRM in the SWI/SNF chromatin-remodeling complex, was recently identified as being associated with schizophrenia (SZ) in a genome-wide approach. Polymorphisms in SMARCA2, associated with the disease, produce changes in the expression of the gene and/or in the encoded amino acid sequence. We show here that an SWI/SNF-centered network including the Smarca2 gene is modified by the down-regulation of REST/NRSF in a mouse neuronal cell line. REST/NRSF down-regulation also modifies the levels of Smarce1, Smarcd3 and SWI/SNF interactors (Hdac1, RcoR1 and Mecp2). Smarca2 down-regulation generates an abnormal dendritic spine morphology that is an intermediate phenotype of SZ. We further found that 8 (CSF2RA, HIST1H2BJ, NOTCH4, NRGN, SHOX, SMARCA2, TCF4 and ZNF804A) out of 10 genome-wide supported SZ-associated genes are part of an interacting network (including SMARCA2), 5 members of which encode transcription regulators. The expression of 3 (TCF4, SMARCA2 and CSF2RA) of the 10 genome-wide supported SZ-associated genes is modified when the REST/NRSF-SWI/SNF chromatin-remodeling complex is experimentally manipulated in mouse cell lines and in transgenic mouse models. The REST/NRSF-SWI/SNF deregulation also results in the differential expression of genes that are clustered in chromosomes suggesting the induction of genome-wide epigenetic changes. Finally, we found that SMARCA2 interactors and the genome-wide supported SZ-associated genes are considerably enriched in genes displaying positive selection in primates and in the human lineage which suggests the occurrence of novel protein interactions in primates. Altogether, these data identify the SWI/SNF chromatin-remodeling complex as a key component of the genetic architecture of SZ. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizotypal |
| 12 | Mol. Psychiatry 2010 Jan 15: 29-37 |
| PMID | 19844207 |
| Title | Replication of association between schizophrenia and ZNF804A in the Irish Case-Control Study of Schizophrenia sample. |
| Abstract | 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. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizotypal |
| 13 | Mol. Psychiatry 2010 Jan 15: 29-37 |
| PMID | 19844207 |
| Title | Replication of association between schizophrenia and ZNF804A in the Irish Case-Control Study of Schizophrenia sample. |
| Abstract | 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. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizotypal |
| 14 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2010 Dec 153B: 1459-64 |
| PMID | 20957649 |
| Title | The impact of a genome-wide supported psychosis variant in the ZNF804A gene on memory function in schizophrenia. |
| Abstract | 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?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. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizotypal |
| 15 | Neuropsychopharmacology 2010 Oct 35: 2284-91 |
| PMID | 20664580 |
| Title | A schizophrenia risk gene, ZNF804A, influences neuroanatomical and neurocognitive phenotypes. |
| Abstract | ZNF804A is one of the strongest candidate genes for schizophrenia (SZ), yet its function and role in disease pathophysiology are largely unknown. The only in vivo endophenotype study of the SZ-associated SNP (rs1344706) pointed towards effects on brain functional connectivity. We examined the relationship of this SNP to neuroanatomical and neurocognitive phenotypes that were assessed in healthy individuals. Volunteers with no history of psychiatric illness were assessed with structural magnetic resonance imaging (1.5T GE scanner, standard gradient-echo acquisition). Carriers of the minor allele were compared with homozygotes for the T (SZ-associated) allele on measures of total volume of the white matter (WM), gray matter (GM), and cerebrospinal fluid compartments, as well as on voxel-wise measurements of regional brain volumes. After examining the correlation between genotype-associated regions of interest and neurocognitive performance measures, the effects of rs1344706 genotype on a measure of visuomotor performance speed (trails A) were examined in an independent cohort of volunteers. Among healthy subjects, risk allele homozygotes showed larger total WM volumes than carriers of the other allele. Controlling for WM volumes, these same subjects showed reduced GM volumes in several regions comprising the 'default mode network,' including angular gyrus, parahippocampal gyrus, posterior cingulate, and medial orbitofrontal gyrus/gyrus rectus (FDR-corrected p<0.05). The risk allele dosage also predicted impairments on a timed visuomotor performance task (trails A). Results support a role of ZNF804A in phenotypes reflecting altered neural connectivity. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizotypal |
| 16 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2010 Dec 153B: 1411-6 |
| PMID | 20862696 |
| Title | No evidence that rare coding variants in ZNF804A confer risk of schizophrenia. |
| Abstract | Strong evidence that rare variants of relatively high penetrance are involved in the etiology of schizophrenia is currently restricted to the data from studies investigating copy number variants and major structural re-arrangements in that disorder. Global tests of the hypothesis of the involvement of fairly high penetrance rare single nucleotide changes or small insertion deletion events await the genesis of data from large-scale sequencing studies, meanwhile, a pragmatic approach to trying to detect such alleles is to target sequencing efforts on genes for which there is compelling evidence from other sources for their involvement in this disorder. We have undertaken a study, which aimed to identify whether rare (frequency ?0.001%) coding variants in the schizophrenia susceptibility gene ZNF804A are involved in this disorder. We screened the coding regions of the gene in 517 schizophrenic cases and 501 controls, and genotyped rare non-synonymous variants in a case-control sample powered to detect association to rare alleles with an effect size (odds ratio) of 5. No single rare variant was associated with schizophrenia, nor was the burden of rare, or even fairly common, non-synonymous variants. Our results do not support the hypothesis that moderately rare non-synonymous variants at the ZNF804A locus are involved in schizophrenia susceptibility. © 2010 Wiley-Liss, Inc. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizotypal |
| 17 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2010 Dec 153B: 1411-6 |
| PMID | 20862696 |
| Title | No evidence that rare coding variants in ZNF804A confer risk of schizophrenia. |
| Abstract | Strong evidence that rare variants of relatively high penetrance are involved in the etiology of schizophrenia is currently restricted to the data from studies investigating copy number variants and major structural re-arrangements in that disorder. Global tests of the hypothesis of the involvement of fairly high penetrance rare single nucleotide changes or small insertion deletion events await the genesis of data from large-scale sequencing studies, meanwhile, a pragmatic approach to trying to detect such alleles is to target sequencing efforts on genes for which there is compelling evidence from other sources for their involvement in this disorder. We have undertaken a study, which aimed to identify whether rare (frequency ?0.001%) coding variants in the schizophrenia susceptibility gene ZNF804A are involved in this disorder. We screened the coding regions of the gene in 517 schizophrenic cases and 501 controls, and genotyped rare non-synonymous variants in a case-control sample powered to detect association to rare alleles with an effect size (odds ratio) of 5. No single rare variant was associated with schizophrenia, nor was the burden of rare, or even fairly common, non-synonymous variants. Our results do not support the hypothesis that moderately rare non-synonymous variants at the ZNF804A locus are involved in schizophrenia susceptibility. © 2010 Wiley-Liss, Inc. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizotypal |
| 18 | Psychol Med 2010 Apr 40: 529-40 |
| PMID | 19818200 |
| Title | What have the genomics ever done for the psychoses? |
| Abstract | Despite the substantial heritability of the psychoses and their genuine public health burden, the applicability of the genomic approach in psychiatry has been strongly questioned or prematurely dismissed. selective review of the recent literature on molecular genetic and genomic approaches to the psychoses including the early output from genome-wide association studies and the genomic analysis of DNA structural variation. Susceptibility variants at strong candidate genes have been identified including neuregulin, dysbindin, DISC1 and neurexin 1. Rare but highly penetrant copy number variants and new mutations affecting genes involved in neurodevelopment, cell signalling and synaptic function have been described showing some overlapping genetic architecture with other developmental disorders including autism. The de-novo mutations described offer an explanation for the familial sporadic divide and the persistence of schizophrenia in the population. The functional effects of risk variants at the level of cognition and connectivity has been described and recently, ZNF804A has been identified, and the MHC re-identified as risk loci, and it has been shown that at least a third of the variation in liability is due to multiple common risk variants of small effect with a substantial shared genetic liability between schizophrenia and bipolar affective disorder. The genomics have done much for the psychoses to date and more is anticipated. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizotypal |
| 19 | CNS Neurosci Ther 2010 Oct 16: e185-92 |
| PMID | 20553308 |
| Title | REVIEW: Genome-wide findings in schizophrenia and the role of gene-environment interplay. |
| Abstract | The recent advent of genome-wide mass-marker technology has resulted in renewed optimism to unravel the genetic architecture of psychotic disorders. Genome-wide association studies have identified a number of common polymorphisms robustly associated with schizophrenia, in ZNF804A, transcription factor 4, major histocompatibility complex, and neurogranin. In addition, copy number variants (CNVs) in 1q21.1, 2p16.3, 15q11.2, 15q13.3, 16p11.2, and 22q11.2 were convincingly implicated in schizophrenia risk. Furthermore, these studies have suggested considerable genetic overlap with bipolar disorder (particularly for common polymorphisms) and neurodevelopmental disorders such as autism (particularly for CNVs). The influence of these risk variants on relevant intermediate phenotypes needs further study. In addition, there is a need for etiological models of psychosis integrating genetic risk with environmental factors associated with the disorder, focusing specifically on environmental impact on gene expression (epigenetics) and convergence of genes and environment on common biological pathways bringing about larger effects than those of genes or environment in isolation (gene-environment interaction). Collaborative efforts that bring together expertise in statistics, genetics, epidemiology, experimental psychiatry, brain imaging, and clinical psychiatry will be required to succeed in this challenging task. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizotypal |
| 20 | Arch. Gen. Psychiatry 2010 Jul 67: 692-700 |
| PMID | 20603450 |
| Title | Psychosis susceptibility gene ZNF804A and cognitive performance in schizophrenia. |
| Abstract | 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. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizotypal |
| 21 | Psychiatry Res 2011 Dec 190: 379-81 |
| PMID | 21663974 |
| Title | To the editor: association of ZNF804A polymorphisms with schizophrenia and antipsychotic drug efficacy in a Chinese Han population. |
| Abstract | -1 |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizotypal |
| 22 | Mol. Psychiatry 2011 Aug 16: 787-9 |
| PMID | 21358713 |
| Title | Allelic differences in nuclear protein binding at a genome-wide significant risk variant for schizophrenia in ZNF804A. |
| Abstract | -1 |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizotypal |
| 23 | Mol. Psychiatry 2011 Apr 16: 360-1 |
| PMID | 20458322 |
| Title | Population-based and family-based association studies of ZNF804A locus and schizophrenia. |
| Abstract | -1 |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizotypal |
| 24 | PLoS ONE 2011 -1 6: e23356 |
| PMID | 21915259 |
| Title | RNA-Seq of human neurons derived from iPS cells reveals candidate long non-coding RNAs involved in neurogenesis and neuropsychiatric disorders. |
| Abstract | Genome-wide expression analysis using next generation sequencing (RNA-Seq) provides an opportunity for in-depth molecular profiling of fundamental biological processes, such as cellular differentiation and malignant transformation. Differentiating human neurons derived from induced pluripotent stem cells (iPSCs) provide an ideal system for RNA-Seq since defective neurogenesis caused by abnormalities in transcription factors, DNA methylation, and chromatin modifiers lie at the heart of some neuropsychiatric disorders. As a preliminary step towards applying next generation sequencing using neurons derived from patient-specific iPSCs, we have carried out an RNA-Seq analysis on control human neurons. Dramatic changes in the expression of coding genes, long non-coding RNAs (lncRNAs), pseudogenes, and splice isoforms were seen during the transition from pluripotent stem cells to early differentiating neurons. A number of genes that undergo radical changes in expression during this transition include candidates for schizophrenia (SZ), bipolar disorder (BD) and autism spectrum disorders (ASD) that function as transcription factors and chromatin modifiers, such as POU3F2 and ZNF804A, and genes coding for cell adhesion proteins implicated in these conditions including NRXN1 and NLGN1. In addition, a number of novel lncRNAs were found to undergo dramatic changes in expression, one of which is HOTAIRM1, a regulator of several HOXA genes during myelopoiesis. The increase we observed in differentiating neurons suggests a role in neurogenesis as well. Finally, several lncRNAs that map near SNPs associated with SZ in genome wide association studies also increase during neuronal differentiation, suggesting that these novel transcripts may be abnormally regulated in a subgroup of patients. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizotypal |
| 25 | Genes Brain Behav. 2011 Mar 10: 223-7 |
| PMID | 21040459 |
| Title | ZNF804A may be associated with executive control of attention. |
| Abstract | ZNF804A, encoding the transcription factor zinc-finger protein 804A, is a genome-wide supported psychosis gene associated with schizophrenia and bipolar disorder. However, only little information is available on the role of ZNF804A regarding the cognitive phenotype of psychosis. In this study, we investigated the relationship between the single-nucleotide polymorphism rs1344706 (A/C, A = risk allele) in ZNF804A and attention in 200 healthy volunteers. We used the attention network test, which was designed to separate the three main components of attention (alerting, orienting and executive control). Results showed a significant association with the executive control network: the A/A genotype and the A-allele were associated with increased reaction time when conflicting information was present. In contrast, rs1344706 was not related to alerting and orienting. These results suggest that the genome-wide supported psychosis risk variant of ZNF804A is associated with altered executive control (larger conflict effect), which is a potential endophenotype of psychotic disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizotypal |
| 26 | Neuroimage 2011 Feb 54: 2132-7 |
| PMID | 20934520 |
| Title | ZNF804A risk allele is associated with relatively intact gray matter volume in patients with schizophrenia. |
| Abstract | ZNF804A rs1344706 is the first genetic risk variant to achieve genome wide significance for psychosis. Following earlier evidence that patients carrying the ZNF804A risk allele had relatively spared memory function compared to patient non-carriers, we investigated whether ZNF804A was also associated with variation in brain volume. In a sample of 70 patients and 38 healthy participants we used voxel based morphometry to compare homozygous (AA) carriers of the ZNF804A risk allele to heterozygous and homozygous (AC/CC) non-carriers for both whole brain volume and specific regions implicated in earlier ZNF804A studies-the dorsolateral pre-frontal cortex, the hippocampus, and the amygdala. For patients, but not for controls, we found that homozygous 'AA' risk carriers had relatively larger gray matter volumes than heterozygous/homozygous non-carriers (AC/CC), particularly for hippocampal volumes. These data are consistent with our earlier behavioral data and suggest that ZNF804A is delineating a schizophrenia subtype characterized by relatively intact brain volume. Establishing if this represents a discrete molecular pathogenesis with consequences for nosology and treatment will be an important next step in understanding ZNF084A's role in illness risk. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizotypal |
| 27 | Schizophr. Res. 2011 Dec 133: 159-64 |
| PMID | 21993378 |
| Title | Is the conserved mammalian region of ZNF804A locus associated with schizophrenia? A population-based genetics analysis. |
| Abstract | Recently, several genome-wide association studies (GWASs) have reproduced the significant association of the single nucleotide polymorphism (SNP) rs1344706 (located in intron 2 of the zinc finger protein 804A (ZNF804A) on chromosome 2q32.1) with schizophrenia. Bioinformatic analysis of the chromosome segment around rs1344706 suggests that a short conserved mammalian region exists approximately 3kb downstream of rs1344706. In the present work, we studied all SNPs in this conserved mammalian region and performed genetic analyses on samples from Chinese schizophrenia patients (n = 516) and compared control subjects (n = 520). Significant association between an allele of rs13423388 and schizophrenia was found (P = 0.0012). Haplotype analysis of the three SNPs rs4666998, rs13423388, and rs56280129 showed significant associations with schizophrenia (global P = 0.00001). Furthermore, we performed a four-SNP haplotype analysis which included the SNPs from the three-SNP haplotype analysis and rs1344706 (global P = 0.0005), and found that haplotype GCCG was associated with schizophrenia (P = 0.003). In summary, the present study adds new evidence for an association between the conserved mammalian region of the ZNF804A gene and schizophrenia. Further research is needed to clarify the transcriptional regulation of ZNF804A gene and to relate this to the pathophysiology of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizotypal |
| 28 | World J. Biol. Psychiatry 2011 Aug 12: 392-7 |
| PMID | 21767209 |
| Title | ANK3, CACNA1C and ZNF804A gene variants in bipolar disorders and psychosis subphenotype. |
| Abstract | OBJECTIVES. The ANK3, CACNA1C and ZNF804A genes have been implicated in both bipolar disorders (BPD) and schizophrenia (SCZ). It has been suggested that BPD with psychosis may be a clinical manifestation of genes overlapping between BPD and SCZ. We therefore tested the association of these genes with BPD in a large family-based sample, and then dissected the phenotype into psychosis present or absent subgroups. METHODS. We genotyped four high interest single nucleotide polymorphisms from ANK3 (rs10994336, rs9804190), CACNA1C (rs1006737), and ZNF804A (rs1344706). Family based association testing (FBAT) was performed on 312 families, and within psychotic (N = 158) and non-psychotic BPD (N = 119) subgroups. RESULTS. In the whole sample, we found a nominal association in ZNF804A (rs1344706, P = 0.046), and a trend in CACNA1C (rs1006737, P = 0.077). In the psychotic BPD subgroup, as hypothesized, stronger signals were observed in ZNF804A (P = 0.019) and CACNA1C (P = 0.017). We found no association in the ANK3 markers, but the rs10994336 variant was nominally associated with non-psychotic BPD (P = 0.046). Exploratory analysis revealed the rs1344706 variant was also implicated in suicide-attempt behaviour (P = 0.038). CONCLUSIONS. These tentative results are consistent with the hypothesis that the subphenotype of BPD with psychosis may represent a clinical manifestation of shared genetic liability between BPD and SCZ. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizotypal |
| 29 | Hum. Mol. Genet. 2011 Jan 20: 387-91 |
| PMID | 21037240 |
| Title | Most genome-wide significant susceptibility loci for schizophrenia and bipolar disorder reported to date cross-traditional diagnostic boundaries. |
| Abstract | Recent findings from genetic epidemiology and from genome-wide association studies point strongly to a partial overlap in the genes that contribute susceptibility to schizophrenia and bipolar disorder (BD). Previous data have also directly implicated one of the best supported schizophrenia-associated loci, zinc finger binding protein 804A (ZNF804A), as showing trans-disorder effects, and the same is true for one of the best supported bipolar loci, calcium channel, voltage-dependent, L type, alpha 1C subunit (CACNA1C) which has also been associated with schizophrenia. We have undertaken a cross-phenotype study based upon the remaining variants that show genome-wide evidence for association in large schizophrenia and BD meta-analyses. These comprise in schizophrenia, SNPs in or in the vicinity of transcription factor 4 (TCF4), neurogranin (NRGN) and an extended region covering the MHC locus on chromosome 6. For BD, the strongly supported variants are in the vicinity of ankyrin 3, node of Ranvier (ANK3) and polybromo-1 (PBRM1). Using data sets entirely independent of their original discoveries, we observed strong evidence that the PBRM1 locus is also associated with schizophrenia (P = 0.00015) and nominally significant evidence (P < 0.05) that the NRGN and the extended MHC region are associated with BD. Moreover, considering this highly restricted set of loci as a group, the evidence for trans-disorder effects is compelling (P = 4.7 × 10(-5)). Including earlier reported data for trans-disorder effects for ZNF804A and CACNA1C, six out of eight of the most robustly associated loci for either disorder show trans-disorder effects. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizotypal |
| 30 | J. Neurogenet. 2011 Oct 25: 88-103 |
| PMID | 21797804 |
| Title | Development of patient-specific neurons in schizophrenia using induced pluripotent stem cells. |
| Abstract | Induced pluripotent stem cell (iPSC) technology has the potential to transform regenerative medicine. It also offers a powerful tool for establishing in vitro models of disease, in particular, for neuropsychiatric disorders where live human neurons are essentially impossible to procure. Using iPSCs derived from three schizophrenia (SZ) patients, one of whom has 22q11.2del (velocardiofacial syndrome; VCFS), the authors developed a culture system to study SZ on a molecular and cellular level. SZ iPSCs were differentiated into functional, primarily glutamatergic neurons that were able to fire action potentials after ?8 weeks in culture. Early differentiating neurons expressed a number of transcription factors/chromatin remodeling proteins and synaptic proteins relevant to SZ pathogenesis, including ZNF804A, RELN, CNTNAP2, CTNNA2, SMARCA2, and NRXN1. Although a small number of lines were developed in this preliminary study, the SZ line containing 22q11.2del showed a significant delay in the reduction of endogenous OCT4 and NANOG expression that normally occurs during differentiation. Constitutive expression of OCT4 has been observed in Dgcr8-deficient mouse embryonic stem cells (mESCs); DGCR8 maps to the 22q11.2-deleted region. These findings demonstrate that the method of inducing neural differentiation employed is useful for disease modeling in SZ and that the transition of iPSCs with 22q11.2 deletions towards a differentiated state may be marked by subtle changes in expression of pluripotency-associated genes. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizotypal |
| 31 | Arch. Gen. Psychiatry 2011 Dec 68: 1207-17 |
| PMID | 21810628 |
| Title | Altered cortical network dynamics: a potential intermediate phenotype for schizophrenia and association with ZNF804A. |
| Abstract | Studies have shown patterns of abnormal dorsolateral prefrontal cortex (DLPFC) functional connectivity with other brain areas in schizophrenia and association of these patterns with a putative susceptibility gene (ZNF804A). However, whether these patterns are trait phenomena linked to genetic risk for illness is unclear. To test the hypotheses that altered DLPFC connectivity is (1) a familial, likely heritable feature of genetic risk for schizophrenia, (2) a novel intermediate phenotype independent of altered DLPFC engagement, and (3) selectively modulated by a polymorphism in ZNF804A. Cross-sectional case-control study using blood oxygen level-dependent functional magnetic resonance imaging during a working memory task and genotyping of rs1344706 in ZNF804A. Research center. A total of 402 subjects (153 cognitively normal controls, 171 healthy siblings of patients with schizophrenia, and 78 patients). Task-independent and task-dependent physiologic coupling between the DLPFC and other brain "target" regions investigated with (1) seeded connectivity and (2) psychophysiological interaction analysis. Siblings and patients showed greater DLPFC "inefficiency" than controls. Abnormal DLPFC functional coupling with the hippocampus and, to a lesser degree, the rest of the prefrontal cortex, was observed in patients and siblings when compared with controls using both connectivity analyses. Prefrontal activation and connectivity measures within siblings did not correlate, implying that they were independent phenomena. The ZNF804A genotype significantly modulated DLPFC coupling with the hippocampus and prefrontal cortex but not DLPFC activity in the control group. Similarly, ZNF804A genotype modulated right DLPFC-hippocampal formation coupling in siblings and patients. Coupling between the DLPFC and hippocampus is compromised in siblings of patients with schizophrenia and is independent of DLPFC engagement. The selective association with a single-nucleotide polymorphism in ZNF804A suggests that this intermediate phenotype proxies a distinct neural system mechanism related to genetic risk for schizophrenia and the biology of this gene. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizotypal |
| 32 | Neuroimage 2011 Feb 54: 2514-23 |
| PMID | 20946959 |
| Title | Cognitive state and connectivity effects of the genome-wide significant psychosis variant in ZNF804A. |
| Abstract | Alterations of connectivity are central to the systems-level pathophysiology of schizophrenia. One of the best-established genome-wide significant risk variants for this highly heritable disorder, the rs1344706 single nucleotide polymorphism in ZNF804A, was recently shown to modulate connectivity in healthy carriers during working memory (WM) in a pattern mirroring that which was found in overt disease. However, it was unclear whether this finding is specific to WM or if it is present regardless of cognitive state. Therefore, we examined genotype effects on connectivity in healthy carriers during rest and an emotion processing task without WM component. 111 healthy German subjects performed a battery of functional imaging tasks. Functional connectivity with the right dorsolateral prefrontal cortex during rest and an implicit emotion recognition task was determined using the seed voxel method and compared to results during WM. During rest and during the emotional task, a pattern of reduced interhemispheric prefrontal connectivity with increasing number of rs1344706 risk alleles could be seen that was close to identical to that during WM, suggesting a state-independent influence of the genetic variant on interhemispheric processing, possibly through structural effects. By contrast, the abnormal prefronto-hippocampal connectivity was only seen during the WM task, indicating a degree of task specificity in agreement with prior results in patients with schizophrenia. Our findings confirm a key role for disturbed functional connectivity in the genetic risk architecture of schizophrenia and identify cognitive state-dependent and independent components with regard to WM function. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizotypal |
| 33 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2011 Mar 156: 198-203 |
| PMID | 21302348 |
| Title | Evaluation of risk loci for schizophrenia derived from genome-wide association studies in a German population. |
| Abstract | In the genome-wide association study (GWAS) on schizophrenia [O'Donovan et al. (2008); Nat Genet 40:1053?1055] a UK-sample of 479 cases with DSM-IV schizophrenia was genotyped in comparison to control subjects with follow up of 12 putative loci in international replication sets of approximately 15,000 cases and controls. In these cohorts and a combined bipolar and schizophrenia UK-sample, six single nucleotide polymorphisms (SNPs) supported association, with the strongest evidence for SNP-marker rs1344706 at the zinc finger ZNF804A locus on chromosome 2q32.1 (P?=?1.61?×?10?7). We attempted replication of these findings in a German population of 2,154 individuals (632 with affective disorders, 937 with schizophrenia, and 585 controls), but found none of the GWAS risk alleles significantly associated with psychosis. Particularly rs1344706, initially surpassing the genome-wide significance level in an extended phenotype of schizophrenia and affective disorder, produced consistently negative results. At the ZNF804A locus estimated Odds ratios reached 1.08 (0.93?1.26 95% CI) for the schizophrenia sample and 1.04 (0.90?1.20 95% CI) for the combined set of cases with schizophrenia and affective disorder. The main limitation of our study may be the reduced power of the sample size, but our data may be useful for future meta-analysis of GWA data sets. Although GWAS have proven extraordinary successful in identifying susceptibility genes for complex genetic disorders, the hypothesis of common genetic variants in the complex group of the schizophrenic psychoses with small effect size but relatively high frequency is still put to further scrutiny. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizotypal |
| 34 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2011 Mar 156: 198-203 |
| PMID | 21302348 |
| Title | Evaluation of risk loci for schizophrenia derived from genome-wide association studies in a German population. |
| Abstract | In the genome-wide association study (GWAS) on schizophrenia [O'Donovan et al. (2008); Nat Genet 40:1053?1055] a UK-sample of 479 cases with DSM-IV schizophrenia was genotyped in comparison to control subjects with follow up of 12 putative loci in international replication sets of approximately 15,000 cases and controls. In these cohorts and a combined bipolar and schizophrenia UK-sample, six single nucleotide polymorphisms (SNPs) supported association, with the strongest evidence for SNP-marker rs1344706 at the zinc finger ZNF804A locus on chromosome 2q32.1 (P?=?1.61?×?10?7). We attempted replication of these findings in a German population of 2,154 individuals (632 with affective disorders, 937 with schizophrenia, and 585 controls), but found none of the GWAS risk alleles significantly associated with psychosis. Particularly rs1344706, initially surpassing the genome-wide significance level in an extended phenotype of schizophrenia and affective disorder, produced consistently negative results. At the ZNF804A locus estimated Odds ratios reached 1.08 (0.93?1.26 95% CI) for the schizophrenia sample and 1.04 (0.90?1.20 95% CI) for the combined set of cases with schizophrenia and affective disorder. The main limitation of our study may be the reduced power of the sample size, but our data may be useful for future meta-analysis of GWA data sets. Although GWAS have proven extraordinary successful in identifying susceptibility genes for complex genetic disorders, the hypothesis of common genetic variants in the complex group of the schizophrenic psychoses with small effect size but relatively high frequency is still put to further scrutiny. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizotypal |
| 35 | Mol. Psychiatry 2011 Apr 16: 429-41 |
| PMID | 20368704 |
| Title | Fine mapping of ZNF804A and genome-wide significant evidence for its involvement in schizophrenia and bipolar disorder. |
| Abstract | A recent genome-wide association study (GWAS) reported evidence for association between rs1344706 within ZNF804A (encoding zinc-finger protein 804A) and schizophrenia (P=1.61 × 10(-7)), and stronger evidence when the phenotype was broadened to include bipolar disorder (P=9.96 × 10(-9)). In this study we provide additional evidence for association through meta-analysis of a larger data set (schizophrenia/schizoaffective disorder N=18?945, schizophrenia plus bipolar disorder N=21?274 and controls N=38?675). We also sought to better localize the association signal using a combination of de novo polymorphism discovery in exons, pooled de novo polymorphism discovery spanning the genomic sequence of the locus and high-density linkage disequilibrium (LD) mapping. The meta-analysis provided evidence for association between rs1344706 that surpasses widely accepted benchmarks of significance by several orders of magnitude for both schizophrenia (P=2.5 × 10(-11), odds ratio (OR) 1.10, 95% confidence interval 1.07-1.14) and schizophrenia and bipolar disorder combined (P=4.1 × 10(-13), OR 1.11, 95% confidence interval 1.07-1.14). After de novo polymorphism discovery and detailed association analysis, rs1344706 remained the most strongly associated marker in the gene. The allelic association at the ZNF804A locus is now one of the most compelling in schizophrenia to date, and supports the accumulating data suggesting overlapping genetic risk between schizophrenia and bipolar disorder. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizotypal |
| 36 | Mol. Psychiatry 2011 Jan 16: 59-66 |
| PMID | 20048749 |
| Title | Expanding the range of ZNF804A variants conferring risk of psychosis. |
| Abstract | A trio of genome-wide association studies recently reported sequence variants at three loci to be significantly associated with schizophrenia. No sequence polymorphism had been unequivocally (P<5 × 10(-8)) associated with schizophrenia earlier. However, one variant, rs1344706[T], had come very close. This polymorphism, located in an intron of ZNF804A, was reported to associate with schizophrenia with a P-value of 1.6 × 10(-7), and with psychosis (schizophrenia plus bipolar disorder) with a P-value of 1.0 × 10(-8). In this study, using 5164 schizophrenia cases and 20,709 controls, we replicated the association with schizophrenia (odds ratio OR = 1.08, P = 0.0029) and, by adding bipolar disorder patients, we also confirmed the association with psychosis (added N = 609, OR = 1.09, P = 0.00065). Furthermore, as it has been proposed that variants such as rs1344706[T]-common and with low relative risk-may also serve to identify regions harboring less common, higher-risk susceptibility alleles, we searched ZNF804A for large copy number variants (CNVs) in 4235 psychosis patients, 1173 patients with other psychiatric disorders and 39,481 controls. We identified two CNVs including at least part of ZNF804A in psychosis patients and no ZNF804A CNVs in controls (P = 0.013 for association with psychosis). In addition, we found a ZNF804A CNV in an anxiety patient (P = 0.0016 for association with the larger set of psychiatric disorders). |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizotypal |
| 37 | Am J Psychiatry 2011 Dec 168: 1318-25 |
| PMID | 21890790 |
| Title | Allelic differences between Han Chinese and Europeans for functional variants in ZNF804A and their association with schizophrenia. |
| Abstract | ZNF804A is a schizophrenia risk gene that was recently identified by genome-wide association studies as well as subsequent replications. Although the results are consistent among studies in European populations, there have been conflicting reports in Chinese populations. The authors conducted both association and functional analyses to test whether ZNF804A is a risk gene for schizophrenia in Chinese populations. The authors recruited two case-control samples of independent Han Chinese (a total of 2,207 participants) from southwestern China. A total of six single-nucleotide polymorphisms (SNPs), including the key SNP (rs1344706) that showed significant association with schizophrenia in European populations and the other five promoter SNPs of ZNF804A, were tested. Based on the results of the association analysis, the authors performed two functional assays to test the impact of the risk SNP on transcriptional factor binding affinity and promoter activity. The SNP rs1344706 was not associated with schizophrenia in either of the two Han Chinese groups, and this result was confirmed by meta-analyses in five Han Chinese samples. However, the authors identified two ZNF804A promoter SNPs that were significantly associated with schizophrenia in both samples, and the significance was strengthened in the combined samples and further supported by haplotype analysis. The functional assays demonstrated that the risk SNP (rs359895) can influence Sp1 binding affinity, resulting in a higher promoter activity of the risk allele. Our results suggest that ZNF804A is a common risk gene for schizophrenia in world populations and that the newly identified functional SNP (rs359895) is likely a risk SNP for schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizotypal |
| 38 | Neurosci. Lett. 2011 May 495: 216-20 |
| PMID | 21457757 |
| Title | Impact on schizotypal personality trait of a genome-wide supported psychosis variant of the ZNF804A gene. |
| Abstract | schizophrenia is a complex disorder with a high heritability. Relatives with schizophrenia have an increased risk not only for schizophrenia but also for schizophrenia spectrum disorders, such as schizotypal personality disorder. A single nucleotide polymorphism (SNP), rs1344706, in the Zinc Finger Protein 804A (ZNF804A) gene, has been implicated in susceptibility to schizophrenia by several genome-wide association studies, follow-up association studies and meta-analyses. This SNP has been shown to affect neuronal connectivities and cognitive abilities. We investigated an association between the ZNF804A genotype of rs1344706 and schizotypal personality traits using the schizotypal Personality Questionnaire (SPQ) in 176 healthy subjects. We also looked for specific associations among ZNF804A polymorphisms and the three factors of schizotypy-cognitive/perceptual, interpersonal and disorganization-assessed by the SPQ. The total score for the SPQ in carriers of the risk T allele was significantly higher than that in individuals with the G/G genotype (p=0.042). For the three factors derived from the SPQ, carriers with the risk T allele showed a higher disorganization factor (p=0.011), but there were no differences in the cognitive/perceptual or interpersonal factors between genotype groups (p>0.30). These results suggest that the genetic variation in ZNF804A might increase susceptibility not only for schizophrenia but also for schizotypal personality traits in healthy subjects. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizotypal |
| 39 | Neurosci. Lett. 2011 May 495: 216-20 |
| PMID | 21457757 |
| Title | Impact on schizotypal personality trait of a genome-wide supported psychosis variant of the ZNF804A gene. |
| Abstract | schizophrenia is a complex disorder with a high heritability. Relatives with schizophrenia have an increased risk not only for schizophrenia but also for schizophrenia spectrum disorders, such as schizotypal personality disorder. A single nucleotide polymorphism (SNP), rs1344706, in the Zinc Finger Protein 804A (ZNF804A) gene, has been implicated in susceptibility to schizophrenia by several genome-wide association studies, follow-up association studies and meta-analyses. This SNP has been shown to affect neuronal connectivities and cognitive abilities. We investigated an association between the ZNF804A genotype of rs1344706 and schizotypal personality traits using the schizotypal Personality Questionnaire (SPQ) in 176 healthy subjects. We also looked for specific associations among ZNF804A polymorphisms and the three factors of schizotypy-cognitive/perceptual, interpersonal and disorganization-assessed by the SPQ. The total score for the SPQ in carriers of the risk T allele was significantly higher than that in individuals with the G/G genotype (p=0.042). For the three factors derived from the SPQ, carriers with the risk T allele showed a higher disorganization factor (p=0.011), but there were no differences in the cognitive/perceptual or interpersonal factors between genotype groups (p>0.30). These results suggest that the genetic variation in ZNF804A might increase susceptibility not only for schizophrenia but also for schizotypal personality traits in healthy subjects. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizotypal |
| 40 | Neurosci. Lett. 2011 May 495: 216-20 |
| PMID | 21457757 |
| Title | Impact on schizotypal personality trait of a genome-wide supported psychosis variant of the ZNF804A gene. |
| Abstract | schizophrenia is a complex disorder with a high heritability. Relatives with schizophrenia have an increased risk not only for schizophrenia but also for schizophrenia spectrum disorders, such as schizotypal personality disorder. A single nucleotide polymorphism (SNP), rs1344706, in the Zinc Finger Protein 804A (ZNF804A) gene, has been implicated in susceptibility to schizophrenia by several genome-wide association studies, follow-up association studies and meta-analyses. This SNP has been shown to affect neuronal connectivities and cognitive abilities. We investigated an association between the ZNF804A genotype of rs1344706 and schizotypal personality traits using the schizotypal Personality Questionnaire (SPQ) in 176 healthy subjects. We also looked for specific associations among ZNF804A polymorphisms and the three factors of schizotypy-cognitive/perceptual, interpersonal and disorganization-assessed by the SPQ. The total score for the SPQ in carriers of the risk T allele was significantly higher than that in individuals with the G/G genotype (p=0.042). For the three factors derived from the SPQ, carriers with the risk T allele showed a higher disorganization factor (p=0.011), but there were no differences in the cognitive/perceptual or interpersonal factors between genotype groups (p>0.30). These results suggest that the genetic variation in ZNF804A might increase susceptibility not only for schizophrenia but also for schizotypal personality traits in healthy subjects. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizotypal |
| 41 | Neuropsychopharmacology 2011 Aug 36: 1871-8 |
| PMID | 21525856 |
| Title | The ZNF804A gene: characterization of a novel neural risk mechanism for the major psychoses. |
| Abstract | schizophrenia and bipolar disorder share genetic risk, brain vulnerability, and clinical symptoms. The ZNF804A risk variant, rs1344706, confers susceptibility for both disorders. This study aimed to identify neural mechanisms common to both schizophrenia and bipolar disorder through this variant's potential effects on cortical thickness, white matter tract integrity, and cognitive function. Imaging, genetics, and cognitive measures were ascertained in 62 healthy adults aged between 18 and 59 years. High-resolution multimodal MRI/DTI imaging was used to measure cortical thickness and major frontotemporal and interhemispheric white matter tracts. The general linear model was used to examine the influence of the ZNF804A rs1344706 risk variant on cortical thickness, white matter tract integrity, and cognitive measures. Individuals homozygous for the risk variant ('A' allele) demonstrated reduced cortical gray matter thickness in the superior temporal gyrus, and in the anterior and posterior cingulate cortices compared with C-allele carriers. No effect of the risk variant on microstructural integrity of white matter tracts was found. Reduced attention control was found in risk allele homozygotes, aligning with findings in the anterior cingulate cortex. Our data provide a novel, genetically based neural risk mechanism for the major psychoses by effects of the ZNF804A risk variant on neural structures and cognitive function susceptible in both disorders. Our findings link genetic, imaging, and cognitive susceptibility relevant to both schizophrenia and bipolar disorder. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizotypal |
| 42 | Biol. Psychiatry 2011 May 69: 914-7 |
| PMID | 21349497 |
| Title | Evidence of sex-modulated association of ZNF804A with schizophrenia. |
| Abstract | The single nucleotide polymorphism (SNP) rs1344706 in ZNF804A (2q32.1) has been associated with schizophrenia in a genome-wide association study (GWAS). A recent candidate gene study, which replicated the positive association with rs1344706, identified another positive SNP (rs7597593) in ZNF804A associated with schizophrenia. We performed an association study of rs7597593 in four GWAS cohorts of European ancestry. Postmortem human brain expression data of normal Caucasian individuals (n = 89) was also analyzed for examining the effect of rs7597593 on ZNF804A messenger RNA expression, using logistic regression and linear regression. We found that rs7597593 was significantly associated with schizophrenia in the combined GWAS datasets (n = 5023, odds ratio [OR](combined) = 1.15, p = .0011). Analysis of stratification by sex showed that the association was driven by the female subjects (OR = 1.29, p = .0002) and was not significant in male subjects (OR = 1.08, p = .148) in the combined sample of four cohorts. A sex by genotype interaction was near significant in both the Genetic Association Information Network sample (p = .0532) and the combined sample of four cohorts (p(combined) = .0531). Gene expression analysis showed no main effects but a significant female-specific association (p(female) = .047, p(male) = .335) and sex by genotype interaction (p = .0166) for rs7597593. Our data suggest a clinical and molecular modulation by sex of the association of ZNF804A SNP rs7597593 and risk of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizotypal |
| 43 | Mol. Psychiatry 2011 Apr 16: 462-70 |
| PMID | 20231838 |
| Title | Effects of a genome-wide supported psychosis risk variant on neural activation during a theory-of-mind task. |
| Abstract | schizophrenia is associated with marked deficits in theory of mind (ToM), a higher-order form of social cognition representing the thoughts, emotions and intentions of others. Altered brain activation in the medial prefrontal cortex and temporo-parietal cortex during ToM tasks has been found in patients with schizophrenia, but the relevance of these neuroimaging findings for the heritable risk for schizophrenia is unclear. We tested the hypothesis that activation of the ToM network is altered in healthy risk allele carriers of the single-nucleotide polymorphism rs1344706 in the gene ZNF804A, a recently discovered risk variant for psychosis with genome-wide support. In all, 109 healthy volunteers of both sexes in Hardy-Weinberg equilibrium for rs1344706 were investigated with functional magnetic resonance imaging during a ToM task. As hypothesised, risk carriers exhibited a significant (P<0.05 false discovery rate, corrected for multiple comparisons) risk allele dose effect on neural activity in the medial prefrontal cortex and left temporo-parietal cortex. Moreover, the same effect was found in the left inferior parietal cortex and left inferior frontal cortex, which are part of the human analogue of the mirror neuron system. In addition, in an exploratory analysis (P<0.001 uncorrected), we found evidence for aberrant functional connectivity between the frontal and temporo-parietal regions in risk allele carriers. To conclude, we show that a dysfunction of the ToM network is associated with a genome-wide supported genetic risk variant for schizophrenia and has promise as an intermediate phenotype that can be mined for the development of biological interventions targeted to social dysfunction in psychiatry. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizotypal |
| 44 | Cell 2012 Apr 149: 525-37 |
| PMID | 22521361 |
| Title | Sequencing chromosomal abnormalities reveals neurodevelopmental loci that confer risk across diagnostic boundaries. |
| Abstract | Balanced chromosomal abnormalities (BCAs) represent a relatively untapped reservoir of single-gene disruptions in neurodevelopmental disorders (NDDs). We sequenced BCAs in patients with autism or related NDDs, revealing disruption of 33 loci in four general categories: (1) genes previously associated with abnormal neurodevelopment (e.g., AUTS2, FOXP1, and CDKL5), (2) single-gene contributors to microdeletion syndromes (MBD5, SATB2, EHMT1, and SNURF-SNRPN), (3) novel risk loci (e.g., CHD8, KIRREL3, and ZNF507), and (4) genes associated with later-onset psychiatric disorders (e.g., TCF4, ZNF804A, PDE10A, GRIN2B, and ANK3). We also discovered among neurodevelopmental cases a profoundly increased burden of copy-number variants from these 33 loci and a significant enrichment of polygenic risk alleles from genome-wide association studies of autism and schizophrenia. Our findings suggest a polygenic risk model of autism and reveal that some neurodevelopmental genes are sensitive to perturbation by multiple mutational mechanisms, leading to variable phenotypic outcomes that manifest at different life stages. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizotypal |
| 45 | Neurosci Biobehav Rev 2012 Jan 36: 556-71 |
| PMID | 21946175 |
| Title | Genome wide association studies (GWAS) and copy number variation (CNV) studies of the major psychoses: what have we learnt? |
| Abstract | schizophrenia (SZ) and bipolar disorder (BPD) have high heritabilities and are clinically and genetically complex. Genome wide association studies (GWAS) and studies of copy number variations (CNV) in SZ and BPD have allowed probing of their underlying genetic risks. In this systematic review, we assess extant genetic signals from published GWAS and CNV studies of SZ and BPD up till March 2011. Risk genes associated with SZ at genome wide significance level (p value<7.2 × 10(-8)) include zinc finger binding protein 804A (ZNF804A), major histocompatibility (MHC) region on chromosome 6, neurogranin (NRGN) and transcription factor 4 (TCF4). Risk genes associated with BPD include ankyrin 3, node of Ranvier (ANK3), calcium channel, voltage dependent, L type, alpha 1C subunit (CACNA1C), diacylglycerol kinase eta (DGKH), gene locus on chromosome 16p12, and polybromo-1 (PBRM1) and very recently neurocan gene (NCAN). Possible common genes underlying psychosis include ZNF804A, CACNA1C, NRGN and PBRM1. The CNV studies suggest that whilst CNVs are found in both SZ and BPD, the large deletions and duplications are more likely found in SZ rather than BPD. The validation of any genetic signal is likely confounded by genetic and phenotypic heterogeneities which are influenced by epistatic, epigenetic and gene-environment interactions. There is a pressing need to better integrate the multiple research platforms including systems biology computational models, genomics, cross disorder phenotyping studies, transcriptomics, proteomics, metabolomics, neuroimaging and clinical correlations in order to get us closer to a more enlightened understanding of the genetic and biological basis underlying these potentially crippling conditions. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizotypal |
| 46 | Front Psychiatry 2012 -1 3: 32 |
| PMID | 22529823 |
| Title | Connectomic intermediate phenotypes for psychiatric disorders. |
| Abstract | Psychiatric disorders are phenotypically heterogeneous entities with a complex genetic basis. To mitigate this complexity, many investigators study so-called intermediate phenotypes (IPs) that putatively provide a more direct index of the physiological effects of candidate genetic risk variants than overt psychiatric syndromes. Magnetic resonance imaging (MRI) is a particularly popular technique for measuring such phenotypes because it allows interrogation of diverse aspects of brain structure and function in vivo. Much of this work however, has focused on relatively simple measures that quantify variations in the physiology or tissue integrity of specific brain regions in isolation, contradicting an emerging consensus that most major psychiatric disorders do not arise from isolated dysfunction in one or a few brain regions, but rather from disturbed interactions within and between distributed neural circuits; i.e., they are disorders of brain connectivity. The recent proliferation of new MRI techniques for comprehensively mapping the entire connectivity architecture of the brain, termed the human connectome, has provided a rich repertoire of tools for understanding how genetic variants implicated in mental disorder impact distinct neural circuits. In this article, we review research using these connectomic techniques to understand how genetic variation influences the connectivity and topology of human brain networks. We highlight recent evidence from twin and imaging genetics studies suggesting that the penetrance of candidate risk variants for mental illness, such as those in SLC6A4, MAOA, ZNF804A, and APOE, may be higher for IPs characterized at the level of distributed neural systems than at the level of spatially localized brain regions. The findings indicate that imaging connectomics provides a powerful framework for understanding how genetic risk for psychiatric disease is expressed through altered structure and function of the human connectome. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizotypal |
| 47 | Schizophr. Res. 2012 Oct 141: 60-4 |
| PMID | 22883350 |
| Title | Experimental validation of candidate schizophrenia gene ZNF804A as target for hsa-miR-137. |
| Abstract | MicroRNAs (miRNAs) are small non-coding RNAs that mainly function as negative regulators of gene expression (Lai, 2002) and have been shown to be involved in schizophrenia etiology through genetic and expression studies (Burmistrova et al., 2007; Hansen et al., 2007a; Perkins et al., 2007; Beveridge et al., 2010; Kim et al., 2010). In a mega analysis of genome-wide association study (GWAS) of schizophrenia (SZ) and bipolar disorders (BP), a polymorphism (rs1625579) located in the primary transcript of a miRNA gene, hsa-miR-137, was reported to be strongly associated with SZ. Four SZ loci (CACNA1C, TCF4, CSMD1, C10orf26) achieving genome-wide significance in the same study were predicted and later experimentally validated (Kwon et al., 2011) as hsa-miR-137 targets. Here, using in silico, cellular and luciferase based approaches we also provide evidence that another well replicated candidate schizophrenia gene, ZNF804A, is also target for hsa-miR-137. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizotypal |
| 48 | Schizophr. Res. 2012 Nov 141: 277-8 |
| PMID | 23010486 |
| Title | Expression analysis of a novel mRNA variant of the schizophrenia risk gene ZNF804A. |
| Abstract | -1 |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizotypal |
| 49 | Biol. Psychiatry 2012 Oct 72: 620-8 |
| PMID | 22883433 |
| Title | Genome-wide association study implicates HLA-C*01:02 as a risk factor at the major histocompatibility complex locus in schizophrenia. |
| Abstract | We performed a genome-wide association study (GWAS) to identify common risk variants for schizophrenia. The discovery scan included 1606 patients and 1794 controls from Ireland, using 6,212,339 directly genotyped or imputed single nucleotide polymorphisms (SNPs). A subset of this sample (270 cases and 860 controls) was subsequently included in the Psychiatric GWAS Consortium-schizophrenia GWAS meta-analysis. One hundred eight SNPs were taken forward for replication in an independent sample of 13,195 cases and 31,021 control subjects. The most significant associations in discovery, corrected for genomic inflation, were (rs204999, p combined = 1.34 × 10(-9) and in combined samples (rs2523722 p combined = 2.88 × 10(-16)) mapped to the major histocompatibility complex (MHC) region. We imputed classical human leukocyte antigen (HLA) alleles at the locus; the most significant finding was with HLA-C*01:02. This association was distinct from the top SNP signal. The HLA alleles DRB1*03:01 and B*08:01 were protective, replicating a previous study. This study provides further support for involvement of MHC class I molecules in schizophrenia. We found evidence of association with previously reported risk alleles at the TCF4, VRK2, and ZNF804A loci. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizotypal |
| 50 | Mol. Psychiatry 2012 Dec 17: 1155-7 |
| PMID | 22270476 |
| Title | Schizophrenia risk gene ZNF804A does not influence macroscopic brain structure: an MRI study in 892 volunteers. |
| Abstract | -1 |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizotypal |
| 51 | Transl Psychiatry 2012 -1 2: e136 |
| PMID | 22781169 |
| Title | Evidence for the involvement of ZNF804A in cognitive processes of relevance to reading and spelling. |
| Abstract | Previous studies have shown that individuals with schizophrenia and dyslexia display common neurocognitive abnormalities. The aim of the present study was to determine whether known schizophrenia-risk genes contribute to dyslexia risk or to disease-relevant cognitive functions. For this purpose, we genotyped the schizophrenia-associated risk variants within zinc-finger protein 804A (ZNF804A), transcription-factor 4 and neurogranin in a large dyslexia case-control sample. We tested all variants for association with dyslexia (927 cases, 1096 controls), and with eight language-relevant cognitive processes (1552 individuals). We observed six significant associations between language-relevant traits and the ZNF804A-variant rs1344706. Interestingly, the ZNF804A schizophrenia risk variant was associated with a better cognitive performance in our data set. This finding might be consistent with a previously reported ZNF804A association in schizophrenia, in which patients carrying the schizophrenia-risk allele at rs1344706 showed a better performance in two memory tests. In conclusion, the present study provides evidence that ZNF804A might have a role in cognitive traits of relevance to reading and spelling, and underlines the phenotypic complexity that might be associated with ZNF804A. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizotypal |
| 52 | Mol. Psychiatry 2012 Feb 17: 118-9 |
| PMID | 21876541 |
| Title | ZNF804A and social cognition in patients with schizophrenia and healthy controls. |
| Abstract | -1 |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizotypal |
| 53 | Genet Test Mol Biomarkers 2012 Sep 16: 1135-7 |
| PMID | 22775511 |
| Title | ZNF804A rs1344706 variant and schizophrenia in a Romanian population from Cluj Napoca. |
| Abstract | The ZNF804A rs1344706 variant was the first risk factor to be identified through genome-wide association studies and follow-up studies with meta-analysis for schizophrenia as well as bipolar disorders; we investigated 231 schizophrenia and 222 controls to see whether this particular variant was associated with schizophrenia in a Romanian population from Cluj Napoca. Clearly, there was no association between the ZNF804A rs1344706 variant and schizophrenia. Our study provides evidence for those that found no association with schizophrenia. A surprising result of our study was that the T allele frequency is the highest, thus far among the ethnic groups studied. We used a PCR-RFLP method that had been recently developed in our laboratory to the genotype ZNF804A rs1344706 variant. In conclusion, the ZNF804A rs1344706 variant was not associated with schizophrenia in the Romanian population from Cluj Napoca (?(2)=0.734, p=0.693). |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizotypal |
| 54 | PLoS ONE 2012 -1 7: e32404 |
| PMID | 22384243 |
| Title | ZNF804a regulates expression of the schizophrenia-associated genes PRSS16, COMT, PDE4B, and DRD2. |
| Abstract | ZNF804A was identified by a genome-wide association study (GWAS) in which a single nucleotide polymorphism (SNP rs1344706) in ZNF804A reached genome-wide statistical significance for association with a combined diagnosis of schizophrenia (SZ) and bipolar disorder. Although the molecular function of ZNF804A is unknown, the amino acid sequence is predicted to contain a C2H2-type zinc-finger domain and suggests ZNF804A plays a role in DNA binding and transcription. Here, we confirm that ZNF804A directly contributes to transcriptional control by regulating the expression of several SZ associated genes and directly interacts with chromatin proximal to the promoter regions of PRSS16 and COMT, the two genes we find upregulated by ZNF804A. Using immunochemistry we establish that ZNF804A is localized to the nucleus of rat neural progenitor cells in culture and in vivo. We demonstrate that expression of ZNF804A results in a significant increase in transcript levels of PRSS16 and COMT, relative to GFP transfected controls, and a statistically significant decrease in transcript levels of PDE4B and DRD2. Furthermore, we show using chromatin immunoprecipitation assays (ChIP) that both epitope-tagged and endogenous ZNF804A directly interacts with the promoter regions of PRSS16 and COMT, suggesting a direct upregulation of transcription by ZNF804A on the expression of these genes. These results are the first to confirm that ZNF804A regulates transcription levels of four SZ associated genes, and binds to chromatin proximal to promoters of two SZ genes. These results suggest a model where ZNF804A may modulate a transcriptional network of SZ associated genes. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizotypal |
| 55 | Hum. Mol. Genet. 2012 Mar 21: 1018-24 |
| PMID | 22080834 |
| Title | Knockdown of the psychosis susceptibility gene ZNF804A alters expression of genes involved in cell adhesion. |
| Abstract | Genome-wide association studies have convincingly implicated several novel genes in susceptibility to schizophrenia and bipolar disorder. The first genome-wide significant association with the broad phenotype of psychosis was with a polymorphism in the ZNF804A gene. However, the biological function(s) of ZNF804A have, to date, been entirely unknown. In this study, we manipulated the expression of ZNF804A in neural progenitor cells derived from human cortical neuroepithelium and assessed its effects on the cellular transcriptome. Gene ontology analysis of differentially expressed genes indicated a significant effect of ZNF804A knockdown on the expression of genes involved in cell adhesion, suggesting a role for ZNF804A in processes such as neural migration, neurite outgrowth and synapse formation. Several highly significant gene expression changes were confirmed in repeat cell culture experiments. Most consistent gene expression changes were seen for C2ORF80, a gene of as-yet-unknown function, and STMN3, a gene involved in neurite outgrowth and axonal and dendritic branching. These data, generated in a hypothesis-free manner, provide a basis for more targeted investigations of ZNF804A function. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizotypal |
| 56 | Arch. Gen. Psychiatry 2012 Sep 69: 885-92 |
| PMID | 22945618 |
| Title | Influence of ZNF804a on brain structure volumes and symptom severity in individuals with schizophrenia. |
| Abstract | CONTEXT The single-nucleotide polymorphism rs1344706 in the gene ZNF804A has been associated with schizophrenia and with quantitative phenotypic features, including brain structure volume and the core symptoms of schizophrenia. OBJECTIVE To evaluate associations of rs1344706 with brain structure and the core symptoms of schizophrenia. DESIGN Case-control analysis of covariance. SETTING University-based research hospital. PARTICIPANTS Volunteer sample of 335 individuals with schizophrenia spectrum disorders (306 with core schizophrenia) and 198 healthy volunteers. MAIN OUTCOME MEASURES Cerebral cortical gray matter and white matter (WM) volumes (total and frontal, parietal, temporal, and occipital lobes), lateral ventricular cerebrospinal fluid volume, and symptom severity from the Scale for the Assessment of Negative Symptoms and the Scale for the Assessment of Positive Symptoms divided into 3 domains: psychotic, negative, and disorganized. RESULTS The rs1344706 genotype produced significant main effects on total, frontal, and parietal lobe WM volumes (F = 3.98, P = .02; F = 4.95, P = .007; and F = 3.08, P = .05, respectively). In the schizophrenia group, rs1344706 produced significant simple effects on total (F = 3.93, P = .02) and frontal WM volumes (F = 7.16, P < .001) and on psychotic symptom severity (F = 6.07, P = .003); the pattern of effects was concordant with risk allele carriers having larger volumes and more severe symptoms of disease than nonrisk homozygotes. In the healthy volunteer group, risk allele homozygotes had increased total WM volume compared with nonrisk allele carriers (F = 4.61, P = .03), replicating a previously reported association. CONCLUSIONS A growing body of evidence suggests that the risk allele of rs1347706 is associated with a distinctive set of phenotypic features in healthy volunteers and individuals with schizophrenia. Our study supports this assertion by finding that specific genotypes of the polymorphism are associated with brain structure volumes in individuals with schizophrenia and healthy volunteers and with symptom severity in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizotypal |
| 57 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2012 Oct 159B: 794-802 |
| PMID | 22887939 |
| Title | ZNF804A and schizophrenia susceptibility in Asian populations. |
| Abstract | ZNF804A, a recently identified risk gene for schizophrenia, has been extensively investigated and the principle finding for this locus has been the association with SNP rs1344706 in populations of European ancestries. However, in Asian populations, only a few studies have been conducted for rs1344706 and the results were inconsistent. Here, we studied rs1344706 and schizophrenia susceptibility in multiple Asian case-control samples (10 Chinese and 2 Japanese samples; N?=?21,062), and the meta-analyses indicated non-significant association of rs1344706 with schizophrenia (P?=?0.26), suggesting the same SNP identified in European samples is not predisposing risk in Asians. Further genotyping and association analyses of a set of SNPs spanning the entire genomic region of ZNF804A (520?kb) identified no association except for SNP rs359895 (P?=?7.8?x?10(-5) , N?=?5,172), a newly reported risk SNP located in the ZNF804A promoter region with functional implications. This suggests that ZNF804A may also contribute to schizophrenia susceptibility in Asians although the risk SNP is different from that in Europeans, and it was supported by the detected up-regulation of ZNF804A mRNA expression in the blood cells of Chinese schizophrenia patients compared with normal controls (P?=?0.004). Additionally, the linkage disequilibrium (LD) structure analyses using data from HapMap indicated distinct LD blocks across ZNF804A between Chinese and Europeans, which may explain the different association patterns between them, and also highlight the compounding difficulty of genetic studies of complex diseases like schizophrenia when studying multiple ethnic populations. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizotypal |
| 58 | Eur Arch Psychiatry Clin Neurosci 2012 Apr 262: 193-7 |
| PMID | 21892778 |
| Title | The schizophrenia risk gene ZNF804A influences the antipsychotic response of positive schizophrenia symptoms. |
| Abstract | Genetic factors determining the response to antipsychotic treatment in schizophrenia are poorly understood. A new schizophrenia susceptibility gene, the zinc-finger gene ZNF804A, has recently been identified. To assess the pharmacogenetic importance of this gene, we treated 144 schizophrenia patients and assessed the response of positive and negative symptoms by PANSS. Patients homozygous for the ZNF804A risk allele for schizophrenia (rs1344706 AA) showed poorer improvement of positive symptoms (7.35 ± 0.46) compared to patients with a protective allele (9.41 ± 0.71, P = 0.022). This provides further evidence that ZNF804A is of functional relevance to schizophrenia and indicates that ZNF804A may be a novel target for pharmacological interventions. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizotypal |
| 59 | Am J Psychiatry 2012 Dec 169: 1301-8 |
| PMID | 23212061 |
| Title | Evidence that schizophrenia risk variation in the ZNF804A gene exerts its effects during fetal brain development. |
| Abstract | The single-nucleotide polymorphism rs1344706, located within an intron of the ZNF804A gene, exhibits genome-wide significant association with schizophrenia. Although genotype at rs1344706 is associated with altered functional brain connectivity, the molecular mechanisms mediating its association with schizophrenia have not been clearly defined. Given its location in noncoding sequence, the authors tested association between rs1344706 and ZNF804A expression in adult and fetal human brain. Highly quantitative measures of relative allelic expression were used to assess the effect of rs1344706 genotype on the mRNA expression of ZNF804A in the dorsolateral prefrontal cortex, hippocampus, and substantia nigra of the adult human brain and in human brain tissue from the first and second trimester of gestation. Genotype at rs1344706 had no significant effect on the regulation of ZNF804A in any of the three adult brain regions examined. In contrast, rs1344706 genotype had a significant effect on ZNF804A allelic expression in second-trimester fetal brain, with the schizophrenia risk (T) allele associated with reduced ZNF804A expression. The T allele of rs1344706 is associated with a relative decrease in ZNF804A expression during the second trimester of fetal brain development. These data provide evidence for a schizophrenia risk mechanism that is operational in (and possibly specific to) the fetal brain. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizotypal |
| 60 | Compr Psychiatry 2012 Oct 53: 1044-8 |
| PMID | 22425527 |
| Title | Association analysis of ZNF804A (zinc finger protein 804A) rs1344706 with therapeutic response to atypical antipsychotics in first-episode Chinese patients with schizophrenia. |
| Abstract | `The single-nucleotide polymorphism rs1344706 located in the ZNF804A zinc finger protein 804A gene is a well-established genome-wide significant variant for schizophrenia. The aim of this study was to investigate the potential association between this ZNF804A polymorphism and treatment response to atypical antipsychotic. Seventy-one first-episode inpatients with schizophrenia receiving olanzapine, aripiprazole, or quetiapine monotherapy were enrolled. Symptom response to treatment was assessed using the Positive and Negative Syndrome Scale (PANSS) on admission and reassessed after 4 weeks of treatment. Single-nucleotide polymorphism rs1344706 was genotyped by direct sequencing. There was substantial difference in treatment response among patients with 3 different genotypes regarding total PANSS score and positive subscore (for total PANSS score, F = 4.608, df = 2, P = .013; for positive subscore, F = 4.183, df = 2, P = .019). Compared with G homozygotes, T carriers showed significantly less improvement in total PANSS score as well as positive subscore (for total PANSS score, F = 8.724, df = 1, P = .004; for positive subscore, F = 9.392, df = 1, P = .005). Our results suggest that ZNF80A rs1344706 polymorphism may play a role in treatment response to atypical antipsychotic, although replication is required to confirm this finding. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizotypal |
| 61 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2012 Apr 159B: 255-62 |
| PMID | 22328493 |
| Title | Genome-wide supported psychosis risk variant in ZNF804A gene and impact on cortico-limbic WM integrity in schizophrenia. |
| Abstract | Genome-wide association, case association genetic and meta-analytic studies have highlighted ZNF804A as a robust genome-wide supported susceptibility gene for schizophrenia (SCZ). In view of the possible involvement of ZNF804A gene in early neurodevelopment and cellular processes including oligodendrocyte proliferation and differentiation, we examined the effect of ZNF804A on brain WM (WM) integrity in patients with SCZ. Based on extant data in healthy controls (HC), we hypothesized that ZNF804A risk variant rs1344706 is associated with lower fractional anisotropy (FA) in brain regions within cortico-limbic circuits, namely frontal, parietal, medial temporal lobes, and cingulate gyri in SCZ. A total of 200 Chinese participants (125 patients with DSM-IV diagnosis of SCZ and 75 controls) were genotyped using blood samples, a subset of 153 participants (89 patients with DSM-IV diagnosis of SCZ and 64 controls) underwent structural magnetic resonance imaging and diffusion tensor imaging (DTI). There are significant effects of diagnosis (left cingulate gyrus: Adjusted F(1,149) ?=?9.36, P?=?0.003) and diagnosis-genotype interactions (left parietal lobe: Adjusted F(1,147) ?=?7.39, P?=?0.007; right parietal lobe: Adjusted F(1,147) ?=?6.95, P?=?0.009; right medial temporal lobe: Adjusted F(1,147) ?=?8.79, P?=?0.004; left cingulate gyrus: Adjusted F(1,147) ?=?8.02, P?=?0.005). Specifically, we found that patients with SCZ who are risk T homozygotes have lower FA in bilateral parietal lobes, and left cingulate gyrus compared with G carriers. Compared with risk T homozygotes in HC, patients with SCZ who are risk T homozygotes have decreased FA in bilateral parietal lobes, and left cingulate gyrus as well as right medial temporal lobe. Our findings suggest that ZNF804A risk variant influence WM integrity involving cortico-limbic brain regions in SCZ and highlight the importance of investigating the impact of genome-wide supported risk factors on intermediate phenotypes with potential to shed light on the neurobiology of SCZ. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizotypal |
| 62 | Genet Test Mol Biomarkers 2012 Mar 16: 157-61 |
| PMID | 21988329 |
| Title | A polymerase chain reaction-restriction fragment length polymorphism method for screening ZNF804A gene polymorphism (rs1344706) in patients with schizophrenia: a significant association. |
| Abstract | The original ZNF804A rs1344706 risk variant was identified through genome-wide association studies as a risk factor for schizophrenia. Follow-up studies involving meta-analysis have confirmed that rs1344706 is a risk factor for schizophrenia as well as bipolar disorders. We describe here a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method to genotype ZNF804A rs1344706 variant in patients with schizophrenia. We generated a 220 bp fragment through PCR and subsequently cleaved it by the restriction endonuclease BsaBI, creating two fragments of 114 and 106 bp. Upon change in the nucleotide from T to G, the 106 bp fragment is further cleaved by BsaBI, thus creating two fragments of 87 and 19 bp. As a result, when the 220 bp fragment is cleaved by BsaBI restriction endonuclease, the TT genotype yields two fragments of 114 and 106 bp, and TG genotype four fragments of 114, 106, 87, and 19 bp, and the GG genotype three fragments of 114, 87, and 19 bp. Thus, this is a simple, fast, and cost-effective method to genotype the ZNF804A rs1344706 risk variant. Using this method, we were able to replicate an association between ZNF804A rs1344706 variant and schizophrenia in a Turkish population. Stratification analysis of the population according to the gender showed an association that was statistically significant among overall schizophrenia and male schizophrenia and the risk T allele and TT genotype of the ZNF804A gene. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizotypal |
| 63 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2012 Jan 36: 122-7 |
| PMID | 21911029 |
| Title | Association of the ZNF804A gene polymorphism rs1344706 with white matter density changes in Chinese schizophrenia. |
| Abstract | ZNF804A gene polymorphism rs1344706, the first genetic risk variant to achieve genome wide significance for schizophrenia, has been linked to neural functional connectivity. Dysconnectivity of WM may be the primary pathological mechanism of schizophrenia. Association of this variant with regional WM density has not been investigated in schizophrenic patients. 69 healthy controls and 80 patients with schizophrenia underwent genotyping of rs1344706 SNPs, and were examined for WM density (T1-weighted MRI). The association of rs1344706 with WM changes in schizophrenia patients and healthy controls was analyzed using a full-factorial 2×2 analysis of variance. 1. There was an interaction on WM density in the left prefrontal lobe between the rs1344706 genotype and schizophrenic diagnosis, where the risk T allele carriers presented higher WM density in the schizophrenia patients and lower WM density in healthy controls in comparison with the non-risk allele carriers. 2. The risk allele was associated with an increased WM density of the bilateral hippocampus in both the patients and the healthy group. The influence of antipsychotics to the white matter in schizophrenic patients was not fully eliminated. The ZNF804A variant may confer risk for schizophrenia by exerting its effects on the WM in the left prefrontal lobe together with other risk factors for schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizotypal |
| 64 | Magn Reson Imaging 2012 Dec 30: 1373-80 |
| PMID | 22840435 |
| Title | An investigation of a genomewide supported psychosis variant in ZNF804A and white matter integrity in the human brain. |
| Abstract | ZNF804A, a genomewide supported susceptibility gene for schizophrenia and bipolar disorder, has been associated with task-independent functional connectivity between the left and right dorsolateral prefrontal cortices. Several lines of evidence have converged on the hypothesis that this effect may be mediated by structural connectivity. We tested this hypothesis using diffusion tensor magnetic resonance imaging in three samples: one German sample of 50 healthy individuals, one Scottish sample of 83 healthy individuals and one Scottish sample of 84 unaffected relatives of bipolar patients. Voxel-based analysis and tract-based spatial statistics did not detect any fractional anisotropy (FA) differences between minor allele carriers and individuals homozygous for the major allele at rs1344706. Similarly, region-of-interest analyses and quantitative tractography of the genu of the corpus callosum revealed no significant FA differences between the genotype groups. Examination of effect sizes and confidence intervals indicated that this negative finding is very unlikely to be due to a lack of statistical power. In summary, despite using various analysis techniques in three different samples, our results were strikingly and consistently negative. These data therefore suggest that it is unlikely that the effects of genetic variation at rs1344706 on functional connectivity are mediated by structural integrity differences in large, long-range white matter fiber connections. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizotypal |
| 65 | Neuropsychobiology 2012 -1 66: 158-66 |
| PMID | 22948380 |
| Title | Less cognitive and neurological deficits in schizophrenia patients carrying risk variant in ZNF804A. |
| Abstract | The rs1344706 single nucleotide polymorphism in the ZNF804A gene is a common variant with strong evidence for association with schizophrenia. Recent studies show an association of rs1344706 with cognitive functioning, and there is some evidence suggesting that the risk allele may increase susceptibility for a subtype of schizophrenia with relatively spared cognition. We tested the effect of rs1344706 genotype in 89 schizophrenia patients on 3 basic cognitive domains (working memory, processing speed and attention) shown to be severely impaired in schizophrenia. Also we investigated the effect of rs1344706 on the severity of neurological soft signs, subtle impairments in motor and sensory functions highly frequent in schizophrenia patients. Neurological soft signs and cognitive deficits are central features of schizophrenia and are tightly linked with clinical, social and functional outcome. Our results show an association of higher rs1344706 risk allele load with improved performance on processing speed and with fewer neurological soft signs. Together with other studies, our findings suggest that ZNF804A is associated with a subtype of schizophrenia with better cognitive and neurological functioning. Discovery of the specific pathways through which ZNF804A is exerting this effect may lead to better prevention, diagnosis and treatment for a specific group of schizophrenia patients. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizotypal |
| 66 | Schizophr. Res. 2012 Oct 141: 40-7 |
| PMID | 22871346 |
| Title | Further evidence for the association of genetic variants of ZNF804A with schizophrenia and a meta-analysis for genome-wide significance variant rs1344706. |
| Abstract | Recent accumulating evidence has indicated that ZNF804A (zinc finger protein 804A) may be one of the most robustly implicated genes in schizophrenia. In this report, we examined ZNF804A single nucleotide polymorphisms (SNPs) encompassing exon 4 by performing an association study that used a Han Chinese sample comprised of 492 schizophrenia patients and 516 healthy control subjects. A meta-analysis based on previous studies was also performed. For markers rs4667000 and rs1366842, significant differences in allele frequencies were found between cases and controls (Mantel-Haenszel corrected P=0.014 and P=0.025, respectively). Analysis of haplotype rs61739290-rs1366842 showed significant association with schizophrenia (global P=0.0018). Moreover, several other two-, three-, and four-SNP tests of haplotype association were also significant. A meta-analysis comprised of studies that utilized sample sets of either European and/or Han Chinese origin revealed statistically significant associations for two SNPs (rs1366842, P=0.002; and rs3731834, P=0.03) and schizophrenia. In addition, we observed a significant association between marker rsl344706 and schizophrenia (P<1.0×10(-5)) in combined populations. When we separately analyzed the studies by population, consistent and significant differences were found between cases and controls both in the European samples (P<1.0×10(-4)) and in the Chinese samples (P=0.03). In summary, we have added new evidence supporting the association between ZNF804A and schizophrenia in our Han Chinese sample. Further functional exploration of ZNF804A will greatly help us to elucidate the pathogenesis of schizophrenia and find promising new approaches for the treatment of this disorder. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizotypal |
| 67 | Neuropsychopharmacology 2012 Jun 37: 1572-8 |
| PMID | 22373944 |
| Title | Evidence of IQ-modulated association between ZNF804A gene polymorphism and cognitive function in schizophrenia patients. |
| Abstract | ZNF804A gene polymorphism rs1344706 has been suggested as the most compelling case of a candidate gene for schizophrenia by a genome-wide association study and several replication studies. The current study of 570 schizophrenia patients and 448 controls again found significantly different genotype frequencies of rs1344706 between patients and controls. More important, we found that this association was modulated by IQ, with a stronger association among individuals with relatively high IQ, which replicated results of Walters et al, 2010. We further examined whether this IQ-modulated association also existed between the SNP and the intermediate phenotypes (working memory and executive functions) of schizophrenia. Data were available from an N-back task (366 patients and 414 controls) and the attention network task (361 patients and 416 controls). We found that the SNP and IQ had significant interaction effects on the intermediate phenotypes for patients, but not for controls. The disease risk allele was associated with poorer cognitive function in patients with high IQ, but better cognitive function in patients with low IQ. Together, these results indicated that IQ may modulate the role of rs1344706 in the etiology of both schizophrenia and its cognitive impairments, and pointed to the necessity of considering general cognitive function as indexed by IQ in the future studies of genetic bases of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizotypal |
| 68 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2012 Jan 36: 122-7 |
| PMID | 21911029 |
| Title | Association of the ZNF804A gene polymorphism rs1344706 with white matter density changes in Chinese schizophrenia. |
| Abstract | ZNF804A gene polymorphism rs1344706, the first genetic risk variant to achieve genome wide significance for schizophrenia, has been linked to neural functional connectivity. Dysconnectivity of WM may be the primary pathological mechanism of schizophrenia. Association of this variant with regional WM density has not been investigated in schizophrenic patients. 69 healthy controls and 80 patients with schizophrenia underwent genotyping of rs1344706 SNPs, and were examined for WM density (T1-weighted MRI). The association of rs1344706 with WM changes in schizophrenia patients and healthy controls was analyzed using a full-factorial 2×2 analysis of variance. 1. There was an interaction on WM density in the left prefrontal lobe between the rs1344706 genotype and schizophrenic diagnosis, where the risk T allele carriers presented higher WM density in the schizophrenia patients and lower WM density in healthy controls in comparison with the non-risk allele carriers. 2. The risk allele was associated with an increased WM density of the bilateral hippocampus in both the patients and the healthy group. The influence of antipsychotics to the white matter in schizophrenic patients was not fully eliminated. The ZNF804A variant may confer risk for schizophrenia by exerting its effects on the WM in the left prefrontal lobe together with other risk factors for schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizotypal |
| 69 | Schizophr. Res. 2013 May 146: 273-8 |
| PMID | 23434502 |
| Title | The regulation of gene expression involved in TGF-? signaling by ZNF804A, a risk gene for schizophrenia. |
| Abstract | ZNF804A has been implicated in susceptibility to schizophrenia by several genome-wide association studies (GWAS), follow-up association studies and meta-analyses. However, the biological functions of ZNF804A are not entirely understood. To identify the genes that are affected by ZNF804A, we manipulated the expression of the ZNF804A protein in HEK293 human embryonic kidney cell lines and performed a cDNA microarray analysis followed by qPCR. We found that ZNF804A-overexpression up-regulated four genes (ANKRD1, INHBE, PIK3AP1, and DDIT3) and down-regulated three genes (CLIC2, MGAM, and BIRC3). Furthermore, we confirmed that the expression of ANKRD1, PIK3AP1, INHBE and DDIT3 at the protein level was significantly increased by ZNF804A-overexpression. This is the first report to identify genes whose protein expressions are regulated by ZNF804A. ANKRD1, PIK3AP1, INHBE and DDIT3 are related to transforming growth factor-? (TGF-?) signaling, which plays a crucial role in cell growth and differentiation. On the other hand, recent studies have reported that TGF-? signaling is associated with schizophrenia. These results provide basis for a more progressive investigation of ZNF804A contributions to the susceptibility or pathophysiology of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizotypal |
| 70 | Schizophr. Res. 2013 Sep 149: 188-9 |
| PMID | 23815973 |
| Title | Meta-analysis supports association of a non-synonymous SNP in ZNF804A with schizophrenia. |
| Abstract | -1 |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizotypal |
| 71 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2013 Jan 162B: 71-2 |
| PMID | 23184508 |
| Title | ZNF804A and schizophrenia: An open peer commentary. |
| Abstract | -1 |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizotypal |
| 72 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2013 Jan 162B: 73-4 |
| PMID | 23184487 |
| Title | Reply to: ZNF804A and schizophrenia: An open peer commentary. |
| Abstract | -1 |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizotypal |
| 73 | J Psychiatr Res 2013 Sep 47: 1215-21 |
| PMID | 23786914 |
| Title | Analysis of miR-137 expression and rs1625579 in dorsolateral prefrontal cortex. |
| Abstract | MicroRNAs (miRNAs) are small non-coding RNAs that act as potent regulators of gene expression. A recent GWAS reported the rs1625579 SNP, located downstream of miR-137, as the strongest new association with schizophrenia [Ripke S, Sanders AR, Kendler KS, Levinson DF, Sklar P, Holmans PA, et al. Genome-wide association study identifies five new schizophrenia loci. Nat Genet 2011;43:969-76.]. Prior to this GWAS finding, a schizophrenia imaging-genetic study found miR-137 target genes significantly enriched for association with activation in the dorsolateral prefrontal cortex (DLPFC) [Potkin SG, Macciardi F, Guffanti G, Fallon JH, Wang Q, Turner JA, et al. Identifying gene regulatory networks in schizophrenia. Neuroimage 2010;53:839-47.]. We investigated the expression levels of miR-137 and three candidate target genes (ZNF804A, CACNA1C, TCF4) in the DLPFC of postmortem brain tissue from 2 independent cohorts: (1) 26 subjects (10 control (CTR), 7 schizophrenia (SZ), 9 bipolar disorder (BD)) collected at the UCI brain bank; and (2) 99 subjects (33 CTR, 35 SZ, 31 BD) obtained from the Stanley Medical Research Institute (SMRI). MiR-137 expression in the DLPFC did not differ between diagnoses. We also explored the relationship between rs1625579 genotypes and miR-137 expression. Significantly lower miR-137 expression levels were observed in the homozygous TT subjects compared to TG and GG subjects in the control group (30% decrease, p-value = 0.03). Moreover, reduced miR-137 levels in TT subjects corresponded to increased levels of the miR-137 target gene TCF4. The miR-137 expression pattern in 9 brain regions was significant for regional effect (ANOVA p-value = 1.83E-12), with amygdala and hippocampus having the highest miR-137 expression level. In conclusion, decreased miR-137 expression is associated with the SZ risk allele of rs1625579, and potential regulation of TCF4, another SZ candidate gene. This study offers additional support for involvement of miR-137 and downstream targets as mechanisms of risk for psychiatric disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizotypal |
| 74 | Front Genet 2013 -1 4: 58 |
| PMID | 23637704 |
| Title | Potential Impact of miR-137 and Its Targets in Schizophrenia. |
| Abstract | The significant impact of microRNAs (miRNAs) on disease pathology is becoming increasingly evident. These small non-coding RNAs have the ability to post-transcriptionally silence the expression of thousands of genes. Therefore, dysregulation of even a single miRNA could confer a large polygenic effect. schizophrenia is a genetically complex illness thought to involve multiple genes each contributing a small risk. Large genome-wide association studies identified miR-137, a miRNA shown to be involved in neuronal maturation, as one of the top risk genes. To assess the potential mechanism of impact of miR-137 in this disorder and identify its targets, we used a combination of literature searches, ingenuity pathway analysis (IPA), and freely accessible bioinformatics resources. Using TargetScan and the schizophrenia gene resource (SZGR) database, we found that in addition to CSMD1, C10orf26, CACNA1C, TCF4, and ZNF804A, five schizophrenia risk genes whose transcripts are also validated miR-137 targets, there are other schizophrenia-associated genes that may be targets of miR-137, including ERBB4, GABRA1, GRIN2A, GRM5, GSK3B, NRG2, and HTR2C. IPA analyses of all the potential targets identified several nervous system (NS) functions as the top canonical pathways including synaptic long-term potentiation, a process implicated in learning and memory mechanisms and recently shown to be altered in patients with schizophrenia. Among the subset of targets involved in NS development and function, the top scoring pathways were ephrin receptor signaling and axonal guidance, processes that are critical for proper circuitry formation and were shown to be disrupted in schizophrenia. These results suggest that miR-137 may indeed play a substantial role in the genetic etiology of schizophrenia by regulating networks involved in neural development and brain function. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizotypal |
| 75 | Schizophr Bull 2013 May 39: 518-26 |
| PMID | 22499782 |
| Title | Brain vs behavior: an effect size comparison of neuroimaging and cognitive studies of genetic risk for schizophrenia. |
| Abstract | Genetic variants associated with increased risk for schizophrenia (SZ) are hypothesized to be more penetrant at the level of brain structure and function than at the level of behavior. However, to date the relative sensitivity of imaging vs cognitive measures of these variants has not been quantified. We considered effect sizes associated with cognitive and imaging studies of 9 robust SZ risk genes (DAOA, DISC1, DTNBP1, NRG1, RGS4, NRGN, CACNA1C, TCF4, and ZNF804A) published between January 2005-November 2011. Summary data was used to calculate estimates of effect size for each significant finding. The mean effect size for each study was categorized as small, medium, or large and the relative frequency of each category was compared between modalities and across genes. Random effects meta-analysis was used to consider the impact of experimental methodology on effect size. Imaging studies reported mostly medium or large effects, whereas cognitive investigations commonly reported small effects. Meta-analysis confirmed that imaging studies were associated with larger effects. Effect size estimates were negatively correlated with sample size but did not differ as a function of gene nor imaging modality. These observations support the notion that SZ risk variants show larger effects, and hence greater penetrance, when characterized using indices of brain structure and function than when indexed by cognitive measures. However, it remains to be established whether this holds true for individual risk variants, imaging modalities, or cognitive functions, and how such effects may be mediated by a relationship with sample size and other aspects of experimental variability. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizotypal |
| 76 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2013 Oct 46: 64-9 |
| PMID | 23778016 |
| Title | Genetic analysis of common variants in the CMYA5 (cardiomyopathy-associated 5) gene with schizophrenia. |
| Abstract | 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. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizotypal |
| 77 | Psychiatry Res 2013 May 212: 154-7 |
| PMID | 23562677 |
| Title | ZNF804A and cortical thickness in schizophrenia and bipolar disorder. |
| Abstract | ZNF804A SNP rs1344706 confers genome-wide risk for schizophrenia and bipolar disorder. Both disorders affect cortical thickness. To determine if single nucleotide polymorphisms (SNPs) across ZNF804A are associated with cortical thinning, we investigated 63 SNPs (including rs1344706) in 365 psychosis patients and healthy controls. Results show no significant associations. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizotypal |
| 78 | Schizophr Bull 2013 Nov 39: 1252-60 |
| PMID | 23155182 |
| Title | Variation in psychosis gene ZNF804A is associated with a refined schizotypy phenotype but not neurocognitive performance in a large young male population. |
| Abstract | Genetic variability within the ZNF804A gene has been recently found to be associated with schizophrenia and bipolar disorder, although the pathways by which this gene may confer risk remain largely unknown. We set out to investigate whether common ZNF804A variants affect psychosis-related intermediate phenotypes such as cognitive performance dependent on prefrontal and frontotemporal brain function, schizotypal traits, and attenuated psychotic experiences in a large young male population. Association analyses were performed using all 4 available self-rated schizotypy questionnaires and cognitive data retrospectively drawn from the Athens Study of Psychosis Proneness and Incidence of schizophrenia (ASPIS). DNA samples from 1507 healthy young men undergoing induction to military training were genotyped for 4 previously studied polymorphic markers in the ZNF804A gene locus. Single-marker analysis revealed significant associations between 2 recently identified candidate schizophrenia susceptibility variants (rs1344706 and rs7597593) and a refined positive schizotypy phenotype characterized primarily by self-rated paranoia/ideas of reference. Nominal associations were noted with all positive, but not negative, schizotypy related factors. ZNF804A genotype effect on paranoia was confirmed at the haplotype level. No significant associations were noted with central indexes of sustained attention or working memory performance. In this study, ZNF804A variation was associated with a population-based self-rated schizotypy phenotype previously suggested to preferentially reflect genetic liability to psychosis and defined by a tendency to misinterpret otherwise neutral social cues and perceptual experiences in one's immediate environment, as personally relevant and significant information. This suggests a novel route by which schizophrenia-implicated ZNF804A genetic variation may confer risk to clinical psychosis at the general population level. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizotypal |
| 79 | Schizophr. Res. 2013 Jun 147: 46-52 |
| PMID | 23590871 |
| Title | Association of rs1344706 in the ZNF804A gene with schizophrenia in a case/control sample from Indonesia. |
| Abstract | Association of rs1344706 in the ZNF804A gene (2q32.1) with schizophrenia was first reported in a genome wide scan conducted in a sample of 479 cases and replicated in 6666 cases. Subsequently, evidence by replication was obtained in several samples with European- and Asian ancestral background. We report ascertainment, clinical characterization, quality control, and determination of ancestral background of a case control sample from Indonesia, comprising 1067 cases and 1111 ancestry matched controls. Genotyping was performed using a fluorescence-based allelic discrimination assay (TaqMan SNP genotyping assay) and a newly designed PCR-RFLP assay for confirmation of rs1344706 genotypes. We confirmed association of the T-allele of rs1344706 with schizophrenia in a newly ascertained sample from Indonesia with Southeast Asian ancestral background (P=0.019, OR=1.155, 95%, CI 1.025-1.301). In addition, we studied several SNPs in the vicinity of rs1344706, for which nominally significant results had been reported. None of the association P values of the additional SNPs exceeded that of rs1344706. We provide additional evidence for association of the ZNF804A gene with schizophrenia. We conclude that rs1344706 or a yet unknown polymorphism in linkage disequilibrium is also involved in conferring susceptibility to schizophrenia in samples with different (Asian) ancestral backgrounds. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizotypal |
| 80 | Neurosci. Lett. 2013 Jan 532: 64-9 |
| PMID | 23147122 |
| Title | No association of ZNF804A rs1344706 with white matter integrity in schizophrenia: a tract-based spatial statistics study. |
| Abstract | Altered brain connectivity has been widely considered as a genetic risk mechanism for schizophrenia. Of the many susceptibility genes identified so far, ZNF804A (rs1344706) is the first common genetic variant associated with schizophrenia on a genome-wide level. Previous fMRI studies have found that carriers of rs1344706 exhibit altered functional connectivity. However, the relationship between ZNF804A and white matter structural connectivity in patients of schizophrenia remains unknown. In this study, 100 patients with schizophrenia and 69 healthy controls were genotyped at the single nucleotide polymorphism rs1344706. Diffusion tensor imaging (DTI) was conducted and analyzed with tract-based spatial statistics. Systematic statistical analysis was conducted on multiple diffusion indices, including fractional anisotropy, axial diffusivity, radial diffusivity, and mean diffusivity. Unpaired two-sample t-test revealed significant differences in fractional anisotropy and diffusivity between schizophrenia and control groups. A two-way ANOVA analysis was conducted to assess the main effects of and the interaction between schizophrenia and ZNF804A. Although significant main effects of the diagnosis of schizophrenia were found on radial diffusivity, no association between the ZNF804A (rs1344706) and white matter connectivity was found in the entire group of subjects or in a selected subgroup of age-matched subjects (n=72). |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizotypal |
| 81 | Int J Psychiatry Med 2013 -1 45: 269-78 |
| PMID | 24066410 |
| Title | Evaluation of the relationship between the ZNF804A single nucleotide polymorphism rs1344706 A/C variant and schizophrenia subtype in Han Chinese patients. |
| Abstract | Recent genome wide association studies (GWASs) assessing the relationship between schizophrenia (SZ) and the ZNF804A gene, particularly the single nucleotide polymorphism (SNP) rs1344706, have yielded conflicting results. schizophrenia is a heterogeneous disorder, so it is possible that an association may be restricted to specific SZ subtypes and that population heterogeneity may obscure a contribution of ZNF804A allelic variation to SZ risk. We thus evaluated the association between rs1344706 and different clinical SZ subtypes in a large Han Chinese patient population. The rs1344706 genotype was determined in 1,025 SZ patients and 977 healthy controls using polymerase chain reaction restriction fragment length polymorphisms (PCR-RFLPs). The clinical SZ subtypes included paranoid, catatonic, disintegrated, and undifferentiated, diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition IV (DSM-IV). No significant differences in genotype and allele frequencies were found between controls and either the total SZ population (A > C, chi2 = 4.339, 2.994; p = 0.227, 0.087, respectively) or paranoid SZ patients (chi2 = 2.053, 0.002; p = 0.562, 0.973, respectively). However, there was a significant association between genotype frequency and SZ subtype (chi2 = 12.632, p = 0.049). We found no evidence that the ZNF804A SNP rs1344706 is a susceptibility locus for SZ. However, conflicting results from previous association studies may be due to genetic heterogeneity between different patient SZ subtypes. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizotypal |
| 82 | PLoS ONE 2013 -1 8: e65780 |
| PMID | 23776546 |
| Title | Meta-analysis indicates that the European GWAS-identified risk SNP rs1344706 within ZNF804A is not associated with schizophrenia in Han Chinese population. |
| Abstract | Recent genetic association studies have implicated several candidate susceptibility variants for schizophrenia among general populations. Rs1344706, an intronic SNP within ZNF804A, was identified as one of the most compelling candidate risk SNPs for schizophrenia in Europeans through genome-wide association studies (GWASs) and replications as well as large-scale meta-analyses. However, in Han Chinese, the results for rs1344706 are inconsistent, and whether rs1344706 is an authentic risk SNP for schizophrenia in Han Chinese is inconclusive. Here, we conducted a systematic meta-analysis of rs1344706 with schizophrenia in Chinese population by combining all available case-control samples (N?=?12), including a total of 8,982 cases and 12,342 controls. The results of our meta-analysis were not able to confirm an association of rs1344706 A-allele with schizophrenia (p?=?0.10, odds ratio?=?1.06, 95% confidence interval?=?0.99-1.13). Such absence of association was further confirmed by the non-superiority test (p?=?0.0003), suggesting that rs1344706 is not a risk SNP for schizophrenia in Han Chinese. Detailed examinations of individual samples revealed potential sampling bias in previous replication studies in Han Chinese. The absence of rs1344706 association in Han Chinese suggest a potential genetic heterogeneity in the susceptibility of schizophrenia on this locus and also demonstrate the difficulties in replicating genome-wide association findings of schizophrenia across different ethnic populations. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizotypal |
| 83 | BMC Res Notes 2013 -1 6: 29 |
| PMID | 23351715 |
| Title | Investigation of the ZNF804A gene polymorphism with genetic risk for bipolar disorder in attention deficit hyperactivity disorder. |
| Abstract | Genome-wide association studies (GWAS) have been conducted on many psychiatric disorders. Evidence from large GWAS indicates that the single nucleotide polymorphism (SNP) rs1344706 in the zinc-finger protein 804A gene (ZNF804A) is associated with psychotic disorders including bipolar disorder and schizophrenia. One study also found significant association between rs1344706 and the executive control network of attention. In this study we examine the role of the rs1344706 polymorphism that previously showed association with BD and is known to alter expression of the gene in two clinical family-based ADHD samples from the UK and Taiwan. To investigate the association between rs1344706 and ADHD, two family samples of ADHD probands from the United Kingdom (n = 180) and Taiwan (n = 212) were genotyped using TaqMan SNP genotyping assays and analysed using within-family transmission disequilibrium test. No significant associations were found between rs1344706 polymorphism and ADHD in either of the samples from Taiwan (P = 0.91) and UK (P = 0.41). Even combining the two datasets together the A allele of rs1344706 SNP was still not significantly over-transmitted to affected probands (P = 0.50). Furthermore, there was no evidence of association with the specific symptoms subgroups of inattention or hyperactivity-impulsivity. In this study we used family-based ADHD data in the UK and Taiwanese population to test for an association between rs1344706 SNP in the ZNF804A gene and ADHD. Results showed no significant association of rs1344706 with ADHD in UK and Taiwanese samples. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizotypal |
| 84 | Neuropsychobiology 2013 -1 67: 84-92 |
| PMID | 23295962 |
| Title | ZNF804A genotype modulates neural activity during working memory for faces. |
| Abstract | Genetic susceptibility to schizophrenia (SZ) has been suggested to influence the cortical systems supporting working memory (WM) and face processing. Genetic imaging studies link the SZ risk variant rs1344706 on the ZNF804A gene to psychosis via alterations in functional brain connectivity during WM, but no work has looked at the effects of ZNF804A on WM with face-processing components. We therefore investigated healthy controls that were genotyped for rs1344706 with a face WM task during functional magnetic resonance imaging. We suggested that variation at the rs1344706 locus would be associated with similar alterations as patients previously tested using the same WM task for faces. The rs1344706 risk allele was indeed associated with altered activation in the right dorsolateral prefrontal (rDLPFC) cortex. We established that the rDLPFC was activated in a task-dependent manner, suggesting that the differences in activation between rs1344706 genotype groups reflected alterations in task processing. Furthermore, we demonstrated that the rDLPFC region showed significant volumetric overlap with the rDLPFC which had previously been reported to be altered during task processing for patients with SZ. The findings support an association between rs1344706 and alterations in DLPFC activity during WM for faces. We further suggest that WM for faces may be a useful intermediate phenotype in the investigation of genetic susceptibility to psychosis. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizotypal |
| 85 | Hum Brain Mapp 2013 Feb 34: 304-13 |
| PMID | 22042765 |
| Title | Partial support for ZNF804A genotype-dependent alterations in prefrontal connectivity. |
| Abstract | Genome-wide association studies identified the single nucleotide polymorphism rs1344706 in ZNF804A as a common risk-variant for schizophrenia and bipolar disorder. Whereas the molecular function of ZNF804A is yet unclear, recent imaging genetics studies have started to characterize the neural systems architecture linking rs1344706 genotype to psychosis. Carring rs1344706 risk-alleles was associated with a decrease in functional connectivity within the dorsolateral prefrontal cortices (DLPFCs) as well as an increase in connectivity between the DLPFC and the hippocampal formation (HF) in the context of a working memory task. The present study aimed at replicating these findings in an independent sample of 94 healthy subjects. Subjects were genotyped for rs1344706 and performed a working memory task during functional magnetic resonance imaging. Results indicate no support for a decrease of functional coupling between the bilateral DLPFCs at higher ZNF804A risk status. However, the current data show the previously described alteration in functional coupling between the right DLPFC and the HFs, albeit with weaker effects. Decoupled by default, the functional connectivity between the right DLPFC and anterior HFs increased with the number of rs1344706 risk alleles. The present data support fronto-hippocampal dysconnectivity as intermediate phenotype linking rs1344706 genotype to psychosis. We discuss the issues in replicating the interhemispheric DLPFC coupling in light of the effect sizes rs1344706 genotype has on brain function, concluding that further independent replication studies are fundamentally needed to ascertain the role of rs1344706 in the functional integration of neural systems. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizotypal |
| 86 | Schizophr Bull 2013 Nov 39: 1252-60 |
| PMID | 23155182 |
| Title | Variation in psychosis gene ZNF804A is associated with a refined schizotypy phenotype but not neurocognitive performance in a large young male population. |
| Abstract | Genetic variability within the ZNF804A gene has been recently found to be associated with schizophrenia and bipolar disorder, although the pathways by which this gene may confer risk remain largely unknown. We set out to investigate whether common ZNF804A variants affect psychosis-related intermediate phenotypes such as cognitive performance dependent on prefrontal and frontotemporal brain function, schizotypal traits, and attenuated psychotic experiences in a large young male population. Association analyses were performed using all 4 available self-rated schizotypy questionnaires and cognitive data retrospectively drawn from the Athens Study of Psychosis Proneness and Incidence of schizophrenia (ASPIS). DNA samples from 1507 healthy young men undergoing induction to military training were genotyped for 4 previously studied polymorphic markers in the ZNF804A gene locus. Single-marker analysis revealed significant associations between 2 recently identified candidate schizophrenia susceptibility variants (rs1344706 and rs7597593) and a refined positive schizotypy phenotype characterized primarily by self-rated paranoia/ideas of reference. Nominal associations were noted with all positive, but not negative, schizotypy related factors. ZNF804A genotype effect on paranoia was confirmed at the haplotype level. No significant associations were noted with central indexes of sustained attention or working memory performance. In this study, ZNF804A variation was associated with a population-based self-rated schizotypy phenotype previously suggested to preferentially reflect genetic liability to psychosis and defined by a tendency to misinterpret otherwise neutral social cues and perceptual experiences in one's immediate environment, as personally relevant and significant information. This suggests a novel route by which schizophrenia-implicated ZNF804A genetic variation may confer risk to clinical psychosis at the general population level. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizotypal |
| 87 | Schizophr Bull 2013 Nov 39: 1252-60 |
| PMID | 23155182 |
| Title | Variation in psychosis gene ZNF804A is associated with a refined schizotypy phenotype but not neurocognitive performance in a large young male population. |
| Abstract | Genetic variability within the ZNF804A gene has been recently found to be associated with schizophrenia and bipolar disorder, although the pathways by which this gene may confer risk remain largely unknown. We set out to investigate whether common ZNF804A variants affect psychosis-related intermediate phenotypes such as cognitive performance dependent on prefrontal and frontotemporal brain function, schizotypal traits, and attenuated psychotic experiences in a large young male population. Association analyses were performed using all 4 available self-rated schizotypy questionnaires and cognitive data retrospectively drawn from the Athens Study of Psychosis Proneness and Incidence of schizophrenia (ASPIS). DNA samples from 1507 healthy young men undergoing induction to military training were genotyped for 4 previously studied polymorphic markers in the ZNF804A gene locus. Single-marker analysis revealed significant associations between 2 recently identified candidate schizophrenia susceptibility variants (rs1344706 and rs7597593) and a refined positive schizotypy phenotype characterized primarily by self-rated paranoia/ideas of reference. Nominal associations were noted with all positive, but not negative, schizotypy related factors. ZNF804A genotype effect on paranoia was confirmed at the haplotype level. No significant associations were noted with central indexes of sustained attention or working memory performance. In this study, ZNF804A variation was associated with a population-based self-rated schizotypy phenotype previously suggested to preferentially reflect genetic liability to psychosis and defined by a tendency to misinterpret otherwise neutral social cues and perceptual experiences in one's immediate environment, as personally relevant and significant information. This suggests a novel route by which schizophrenia-implicated ZNF804A genetic variation may confer risk to clinical psychosis at the general population level. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizotypal |
| 88 | Schizophr. Res. 2014 Mar 153: 243-5 |
| PMID | 24462263 |
| Title | Allelic imbalance associated with the schizophrenia risk SNP rs1344706 indicates a cis-acting variant in ZNF804A. |
| Abstract | -1 |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizotypal |
| 89 | Schizophr Bull 2014 May 40: 499-500 |
| PMID | 24442852 |
| Title | ZNF804A protein is widely expressed in human brain neurons: possible implications on normal brain structure and pathomorphologic changes in schizophrenia. |
| Abstract | -1 |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizotypal |
| 90 | Schizophr. Res. 2014 Nov 159: 329-32 |
| PMID | 25217366 |
| Title | No effect of schizophrenia risk genes MIR137, TCF4, and ZNF804A on macroscopic brain structure. |
| Abstract | Single nucleotide polymorphisms (SNPs) within the MIR137, TCF4, and ZNF804A genes show genome-wide association to schizophrenia. However, the biological basis for the associations is unknown. Here, we tested the effects of these genes on brain structure in 1300 healthy adults. Using volumetry and voxel-based morphometry, neither gene-wide effects--including the combined effect of the genes--nor single SNP effects--including specific psychosis risk SNPs--were found on total brain volume, grey matter, white matter, or hippocampal volume. These results suggest that the associations between these risk genes and schizophrenia are unlikely to be mediated via effects on macroscopic brain structure. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizotypal |
| 91 | Genes Brain Behav. 2014 Jan 13: 104-17 |
| PMID | 23927712 |
| Title | Theory of mind and the social brain: implications for understanding the genetic basis of schizophrenia. |
| Abstract | Genome-wide association studies in schizophrenia have recently made significant progress in our understanding of the complex genetic architecture of this disorder. Many genetic loci have been identified and now require functional investigation. One approach involves studying their correlation with neuroimaging and neurocognitive endophenotypes. Theory of Mind (ToM) deficits are well established in schizophrenia and they appear to fulfill criteria for being considered an endophenotype. We aim to review the behavioral and neuroimaging-based studies of ToM in schizophrenia, assess its suitability as an endophenotype, discuss current findings, and propose future research directions. Suitable research articles were sourced from a comprehensive literature search and from references identified through other studies. ToM deficits are repeatable, stable, and heritable: First-episode patients, those in remission and unaffected relatives all show deficits. Activation and structural differences in brain regions believed important for ToM are also consistently reported in schizophrenia patients at all stages of illness, although no research to date has examined unaffected relatives. Studies using ToM as an endophenotype are providing interesting genetic associations with both single nucleotide polymorphisms (SNPs) and specific copy number variations (CNVs) such as the 22q11.2 deletion syndrome. We conclude that ToM is an important cognitive endophenotype for consideration in future studies addressing the complex genetic architecture of schizophrenia, and may help identify more homogeneous clinical sub-types for further study. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizotypal |
| 92 | Transl Psychiatry 2014 -1 4: e345 |
| PMID | 24424391 |
| Title | Effects of ZNF804A on auditory P300 response in schizophrenia. |
| Abstract | The common variant rs1344706 within the zinc-finger protein gene ZNF804A has been strongly implicated in schizophrenia (SZ) susceptibility by a series of recent genetic association studies. Although associated with a pattern of altered neural connectivity, evidence that increased risk is mediated by an effect on cognitive deficits associated with the disorder has been equivocal. This study investigated whether the same ZNF804A risk allele was associated with variation in the P300 auditory-evoked response, a cognitively relevant putative endophenotype for SZ. We compared P300 responses in carriers and noncarriers of the ZNF804A risk allele genotype groups in Irish patients and controls (n=97). P300 response was observed to vary according to genotype in this sample, such that risk allele carriers showed relatively higher P300 response compared with noncarriers. This finding accords with behavioural data reported by our group and others. It is also consistent with the idea that ZNF804A may have an impact on cortical efficiency, reflected in the higher levels of activations required to achieve comparable behavioural accuracy on the task used. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizotypal |
| 93 | PLoS ONE 2014 -1 9: e94968 |
| PMID | 24736721 |
| Title | Heat shock alters the expression of schizophrenia and autism candidate genes in an induced pluripotent stem cell model of the human telencephalon. |
| Abstract | schizophrenia (SZ) and autism spectrum disorders (ASD) are highly heritable neuropsychiatric disorders, although environmental factors, such as maternal immune activation (MIA), play a role as well. Cytokines mediate the effects of MIA on neurogenesis and behavior in animal models. However, MIA stimulators can also induce a febrile reaction, which could have independent effects on neurogenesis through heat shock (HS)-regulated cellular stress pathways. However, this has not been well-studied. To help understand the role of fever in MIA, we used a recently described model of human brain development in which induced pluripotent stem cells (iPSCs) differentiate into 3-dimensional neuronal aggregates that resemble a first trimester telencephalon. RNA-seq was carried out on aggregates that were heat shocked at 39°C for 24 hours, along with their control partners maintained at 37°C. 186 genes showed significant differences in expression following HS (p<0.05), including known HS-inducible genes, as expected, as well as those coding for NGFR and a number of SZ and ASD candidates, including SMARCA2, DPP10, ARNT2, AHI1 and ZNF804A. The degree to which the expression of these genes decrease or increase during HS is similar to that found in copy loss and copy gain copy number variants (CNVs), although the effects of HS are likely to be transient. The dramatic effect on the expression of some SZ and ASD genes places HS, and perhaps other cellular stressors, into a common conceptual framework with disease-causing genetic variants. The findings also suggest that some candidate genes that are assumed to have a relatively limited impact on SZ and ASD pathogenesis based on a small number of positive genetic findings, such as SMARCA2 and ARNT2, may in fact have a much more substantial role in these disorders - as targets of common environmental stressors. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizotypal |
| 94 | Schizophr. Res. 2014 May 155: 15-20 |
| PMID | 24685285 |
| Title | A schizophrenia risk gene, ZNF804A, is associated with brain white matter microstructure. |
| Abstract | Genome-wide association studies have provided strong evidence for association of the SNP rs1344706 in the ZNF804A gene with schizophrenia and bipolar disorder. Neuroimaging studies have suggested that variation at rs1344706 may be associated with neural endophenotypes such as white matter volumes and densities. However, analyses of white matter microstructure using diffusion tensor imaging (DTI) have produced conflicting results. We examined the association between rs1344706 and white matter microstructure in 107 healthy individuals using tract-based spatial statistics (TBSS). TBSS analysis showed significant association between the risk allele and lower fractional anisotropy in the corpus callosum, left forceps minor, and right parietal white matter (p<.05; FWE corrected). Post-hoc analyses indicated that this association was largely driven by alterations in radial diffusivity, consistent with an effect of genotype on myelination. In light of the strong DTI evidence for white matter microstructural abnormalities in schizophrenia, the current results implicate a potential mechanism for schizophrenia risk formation by ZNF804A rs1344706 genotype. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizotypal |
| 95 | Neurosci. Lett. 2014 May 568: 12-6 |
| PMID | 24686180 |
| Title | Expression analysis of the genes identified in GWAS of the postmortem brain tissues from patients with schizophrenia. |
| Abstract | Many gene expression studies have examined postmortem brain tissues of patients with schizophrenia. However, only a few expression studies of the genes identified in genome-wide association study (GWAS) have been published to date. We measured the expression levels of the genes identified in GWAS (ZNF804A, OPCML, RPGRIP1L, NRGN, and TCF4) of the postmortem brain tissues of patients with schizophrenia and controls from two separate sample sets (i.e., the Australian Tissue Resource Center and Stanley Medical Research Institute). We also determined whether the single-nucleotide polymorphisms (SNPs) identified in the GWAS were related to the gene expression changes in the prefrontal cortex. No difference was observed between the patients with schizophrenia and controls from the Australian Tissue Resource Center samples in the mRNA levels of ZNF804A, OPCML, RPGRIP1L, NRGN, or TCF4. The lack of mRNA change for these five transcripts was also found in the brain samples from the Stanley Medical Research Institute. In addition, no relationship between the schizophrenia-associated SNPs identified in the GWAS and the corresponding gene expression was observed in either sample set. Our results suggest that major changes in the transcript levels of the five candidate genes identified in the GWAS may not occur in adult patients with schizophrenia. The lack of linkage between the risk gene polymorphisms and the expression levels of their major transcripts suggests that the control of pan mRNA levels may not be a prominent mechanism by which the genes identified in the GWAS contribute to the pathophysiology of schizophrenia. Further studies are needed to examine how the genes identified in the GWAS contribute to the pathophysiology of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizotypal |
| 96 | JAMA Psychiatry 2014 Jul 71: 778-85 |
| PMID | 24828433 |
| Title | Variability in working memory performance explained by epistasis vs polygenic scores in the ZNF804A pathway. |
| Abstract | We investigated the variation in neuropsychological function explained by risk alleles at the psychosis susceptibility gene ZNF804A and its interacting partners using single nucleotide polymorphisms (SNPs), polygenic scores, and epistatic analyses. Of particular importance was the relative contribution of the polygenic score vs epistasis in variation explained. To (1) assess the association between SNPs in ZNF804A and the ZNF804A polygenic score with measures of cognition in cases with psychosis and (2) assess whether epistasis within the ZNF804A pathway could explain additional variation above and beyond that explained by the polygenic score. Patients with psychosis (n?=?424) were assessed in areas of cognitive ability impaired in schizophrenia including IQ, memory, attention, and social cognition. We used the Psychiatric GWAS Consortium 1 schizophrenia genome-wide association study to calculate a polygenic score based on identified risk variants within this genetic pathway. Cognitive measures significantly associated with the polygenic score were tested for an epistatic component using a training set (n?=?170), which was used to develop linear regression models containing the polygenic score and 2-SNP interactions. The best-fitting models were tested for replication in 2 independent test sets of cases: (1) 170 individuals with schizophrenia or schizoaffective disorder and (2) 84 patients with broad psychosis (including bipolar disorder, major depressive disorder, and other psychosis). Participants completed a neuropsychological assessment battery designed to target the cognitive deficits of schizophrenia including general cognitive function, episodic memory, working memory, attentional control, and social cognition. Higher polygenic scores were associated with poorer performance among patients on IQ, memory, and social cognition, explaining 1% to 3% of variation on these scores (range, P?=?.01 to .03). Using a narrow psychosis training set and independent test sets of narrow phenotype psychosis (schizophrenia and schizoaffective disorder), broad psychosis, and control participants (n?=?89), the addition of 2 interaction terms containing 2 SNPs each increased the R2 for spatial working memory strategy in the independent psychosis test sets from 1.2% using the polygenic score only to 4.8% (P?=?.11 and .001, respectively) but did not explain additional variation in control participants. These data support a role for the ZNF804A pathway in IQ, memory, and social cognition in cases. Furthermore, we showed that epistasis increases the variation explained above the contribution of the polygenic score. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizotypal |
| 97 | Psychiatry Res 2014 Apr 222: 60-6 |
| PMID | 24636489 |
| Title | Lack of association of the rs1344706 ZNF804A variant with cognitive functions and DTI indices of white matter microstructure in two independent healthy populations. |
| Abstract | The rs1344706 single nucleotide polymorphism within intron 2 of the ZNF804A gene is strongly associated with schizophrenia and bipolar disorder. This variant has also been associated in some studies with a range of cognitive and neuroimaging phenotypes, but several studies have reported no effect on the same phenotypes in other samples. Here, we genotyped 670 healthy adult Norwegian subjects and 1753 healthy adult Swedish subjects for rs1344706, and tested for associations with cognitive phenotypes including general intellectual abilities, memory functions and cognitive inhibition. We also tested whether rs1344706 is associated with white matter microstructural properties using diffusion tensor imaging (DTI) data from 250 to 340 of the Norwegian and Swedish subjects, respectively. Whole-brain voxel-wise statistical modeling of the effect of the ZNF804A variant on two DTI indices, fractional anisotropy (FA) and radial diffusivity (RD), was performed using tract-based spatial statistics (TBSS), and commonly reported effect sizes were calculated within several large-scale white matter pathways based on neuroanatomical atlases. No significant associations were found between rs1344706 and the cognitive traits or white matter microstructure. We conclude that the rs1344706 SNP has no significant effect on these phenotypes in our two reasonably powered samples. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizotypal |
| 98 | Cortex 2014 Jun 55: 182-91 |
| PMID | 24447899 |
| Title | Category fluency, latent semantic analysis and schizophrenia: a candidate gene approach. |
| Abstract | Category fluency is a widely used task that relies on multiple neurocognitive processes and is a sensitive assay of cortical dysfunction, including in schizophrenia. The test requires naming of as many words belonging to a certain category (e.g., animals) as possible within a short period of time. The core metrics are the overall number of words produced and the number of errors, namely non-members generated for a target category. We combine a computational linguistic approach with a candidate gene approach to examine the genetic architecture of this traditional fluency measure. In addition to the standard metric of overall word count, we applied a computational approach to semantics, Latent Semantic Analysis (LSA), to analyse the clustering pattern of the categories generated, as it likely reflects the search in memory for meanings. Also, since fluency performance probably also recruits verbal learning and recall processes, we included two standard measures of this cognitive process: the Wechsler Memory Scale and California Verbal Learning Test (CVLT). To explore the genetic architecture of traditional and LSA-derived fluency measures we employed a candidate gene approach focused on SNPs with known function that were available from a recent genome-wide association study (GWAS) of schizophrenia. The selected candidate genes were associated with language and speech, verbal learning and recall processes, and processing speed. A total of 39 coding SNPs were included for analysis in 665 subjects. Given the modest sample size, the results should be regarded as exploratory and preliminary. Nevertheless, the data clearly illustrate how extracting the meaning from participants' responses, by analysing the actual content of words, generates useful and neurocognitively viable metrics. We discuss three replicated SNPs in the genes ZNF804A, DISC1 and KIAA0319, as well as the potential for computational analyses of linguistic and textual data in other genomics tasks. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizotypal |
| 99 | PLoS ONE 2014 -1 9: e90894 |
| PMID | 24625750 |
| Title | Sequencing of a patient with balanced chromosome abnormalities and neurodevelopmental disease identifies disruption of multiple high risk loci by structural variation. |
| Abstract | Balanced chromosome abnormalities (BCAs) occur at a high frequency in healthy and diseased individuals, but cost-efficient strategies to identify BCAs and evaluate whether they contribute to a phenotype have not yet become widespread. Here we apply genome-wide mate-pair library sequencing to characterize structural variation in a patient with unclear neurodevelopmental disease (NDD) and complex de novo BCAs at the karyotype level. Nucleotide-level characterization of the clinically described BCA breakpoints revealed disruption of at least three NDD candidate genes (LINC00299, NUP205, PSMD14) that gave rise to abnormal mRNAs and could be assumed as disease-causing. However, unbiased genome-wide analysis of the sequencing data for cryptic structural variation was key to reveal an additional submicroscopic inversion that truncates the schizophrenia- and bipolar disorder-associated brain transcription factor ZNF804A as an equally likely NDD-driving gene. Deep sequencing of fluorescent-sorted wild-type and derivative chromosomes confirmed the clinically undetected BCA. Moreover, deep sequencing further validated a high accuracy of mate-pair library sequencing to detect structural variants larger than 10 kB, proposing that this approach is powerful for clinical-grade genome-wide structural variant detection. Our study supports previous evidence for a role of ZNF804A in NDD and highlights the need for a more comprehensive assessment of structural variation in karyotypically abnormal individuals and patients with neurocognitive disease to avoid diagnostic deception. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizotypal |
| 100 | Neuropsychopharmacology 2014 Apr 39: 1196-205 |
| PMID | 24247043 |
| Title | Further evidence for the impact of a genome-wide-supported psychosis risk variant in ZNF804A on the Theory of Mind Network. |
| Abstract | The single-nucleotide polymorphism (SNP) rs1344706 in ZNF804A is one of the best-supported risk variants for psychosis. We hypothesized that this SNP contributes to the development of schizophrenia by affecting the ability to understand other people's mental states. This skill, commonly referred to as Theory of Mind (ToM), has consistently been found to be impaired in schizophrenia. Using functional magnetic resonance imaging, we previously showed that in healthy individuals rs1344706 impacted on activity and connectivity of key areas of the ToM network, including the dorsomedial prefrontal cortex, temporo-parietal junction, and the posterior cingulate cortex, which show aberrant activity in schizophrenia patients, too. We aimed to replicate these results in an independent sample of 188 healthy German volunteers. In order to assess the reliability of brain activity elicited by the ToM task, 25 participants performed the task twice with an interval of 14 days showing excellent accordance in recruitment of key ToM areas. Confirming our previous results, we observed decreasing activity of the left temporo-parietal junction, dorsomedial prefrontal cortex, and the posterior cingulate cortex with increasing number of risk alleles during ToM. Complementing our replication sample with the discovery sample, analyzed in a previous report (total N=297), further revealed negative genotype effects in the left dorsomedial prefrontal cortex as well as in the temporal and parietal regions. In addition, as shown previously, rs1344706 risk allele dose positively predicted increased frontal-temporo-parietal connectivity. These findings confirm the effects of the psychosis risk variant in ZNF804A on the dysfunction of the ToM network. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizotypal |
| 101 | Schizophr Bull 2014 May 40: 532-41 |
| PMID | 24078172 |
| Title | ZNF804A and cortical structure in schizophrenia: in vivo and postmortem studies. |
| Abstract | Recent evidence indicated that the ZNF804A (rs1344706) risk allele A is associated with better cognitive performance in patients with schizophrenia. Moreover, it has been demonstrated that ZNF804A may also be related to relatively intact gray matter volume in patients. To further explore these putatively protective effects, the impact of ZNF804A on cortical thickness and folding was examined in this study. To elucidate potential molecular mechanisms, an allelic-specific gene expression study was also carried out. Magnetic resonance imaging cortical thickness and folding were computed in 55 genotyped patients with schizophrenia and 40 healthy controls. Homozygous risk allele carriers (AA) were compared with AC/CC carriers. ZNF804A gene expression was analyzed in a prefrontal region using postmortem tissue from another cohort of 35 patients. In patients, AA carriers exhibited significantly thicker cortex in prefrontal and temporal regions and less disturbed superior temporal cortical folding, whereas the opposite effect was observed in controls, ie, AA carrier status was associated with thinner cortex and more severe altered cortical folding. Along with this, our expression analysis revealed that the risk allele is associated with lower prefrontal ZNF804A expression in patients, whereas the opposite effect in controls has been observed by prior analyses. In conclusion, our analyses provide convergent support for the hypothesis that the schizophrenia-associated ZNF804A variant mediates protective effects on cortex structure in patients. In particular, the allele-specific expression profile in patients might constitute a molecular mechanism for the observed protective influence of ZNF804A on cortical thickness and folding and potentially other intermediate phenotypes. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizotypal |
| 102 | Genomics Proteomics Bioinformatics 2014 Dec 12: 292-6 |
| PMID | 25526981 |
| Title | Association between rs1344706 of ZNF804A and schizophrenia: a meta-analysis. |
| Abstract | schizophrenia is one of the most serious mental diseases found in humans. Previous studies indicated that the single nucleotide polymorphism (SNP) rs1344706 in the gene ZNF804A encoding zinc finger protein 804A was associated with schizophrenia in Caucasian population but not in Chinese Han population. However, current results are conflicting in Asian population. In the present study, a meta-analysis was performed to revisit the association between rs1344706 and the risk of schizophrenia in Asian, Caucasian and other populations. Electronic search of PubMed database identified 25 case-control studies with available genotype frequencies of rs1344706 for the meta-analysis, involving a total of 15,788 cases and 22,654 controls. A pooled odds ratio (OR) with 95% confidence interval (CI) was used to assess the association. The current meta-analysis showed an association between rs1344706 and schizophrenia in Caucasian populations (P=0.028, OR=1.138, 95% CI: 1.014-1.278; P=0.004 for heterogeneity) and Asian populations (P=0.008, OR=1.092, 95% CI: 1.023-1.165; P=0.001 for heterogeneity), but not in other populations (P=0.286, OR=1.209, 95% CI: 0.853-1.714, P=0.120 for heterogeneity). Egger's test (P>0.05) and Begg's test (P>0.05) are both suggestive of the lack of publication bias for the included studies. Thus, the absence of association in other populations suggests a genetic heterogeneity in the susceptibility of schizophrenia and demonstrates the difficulties in replicating genome-wide association study findings regarding schizophrenia across different ethnic populations. To validate the association between rs1344706 and schizophrenia, further studies with larger participant populations worldwide are needed. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizotypal |
| 103 | JAMA Psychiatry 2014 Oct 71: 1112-20 |
| PMID | 25162540 |
| Title | Expression of ZNF804A in human brain and alterations in schizophrenia, bipolar disorder, and major depressive disorder: a novel transcript fetally regulated by the psychosis risk variant rs1344706. |
| Abstract | The single-nucleotide polymorphism rs1344706 in the zinc finger protein 804A gene (ZNF804A) shows genome-wide association with schizophrenia and bipolar disorder. Little is known regarding the expression of ZNF804A and the functionality of rs1344706. To characterize ZNF804A expression in human brain and to investigate how it changes across the life span and how it is affected by rs1344706, schizophrenia, bipolar disorder, and major depressive disorder. Molecular and immunochemical methods were used to study ZNF804A messenger RNA (mRNA) and ZNF804A protein, respectively. ZNF804A transcripts were investigated using next-generation sequencing and polymerase chain reaction-based methods, and ZNF804A protein was investigated using Western blots and immunohistochemistry. Samples of dorsolateral prefrontal cortex and inferior parietal lobe tissue were interrogated from 697 participants between 14 weeks' gestational age and age 85 years, including patients with schizophrenia, bipolar disorder, or major depressive disorder. Quantitative measurements of ZNF804A mRNA and immunoreactivity, and the effect of diagnosis and rs1344706 genotype. ZNF804A was expressed across the life span, with highest expression prenatally. An abundant and developmentally regulated truncated ZNF804A transcript was identified, missing exons 1 and 2 (ZNF804AE3E4) and predicted to encode a protein lacking the zinc finger domain. rs1344706 influenced expression of ZNF804AE3E4 mRNA in fetal brain (P?=?.02). In contrast, full-length ZNF804A showed no association with genotype (P?>?.05). ZNF804AE3E4 mRNA expression was decreased in patients with schizophrenia (P?=?.006) and increased in those with major depressive disorder (P?ZNF804A immunoreactivity was detected in fetal and adult human cerebral cortex. It was localized primarily to pyramidal neurons, with cytoplasmic as well as dendritic and nuclear staining. No differences in ZNF804A-immunoreactive neurons were seen in schizophrenia or related to rs1344706 (P?>?.05). rs1344706 influences the expression of ZNF804AE3E4, a novel splice variant. The effect is limited to fetal brain and to this isoform. It may be part of the mechanism by which allelic variation in ZNF804A affects risk of psychosis. ZNF804A is translated in human brain, where its functions may extend beyond its predicted role as a transcription factor. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizotypal |
| 104 | Transl Psychiatry 2014 -1 4: e346 |
| PMID | 24424392 |
| Title | Analysis of schizophrenia-related genes and electrophysiological measures reveals ZNF804A association with amplitude of P300b elicited by novel sounds. |
| Abstract | Several genes have recently been identified as risk factors for schizophrenia (SZ) by genome-wide association studies (GWAS), including ZNF804A which is thought to function in transcriptional regulation. However, the downstream pathophysiological changes that these genes confer remain to be elucidated. In 143 subjects (68 clinical high risk, first episode or chronic cases; 75 controls), we examined the association between 21 genetic markers previously identified by SZ GWAS or associated with putative intermediate phenotypes of SZ against three event-related potential (ERP) measures: mismatch negativity (MMN), amplitude of P300 during an auditory oddball task, and P300 amplitude during an auditory novelty oddball task. Controlling for age and sex, significant genetic association surpassing Bonferroni correction was detected between ZNF804A marker rs1344706 and P300 amplitude elicited by novel sounds (beta=4.38, P=1.03 × 10(-4)), which is thought to index orienting of attention to unexpected, salient stimuli. Subsequent analyses revealed that the association was driven by the control subjects (beta=6.35, P=9.08 × 10(-5)), and that the risk allele was correlated with higher novel P300b amplitude, in contrast to the significantly lower amplitude observed in cases compared to controls. Novel P300b amplitude was significantly correlated with a neurocognitive measure of auditory attention under interference conditions, suggesting a relationship between novel P300b amplitude and higher-order attentional processes. Our results suggest pleiotropic effects of ZNF804A on risk for SZ and neural mechanisms that are indexed by the novel P300b ERP component. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizotypal |
| 105 | Schizophr. Res. 2014 Jan 152: 111-6 |
| PMID | 24315717 |
| Title | Evidence of allelic imbalance in the schizophrenia susceptibility gene ZNF804A in human dorsolateral prefrontal cortex. |
| Abstract | The rs1344706, an intronic SNP within the zinc-finger protein 804A gene (ZNF804A), was identified as one of the most compelling risk SNPs for schizophrenia (SZ) and bipolar disorder (BD). It is however not clear by which molecular mechanisms ZNF804A increases disease risk. We evaluated the role of ZNF804A in SZ and BD by genotyping the originally associated rs1344706 SNP and an exonic SNP (rs12476147) located in exon four of ZNF804A in a sample of 422 SZ, 382 BD, and 507 controls from the isolated population of the Costa Rica Central Valley. We also investigated the rs1344706 SNP for allelic specific expression (ASE) imbalance in the dorsolateral prefrontal cortex (DLPFC) of 46 heterozygous postmortem brains. While no significant association between rs1344706 and SZ or BD was observed in the Costa Rica sample, we observed an increased risk of SZ for the minor allele (A) of the exonic rs12476147 SNP (p=0.026). Our ASE assay detected a significant over-expression of the rs12476147 A allele in DLPFC of rs1344706 heterozygous subjects. Interestingly, cDNA allele ratios were significantly different according to the intronic rs1344706 genotypes (p-value=0.03), with the rs1344706 A allele associated with increased ZNF804A rs12476147 A allele expression (average 1.06, p-value=0.02, for heterozygous subjects vs. genomic DNA). In conclusion, we have demonstrated a significant association of rs12476147 with SZ, and using a powerful within-subject design, an allelic expression imbalance of ZNF804A exonic SNP rs12476147 in the DLPFC. Although this data does not preclude the possibility of other functional variants in ZNF804A, it provides evidence that the rs1344706 SZ risk allele is the cis-regulatory variant directly responsible for this allelic expression imbalance in adult cortex. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizotypal |
| 106 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2014 Jan 165B: 28-40 |
| PMID | 24123948 |
| Title | How might ZNF804A variants influence risk for schizophrenia and bipolar disorder? A literature review, synthesis, and bioinformatic analysis. |
| 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. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizotypal |
| 107 | Psychol Med 2015 -1 45: 2461-80 |
| PMID | 25858580 |
| Title | What is the impact of genome-wide supported risk variants for schizophrenia and bipolar disorder on brain structure and function? A systematic review. |
| Abstract | The powerful genome-wide association studies (GWAS) revealed common mutations that increase susceptibility for schizophrenia (SZ) and bipolar disorder (BD), but the vast majority were not known to be functional or associated with these illnesses. To help fill this gap, their impact on human brain structure and function has been examined. We systematically discuss this output to facilitate its timely integration in the psychosis research field; and encourage reflection for future research. Irrespective of imaging modality, studies addressing the effect of SZ/BD GWAS risk genes (ANK3, CACNA1C, MHC, TCF4, NRGN, DGKH, PBRM1, NCAN and ZNF804A) were included. Most GWAS risk variations were reported to affect neuroimaging phenotypes implicated in SZ/BD: white-matter integrity (ANK3 and ZNF804A), volume (CACNA1C and ZNF804A) and density (ZNF804A); grey-matter (CACNA1C, NRGN, TCF4 and ZNF804A) and ventricular (TCF4) volume; cortical folding (NCAN) and thickness (ZNF804A); regional activation during executive tasks (ANK3, CACNA1C, DGKH, NRGN and ZNF804A) and functional connectivity during executive tasks (CACNA1C and ZNF804A), facial affect recognition (CACNA1C and ZNF804A) and theory-of-mind (ZNF804A); but inconsistencies and non-replications also exist. Further efforts such as standardizing reporting and exploring complementary designs, are warranted to test the reproducibility of these early findings. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizotypal |
| 108 | Schizophr. Res. 2015 Oct 168: 402-10 |
| PMID | 26164821 |
| Title | Postnatal neurodevelopmental expression and glutamate-dependent regulation of the ZNF804A rodent homologue. |
| 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 [20?M], 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. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizotypal |
| 109 | PLoS ONE 2015 -1 10: e0132456 |
| PMID | 26148198 |
| Title | The Rat Homolog of the Schizophrenia Susceptibility Gene ZNF804A Is Highly Expressed during Brain Development, Particularly in Growth Cones. |
| Abstract | A single nucleotide polymorphism in the ZNF804A gene, rs1344706, is associated with schizophrenia. The polymorphism has been suggested to alter fetal expression of ZNF804A. It has also been reported to be associated with altered cortical functioning and neural connectivity in the brain. Since developmental mechanisms are suggested in the pathophysiology for schizophrenia, expression of Zfp804A, the rat homolog of ZNF804A, was investigated in the developing rat brain. We found that expression of Zfp804A in most brain regions is developmentally regulated and peaks around birth, where after it decreases towards adult levels. This time point is developmentally the equivalent to the second trimester of fetal development in humans. An exception to this expression pattern is the hippocampus where the expression of Zfp804A appears to increase again in the adult brain. Using laser capture and quantitative PCR we found that Zfp804A mRNA expression in the adult rat hippocampus is highest in the CA1 sub region, where the overall firing rates of neurons is higher than in the CA3 region. In cultured cortical neurons Zfp804A mRNA expression peaked at day 4 and then decreased. The ZFP804A protein expression was therefore investigated with immunochemistry in such cultures. Interestingly, before day 4, the protein is mostly found in the perinuclear region of the cell but at day 4, ZFP804A was instead found throughout the cell and particularly in the growth cones. In conclusion we demonstrate that Zfp804A increases in the rat brain at the time of birth, coinciding with neuronal differentiation. We also show that ZFP804A is localized to growth cones of growing neurites. These data implicate ZFP804A in growth cone function and neurite elongation. The polymorphism rs1344706 lowers expression of ZNF804A during prenatal brain development. This may affect ZNF804A's role in cone function and neurite elongation leading to synaptic deficits and altered neural connectivity. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizotypal |
| 110 | Transl Psychiatry 2015 -1 5: e698 |
| PMID | 26670283 |
| Title | Associations between the schizophrenia susceptibility gene ZNF804A and clinical outcomes in psychosis. |
| Abstract | We sought to test the hypothesis that the rs1344706 A allele will be associated with worse clinical outcome in first-episode psychosis. A data linkage was set up between a large systematic study of first-episode psychosis and an electronic health-record case register at the South London and Maudsley NHS Foundation Trust--a large provider of secondary mental-health care. A sample of 291 patients, who presented with a first psychotic episode (ICD10 diagnoses F20-29 or F30-33) and in whom the rs1344706 genotype had been assayed, were followed to examine the duration of mental-health in-patient care during the 2 years following first service contact, as a primary outcome. Secondary outcome measures were whether or not an in-patient episode occurred and the number of in-patient episodes during this period. A strong association was found between the number of rs1344706 A alleles and the cumulative duration of mental-health in-patient stay over the 2 years since initial presentation. In the 84.2% who experienced an in-patient episode during this period, the mean duration of admission was an additional 38 days for each A allele increment. Therefore, in addition to its potential role as a risk factor for psychosis, the ZNF804A rs1344706 A allele is associated with worse clinical outcome. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizotypal |
| 111 | PLoS ONE 2015 -1 10: e0124597 |
| PMID | 25905630 |
| Title | ZNF804A Transcriptional Networks in Differentiating Neurons Derived from Induced Pluripotent Stem Cells of Human Origin. |
| Abstract | ZNF804A (Zinc Finger Protein 804A) has been identified as a candidate gene for schizophrenia (SZ), autism spectrum disorders (ASD), and bipolar disorder (BD) in replicated genome wide association studies (GWAS) and by copy number variation (CNV) analysis. Although its function has not been well-characterized, ZNF804A contains a C2H2-type zinc-finger domain, suggesting that it has DNA binding properties, and consequently, a role in regulating gene expression. To further explore the role of ZNF804A on gene expression and its downstream targets, we used a gene knockdown (KD) approach to reduce its expression in neural progenitor cells (NPCs) derived from induced pluripotent stem cells (iPSCs). KD was accomplished by RNA interference (RNAi) using lentiviral particles containing shRNAs that target ZNF804A mRNA. Stable transduced NPC lines were generated after puromycin selection. A control cell line expressing a random (scrambled) shRNA was also generated. Neuronal differentiation was induced, RNA was harvested after 14 days and transcriptome analysis was carried out using RNA-seq. 1815 genes were found to be differentially expressed at a nominally significant level (p<0.05); 809 decreased in expression in the KD samples, while 1106 increased. Of these, 370 achieved genome wide significance (FDR<0.05); 125 were lower in the KD samples, 245 were higher. Pathway analysis showed that genes involved in interferon-signaling were enriched among those that were down-regulated in the KD samples. Correspondingly, ZNF804A KD was found to affect interferon-alpha 2 (IFNA2)-mediated gene expression. The findings suggest that ZNF804A may affect a differentiating neuron's response to inflammatory cytokines, which is consistent with models of SZ and ASD that support a role for infectious disease, and/or autoimmunity in a subgroup of patients. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizotypal |
| 112 | Hum Brain Mapp 2015 Jun 36: 2387-95 |
| PMID | 25757652 |
| Title | Modulation of hippocampal theta and hippocampal-prefrontal cortex function by a schizophrenia risk gene. |
| Abstract | Hippocampal theta-band oscillations are thought to facilitate the co-ordination of brain activity across distributed networks, including between the hippocampus and prefrontal cortex (PFC). Impairments in hippocampus-PFC functional connectivity are implicated in schizophrenia and are associated with a polymorphism within the ZNF804A gene that shows a genome-wide significant association with schizophrenia. However, the mechanisms by which ZNF804A affects hippocampus-PFC connectivity are unknown. We used a multimodal imaging approach to investigate the impact of the ZNF804A polymorphism on hippocampal theta and hippocampal network coactivity. Healthy volunteers homozygous for the ZNF804A rs1344706 (A[risk]/C[nonrisk]) polymorphism were imaged at rest using both magnetoencephalography (MEG) and functional magnetic resonance imaging (fMRI). A dual-regression approach was used to investigate coactivations between the hippocampal network and other brain regions for both modalities, focusing on the theta band in the case of MEG. We found a significant decrease in intrahippocampal theta (using MEG) and greater coactivation of the superior frontal gyrus with the hippocampal network (using fMRI) in risk versus nonrisk homozygotes. Furthermore, these measures showed a significant negative correlation. Our demonstration of an inverse relationship between hippocampal theta and hippocampus-PFC coactivation supports a role for hippocampal theta in coordinating hippocampal-prefrontal activity. The ZNF804A-related differences that we find in hippocampus-PFC coactivation are consistent with previously reported associations with functional connectivity and with these changes lying downstream of altered hippocampal theta. Changes in hippocampal-PFC co-ordination, driven by differences in oscillatory activity, may be one mechanism by which ZNF804A impacts on brain function and risk for psychosis. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizotypal |
| 113 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2015 Jun 168B: 265-73 |
| PMID | 25921517 |
| Title | ZNF804A rs1344706 is associated with cortical thickness, surface area, and cortical volume of the unmedicated first episode schizophrenia and healthy controls. |
| Abstract | The effects of ZNF804A rs1344706, a prominent susceptibility gene for schizophrenia, on gray matter (GM) structure in unmedicated schizophrenia (SZ) patients are still unknown, although several previous studies investigated the effects in medicated SZ patients and healthy controls (HC). Analyzing cortical thickness, surface area, and GM volume simultaneously may provide a more precise and complete picture of the effects. We genotyped 59 unmedicated first episode SZ patients and 60 healthy controls for the ZNF804A single nucleotide polymorphism (SNP) rs1344706, and examined between-group differences in cortical thickness, surface area, and cortical volume using a full-factorial 2 × 2 analysis of variance (ANOVA). We found the risk allele (T) in ZNF804A rs1344706, compared to the non-risk allele (G), was associated with thinner cortex in the bilateral precuneus, left precentral gyrus, and several other regions, associated with a smaller cortical surface area in the left superior parietal, precuneus cortex and left superior frontal, and associated with a lower cortical volume in the left superior frontal, left precentral, and right precuneus in SZ patients. In contrast, in the controls, the T allele was associated with the increased cortical measurements compared to the G allele in the same regions as those mentioned above. ZNF804A rs1344706 has significant, but different, effects on cortical thickness, surface area, and cortical volume in multiple regions of the brain cortex. Our findings suggest that ZNF804A rs1344706 may aggravate the risk for schizophrenia by exerting its effects on cortical thickness, surface area, and cortical volume in these brain regions. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizotypal |
| 114 | BMC Med. Genet. 2015 -1 16: 96 |
| PMID | 26498712 |
| Title | Genetics, sleep and memory: a recall-by-genotype study of ZNF804A variants and sleep neurophysiology. |
| Abstract | schizophrenia is a complex, polygenic disorder for which over 100 genetic variants have been identified that correlate with diagnosis. However, the biological mechanisms underpinning the different symptom clusters remain undefined. The rs1344706 single nucleotide polymorphism within ZNF804A was among the first genetic variants found to be associated with schizophrenia. Previously, neuroimaging and cognitive studies have revealed several associations between rs1344706 and brain structure and function. The aim of this study is to use a recall-by-genotype (RBG) design to investigate the biological basis for the association of ZNF804A variants with schizophrenia. A RBG study, implemented in a population cohort, will be used to evaluate the impact of genetic variation at rs1344706 on sleep neurophysiology and procedural memory consolidation in healthy participants. Participants will be recruited from the Avon Longitudinal Study of Parents and Children (ALSPAC) on the basis of genotype at rs1344706 (n = 24). Each participant will be asked to take part in two nights of in-depth sleep monitoring (polysomnography) allowing collection of neurophysiological sleep data in a manner not amenable to large-scale study. Sleep questionnaires will be used to assess general sleep quality and subjective sleep experience after each in-house recording. A motor sequencing task (MST) will be performed before and after the second night of polysomnography. In order to gather additional data about habitual sleep behaviour participants will be asked to wear a wrist worn activity monitor (actiwatch) and complete a sleep diary for two weeks. This study will explore the biological function of ZNF804A genotype (rs1344706) in healthy volunteers by examining detailed features of sleep architecture and physiology in relation to motor learning. Using a RBG approach will enable us to collect precise and detailed phenotypic data whilst achieving an informative biological gradient. It would not be feasible to collect such data in the large sample sizes that would be required under a random sampling scheme. By dissecting the role of individual variants associated with schizophrenia in this way, we can begin to unravel the complex genetic mechanisms of psychiatric disorders and pave the way for future development of novel therapeutic approaches. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizotypal |
| 115 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2015 Jan 168B: 14-35 |
| PMID | 25522715 |
| Title | Bioinformatic analyses and conceptual synthesis of evidence linking ZNF804A to risk for schizophrenia and bipolar disorder. |
| Abstract | Advances in molecular genetics, fueled by the results of large-scale genome-wide association studies, meta-analyses, and mega-analyses, have provided the means of identifying genetic risk factors for human disease, thereby enriching our understanding of the functionality of the genome in the post-genomic era. In the past half-decade, research on neuropsychiatric disorders has reached an important milestone: the identification of susceptibility genes reliably associated with complex psychiatric disorders at genome-wide levels of significance. This age of discovery provides the groundwork for follow-up studies designed to elucidate the mechanism(s) by which genetic variants confer susceptibility to these disorders. The gene encoding zinc-finger protein 804?A (ZNF804A) is among these candidate genes, recently being found to be strongly associated with schizophrenia and bipolar disorder via one of its non-coding mutations, rs1344706. Neurobiological, molecular, and bioinformatic analyses have improved our understanding of ZNF804A in general and this variant in particular; however, more work is needed to establish the mechanism(s) by which ZNF804A variants impinge on the biological substrates of the two disorders. Here, we review literature recently published on ZNF804A, and analyze critical concepts related to the biology of ZNF804A and the role of rs1344706 in schizophrenia and bipolar disorder. We synthesize the results of new bioinformatic analyses of ZNF804A with key elements of the existing literature and knowledge base. Furthermore, we suggest some potentially fruitful short- and long-term research goals in the assessment of ZNF804A. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizotypal |
| 116 | Schizophr. Res. 2015 Mar 162: 124-37 |
| PMID | 25667193 |
| Title | Association between variants of zinc finger genes and psychiatric disorders: systematic review and meta-analysis. |
| Abstract | Psychiatric disorders have a negative impact on society and human lives. Genetic factors are involved in the occurrence and development of psychiatric diseases. ZNF804A has been identified as one of the most compelling risk genes associated with broad phenotypes related to psychosis. We conducted a systematic meta-analysis and reviewed ZNF804A variants in psychosis-related disorders, including schizophrenia, bipolar disorder, and attention-deficit hyperactivity disorder. We also summarized the association between other zinc finger protein genes (ZNFs) and psychiatric diseases. The meta-analysis included a total of six variants of ZNF804A and three variants of other ZNFs (ZDHHC8 and ZKSCAN4), and the effects of ZNF variants on neurocognition and neuroimaging phenotypes were reviewed. The biological functions of these variants are also presented. We verified that ZNF804A was significantly related to psychiatric diseases, and the association between ZNF804A rs1344706 and psychosis (schizophrenia and bipolar disorder) did not vary with disease or ethnicity. The main brain area regulated by ZNF804A rs1344706 was the dorsolateral prefrontal cortex. The effect of ZNF804A variants on cognition did not display consistency with different diseases or methodologies. These findings suggest that ZNF804A might play an important role in common pathogenesis of psychiatric diseases, and its variants are likely involved in regulating the expression of psychosis-related genes, especially the dopamine pathway genes. Further research should focus on the molecular mechanisms by which ZNF804A variants act in psychiatric diseases and related phenotypes. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizotypal |
| 117 | Psychol Med 2015 Jan 45: 143-52 |
| PMID | 25065377 |
| Title | ZNF804A genetic variation (rs1344706) affects brain grey but not white matter in schizophrenia and healthy subjects. |
| Abstract | Genetic variation in the gene encoding ZNF804A, a risk gene for schizophrenia, has been shown to affect brain functional endophenotypes of the disorder, while studies of white matter structure have been inconclusive. We analysed effects of ZNF804A single nucleotide polymorphism rs1344706 on grey and white matter using voxel-based morphometry (VBM) in high-resolution T1-weighted magnetic resonance imaging scans of 62 schizophrenia patients and 54 matched healthy controls. We found a significant (p < 0.05, family-wise error corrected for multiple comparisons) interaction effect of diagnostic group x genotype for local grey matter in the left orbitofrontal and right and left lateral temporal cortices, where patients and controls showed diverging effects of genotype. Analysing the groups separately (at p < 0.001, uncorrected), variation in rs1344706 showed effects on brain structure within the schizophrenia patients in several areas including the left and right inferior temporal, right supramarginal/superior temporal, right and left inferior frontal, left frontopolar, right and left dorsolateral/ventrolateral prefrontal cortices, and the right thalamus, as well as effects within the healthy controls in left lateral temporal, right anterior insula and left orbitofrontal cortical areas. We did not find effects of genotype of regional white matter in either of the two cohorts. Our findings demonstrate effects of ZNF804A genetic variation on brain structure, with diverging regional effects in schizophrenia patients and healthy controls in frontal and temporal brain areas. These effects, however, might be dependent on the impact of other (genetic or non-genetic) disease factors. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizotypal |
| 118 | Neuroimage 2015 Aug 116: 207-13 |
| PMID | 25896933 |
| Title | Elevated P3b latency variability in carriers of ZNF804A risk allele for psychosis. |
| Abstract | Increased intra-subject variability (ISV) in reaction times (RTs) is a candidate endophenotype for several psychiatric and neurological conditions, including schizophrenia. ISV reflects the degree of variability in RTs and is thought to be an index of the stability of cognition. It is generally assumed to have the same underlying physiological basis across conditions, but recent evidence raises the possibility that the neural underpinnings of ISV vary with aetiology. Combining genetics with single-trial event-related potentials is an ideal method for investigating the neural basis of ISV in groups where ISV may vary for relatively homogenous reasons. Here we examine the association between P3b latency variability and a polymorphism on the ZNF804A gene associated with psychosis. Ninety-one healthy volunteers genotyped for rs1344706, a polymorphism on ZNF804A, had electroencephalographic data recorded while carrying out three n-back tasks. Data were analysed with a single-trial approach and latency variability of the P3b was compared between the AA homozygous risk group (N=30) and C allele carriers (N=61). P3b latencies were more variable for AA carriers than C carriers. Behavioural ISV, however, was not associated with genotype. The increase in neurophysiological variability, unaccompanied by increased behavioural variability, suggests that this risk gene is associated with an attenuated form of an endophenotype associated with the psychosis phenotype. The increase in both stimulus and response-locked variability also contrasts with previous work into attention-deficit hyperactivity disorder, where only response-locked P3b variability was elevated, suggesting that increased ISV may not signify the same underlying processes in all conditions with which it is associated. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizotypal |
| 119 | J. Psychopharmacol. (Oxford) 2015 Feb 29: 85-96 |
| PMID | 25315827 |
| Title | Recent genetic findings in schizophrenia and their therapeutic relevance. |
| Abstract | Over 100 loci are now associated with schizophrenia risk as identified by single nucleotide polymorphisms (SNPs) in genome-wide association studies. These findings mean that 'genes for schizophrenia' have unquestionably been found. However, many questions remain unanswered, including several which affect their therapeutic significance. The SNPs individually have minor effects, and even cumulatively explain only a modest fraction of the genetic predisposition. The remainder likely results from many more loci, from rare variants, and from gene-gene and gene-environment interactions. The risk SNPs are almost all non-coding, meaning that their biological significance is unclear; probably their effects are mediated via an influence on gene regulation, and emerging evidence suggests that some key molecular events occur during early brain development. The loci include novel genes of unknown function as well as genes and pathways previously implicated in the pathophysiology of schizophrenia, e.g. NMDA receptor signalling. Genes in the latter category have the clearer therapeutic potential, although even this will be a challenging process because of the many complexities concerning the genetic architecture and mediating mechanisms. This review summarises recent schizophrenia genetic findings and some key issues they raise, particularly with regard to their implications for identifying and validating novel drug targets. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizotypal |
| 120 | Metallomics 2016 Jan -1: -1 |
| PMID | 26745006 |
| Title | Lead neurotoxicity: exploring the potential impact of lead substitution in zinc-finger proteins on mental health. |
| Abstract | Childhood lead poisoning is a costly and largely preventable public health problem that lowers IQs, decreases attention spans, and leads to the development of other childhood intellectual disabilities. Furthermore, recent evidence links developmental lead poisoning with the etiology of disorders that appear much later in life, such as Alzheimer's disease, Parkinson's disease, and schizophrenia. Little is known about how lead influences the onset of these disorders. This paper reviews the evidence that lead substitution for zinc in zinc-finger proteins contributes to the development of Alzheimer's disease, Parkinson's disease, and schizophrenia. The zinc-finger proteins potentially impacted by lead include DNA methyltransferase 1 (DNMT1) and Presenilin 1 and 2 (PSEN1/2) in Alzheimer's disease, the dopamine receptor in Parkinson's disease, and the NMDA receptor, zinc-finger protein 804A (ZNF804A), and disrupted-in-schizophrenia 1 (DISC1)-binding zinc-finger (DBZ) in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizotypal |
| 121 | Neurosci. Lett. 2016 Apr 618: 14-8 |
| PMID | 26934312 |
| Title | No association between ZNF804A rs1344706 and schizophrenia in a case-control study of Han Chinese. |
| Abstract | 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. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizotypal |
| 122 | PeerJ 2016 -1 4: e1570 |
| PMID | 26966642 |
| Title | Genome-wide discovered psychosis-risk gene ZNF804A impacts on white matter microstructure in health, schizophrenia and bipolar disorder. |
| Abstract | Background. schizophrenia (SZ) and bipolar disorder (BD) have both been associated with reduced microstructural white matter integrity using, as a proxy, fractional anisotropy (FA) detected using diffusion tensor imaging (DTI). Genetic susceptibility for both illnesses has also been positively correlated in recent genome-wide association studies with allele A (adenine) of single nucleotide polymorphism (SNP) rs1344706 of the ZNF804A gene. However, little is known about how the genomic linkage disequilibrium region tagged by this SNP impacts on the brain to increase risk for psychosis. This study aimed to assess the impact of this risk variant on FA in patients with SZ, in those with BD and in healthy controls. Methods. 230 individuals were genotyped for the rs1344706 SNP and underwent DTI. We used tract-based spatial statistics (TBSS) followed by an analysis of variance, with threshold-free cluster enhancement (TFCE), to assess underlying effects of genotype, diagnosis and their interaction, on FA. Results. As predicted, statistically significant reductions in FA across a widely distributed brain network (p < 0.05, TFCE-corrected) were positively associated both with a diagnosis of SZ or BD and with the double (homozygous) presence of the ZNF804A rs1344706 risk variant (A). The main effect of genotype was medium (d = 0.48 in a 44,054-voxel cluster) and the effect in the SZ group alone was large (d = 1.01 in a 51,260-voxel cluster), with no significant effects in BD or controls, in isolation. No areas under a significant diagnosis by genotype interaction were found. Discussion. We provide the first evidence in a predominantly Caucasian clinical sample, of an association between ZNF804A rs1344706 A-homozygosity and reduced FA, both irrespective of diagnosis and particularly in SZ (in overlapping brain areas). This suggests that the previously observed involvement of this genomic region in psychosis susceptibility, and in impaired functional connectivity, may be conferred through it inducing abnormalities in white matter microstructure. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizotypal |
| 123 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2016 Apr 171: 437-46 |
| PMID | 26866941 |
| Title | A comprehensive meta-analysis of ZNF804A SNPs in the risk of schizophrenia among Asian populations. |
| Abstract | Common variants in ZNF804A increased the risk of schizophrenia (and bipolar disorder), with low effect sizes in Europeans, which is in line with the polygenic nature of the illnesses, and implies that genetic analyses in small samples may not be sufficient to detect stable results. This notion is supported by the inconsistent replications of ZNF804A variations among individual small Asian samples, indicating the absence of definitive conclusions in this population. We collected psychiatric phenotypic and genetic data from Asian genome-wide association (GWA) and individual replication studies, which include up to 13,452 cases, 17,826 healthy controls, and 680 families, that is, the largest-scale study on ZNF804A in Asian populations to date. The European GWAS risk single nucleotide polymorphism (SNP) rs1344706 was nominally associated with schizophrenia in these Asian samples (one-tailed P?=?4.26?×?10(-2) , odds ratio [OR]?=?1.048), and the association was further strengthened when bipolar disorder data was also included (one-tailed P?=?1.85?×?10(-2) , OR?=?1.057). Besides, a non-synonymous SNP rs1366842 in the exon 4 of ZNF804A was also associated with schizophrenia (P?=?9.96?×?10(-3) , OR?=?1.095). We additionally analyzed other 163 SNPs covering ZNF804A region, but none of them showed any evidence of association. Though the two SNPs did not remain significant if we applied multiple corrections, our analysis should be interpreted as a primary replication study with in prior hypothesis, and rs1344706 and rs1366842 might confer a small but detectable risk of schizophrenia (and bipolar disorder) in Asians. Moreover, the current data suggest the necessity of replication analyses in a large enough scale samples. © 2016 Wiley Periodicals, Inc. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizotypal |
| 124 | Schizophr. Res. 2016 Jan 170: 48-54 |
| PMID | 26654932 |
| Title | Effect of rs1344706 in the ZNF804A gene on the connectivity between the hippocampal formation and posterior cingulate cortex. |
| Abstract | ZNF804A is one of the most promising candidate genes for schizophrenia. Previous fMRI studies have repeatedly shown an association between SNP rs1344706 in this gene and the functional connectivity from the right dorsolateral prefrontal cortex (rDLPFC) to the left hippocampal formation (lHF) during the N-back task. However, the rDLPFC-lHF functional connectivity included several subconnections and it is not known whether rs1344706 plays the same role in these subconnections. This study addressed that question using both fMRI and DTI data of 87 subjects. First, we replicated the association between rs1344706 and the rDLPFC-lHF functional connectivity using our fMRI data from the N-back task. Second, we reconstructed fiber connections between rDLPFC and lHF using our DTI data, which included three subconnections: from lHF to posterior cingulate cortex (PCC), from PCC to anterior cingulated cortex (ACC), and from ACC to rDLPFC. We found that only the lHF-PCC tract showed significantly lower fractional anisotropy (FA) in risk allele homozygotes. Finally, we analyzed the fMRI data (from the N-back task and the resting state). Both consistently showed relatively lower lHF-PCC functional connectivity in risk allele homozygotes. Taken together, the disconnectivity of the lHF-PCC tract seems to be a plausible intermediate phenotype that links rs1344706 and schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy, schizotypal |