| 1 | Proc. Natl. Acad. Sci. U.S.A. 2007 Feb 104: 2815-20 |
|---|---|
| PMID | 17360599 |
| Title | Genetic analysis of the calcineurin pathway identifies members of the EGR gene family, specifically EGR3, as potential susceptibility candidates in schizophrenia. |
| Abstract | The calcineurin cascade is central to neuronal signal transduction, and genes in this network are intriguing candidate schizophrenia susceptibility genes. To replicate and extend our previously reported association between the PPP3CC gene, encoding the calcineurin catalytic gamma-subunit, and schizophrenia, we examined 84 SNPs from 14 calcineurin-related candidate genes for genetic association by using 124 Japanese schizophrenic pedigrees. Four of these genes (PPP3CC, EGR2, EGR3, and EGR4) showed nominally significant association with schizophrenia. In a postmortem brain study, EGR1, EGR2, and EGR3 transcripts were shown to be down-regulated in the prefrontal cortex of schizophrenic, but not bipolar, patients. These findings raise a potentially important role for EGR genes in schizophrenia pathogenesis. Because EGR3 is an attractive candidate gene based on its chromosomal location close to PPP3CC within 8p21.3 and its functional link to dopamine, glutamate, and neuregulin signaling, we extended our analysis by resequencing the entire EGR3 genomic interval and detected 15 SNPs. One of these, IVS1 + 607A-->G SNP, displayed the strongest evidence for disease association, which was confirmed in 1,140 independent case-control samples. An in vitro promoter assay detected a possible expression-regulatory effect of this SNP. These findings support the previous genetic association of altered calcineurin signaling with schizophrenia pathogenesis and identify EGR3 as a compelling susceptibility gene. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 2 | Proc. Natl. Acad. Sci. U.S.A. 2007 Feb 104: 2815-20 |
| PMID | 17360599 |
| Title | Genetic analysis of the calcineurin pathway identifies members of the EGR gene family, specifically EGR3, as potential susceptibility candidates in schizophrenia. |
| Abstract | The calcineurin cascade is central to neuronal signal transduction, and genes in this network are intriguing candidate schizophrenia susceptibility genes. To replicate and extend our previously reported association between the PPP3CC gene, encoding the calcineurin catalytic gamma-subunit, and schizophrenia, we examined 84 SNPs from 14 calcineurin-related candidate genes for genetic association by using 124 Japanese schizophrenic pedigrees. Four of these genes (PPP3CC, EGR2, EGR3, and EGR4) showed nominally significant association with schizophrenia. In a postmortem brain study, EGR1, EGR2, and EGR3 transcripts were shown to be down-regulated in the prefrontal cortex of schizophrenic, but not bipolar, patients. These findings raise a potentially important role for EGR genes in schizophrenia pathogenesis. Because EGR3 is an attractive candidate gene based on its chromosomal location close to PPP3CC within 8p21.3 and its functional link to dopamine, glutamate, and neuregulin signaling, we extended our analysis by resequencing the entire EGR3 genomic interval and detected 15 SNPs. One of these, IVS1 + 607A-->G SNP, displayed the strongest evidence for disease association, which was confirmed in 1,140 independent case-control samples. An in vitro promoter assay detected a possible expression-regulatory effect of this SNP. These findings support the previous genetic association of altered calcineurin signaling with schizophrenia pathogenesis and identify EGR3 as a compelling susceptibility gene. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 3 | Neuropsychopharmacology 2008 May 33: 1266-75 |
| PMID | 17637609 |
| Title | Mice lacking the immediate early gene Egr3 respond to the anti-aggressive effects of clozapine yet are relatively resistant to its sedating effects. |
| Abstract | Immediate early genes (IEGs) of the early growth response gene (Egr) family are activated in the brain in response to stress, social stimuli, and administration of psycho-active medications. However, little is known about the role of these genes in the biological or behavioral response to these stimuli. Here we show that mice lacking the IEG transcription factor EGR3 (EGR3-/- mice) display increased aggression, and a decreased latency to attack, in response to the stressful social stimulus of a foreign intruder. Together with our findings of persistent and intrusive olfactory-mediated social investigation of conspecifics, these results suggest increased impulsivity in EGR3-/- mice. We also show that the aggression of EGR3-/- mice is significantly inhibited with chronic administration of the antipsychotic medication clozapine. Despite their sensitivity to this therapeutic effect of clozapine, EGR3-/- mice display a marked resistance to the sedating effects of acute clozapine compared with WT littermate controls. This indicates that the therapeutic, anti-aggressive action of clozapine is separable from its sedating activity, and that the biological abnormality resulting from loss of EGR3 distinguishes these different mechanisms. Thus EGR3-/- mice may provide an important tool for elucidating the mechanism of action of clozapine, as well as for understanding the biology underlying aggressive behavior. Notably, schizophrenia patients display a similar decreased susceptibility to the side effects of antipsychotic medications compared to non-psychiatric controls, despite the medications producing a therapeutic response. This suggests the possibility that EGR3-/- mice may provide insight into the neurobiological abnormalities underlying schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 4 | Mol. Psychiatry 2009 Jun 14: 563-89 |
| PMID | 19204725 |
| Title | Chromosome 8p as a potential hub for developmental neuropsychiatric disorders: implications for schizophrenia, autism and cancer. |
| Abstract | Defects in genetic and developmental processes are thought to contribute susceptibility to autism and schizophrenia. Presumably, owing to etiological complexity identifying susceptibility genes and abnormalities in the development has been difficult. However, the importance of genes within chromosomal 8p region for neuropsychiatric disorders and cancer is well established. There are 484 annotated genes located on 8p; many are most likely oncogenes and tumor-suppressor genes. Molecular genetics and developmental studies have identified 21 genes in this region (ADRA1A, ARHGEF10, CHRNA2, CHRNA6, CHRNB3, DKK4, DPYSL2, EGR3, FGF17, FGF20, FGFR1, FZD3, LDL, NAT2, NEF3, NRG1, PCM1, PLAT, PPP3CC, SFRP1 and VMAT1/SLC18A1) that are most likely to contribute to neuropsychiatric disorders (schizophrenia, autism, bipolar disorder and depression), neurodegenerative disorders (Parkinson's and Alzheimer's disease) and cancer. Furthermore, at least seven nonprotein-coding RNAs (microRNAs) are located at 8p. Structural variants on 8p, such as copy number variants, microdeletions or microduplications, might also contribute to autism, schizophrenia and other human diseases including cancer. In this review, we consider the current state of evidence from cytogenetic, linkage, association, gene expression and endophenotyping studies for the role of these 8p genes in neuropsychiatric disease. We also describe how a mutation in an 8p gene (Fgf17) results in a mouse with deficits in specific components of social behavior and a reduction in its dorsomedial prefrontal cortex. We finish by discussing the biological connections of 8p with respect to neuropsychiatric disorders and cancer, despite the shortcomings of this evidence. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 5 | Bipolar Disord 2009 Nov 11: 701-10 |
| PMID | 19839995 |
| Title | Association study of 21 circadian genes with bipolar I disorder, schizoaffective disorder, and schizophrenia. |
| Abstract | Published studies suggest associations between circadian gene polymorphisms and bipolar I disorder (BPI), as well as schizoaffective disorder (SZA) and schizophrenia (SZ). The results are plausible, based on prior studies of circadian abnormalities. As replications have not been attempted uniformly, we evaluated representative, common polymorphisms in all three disorders. We assayed 276 publicly available 'tag' single nucleotide polymorphisms (SNPs) at 21 circadian genes among 523 patients with BPI, 527 patients with SZ/SZA, and 477 screened adult controls. Detected associations were evaluated in relation to two published genome-wide association studies (GWAS). Using gene-based tests, suggestive associations were noted between EGR3 and BPI (p = 0.017), and between NPAS2 and SZ/SZA (p = 0.034). Three SNPs were associated with both sets of disorders (NPAS2: rs13025524 and rs11123857; RORB: rs10491929; p < 0.05). None of the associations remained significant following corrections for multiple comparisons. Approximately 15% of the analyzed SNPs overlapped with an independent study that conducted GWAS for BPI; suggestive overlap between the GWAS analyses and ours was noted at ARNTL. Several suggestive, novel associations were detected with circadian genes and BPI and SZ/SZA, but the present analyses do not support associations with common polymorphisms that confer risk with odds ratios greater than 1.5. Additional analyses using adequately powered samples are warranted to further evaluate these results. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 6 | Int. J. Neuropsychopharmacol. 2010 Nov 13: 1369-81 |
| PMID | 20633309 |
| Title | Inflammatory gene expression in monocytes of patients with schizophrenia: overlap and difference with bipolar disorder. A study in naturalistically treated patients. |
| Abstract | Accumulating evidence indicates an activated inflammatory response system as a vulnerability factor for schizophrenia (SZ) and bipolar disorder (BD). We aimed to detect a specific inflammatory monocyte gene expression signature in SZ and compare such signature with our recently described inflammatory monocyte gene signature in BD. A quantitative-polymerase chain reaction (Q-PCR) case-control gene expression study was performed on monocytes of 27 SZ patients and compared to outcomes collected in 56 BD patients (all patients naturalistically treated). For Q-PCR we used nine 'SZ specific genes' (found in whole genome analysis), the 19 BD signature genes (previously found by us) and six recently described autoimmune diabetes inflammatory monocyte genes. Monocytes of SZ patients had (similar to those of BD patients) a high inflammatory set point composed of three subsets of strongly correlating genes characterized by different sets of transcription/MAPK regulating factors. Subset 1A, characterized by ATF3 and DUSP2, and subset 1B, characterized by EGR3 and MXD1, were shared between BD and SZ patients (up-regulated in 67% and 51%, and 34% and 41%, respectively). Subset 2, characterized by PTPN7 and NAB2 was up-regulated in the monocytes of 62% BD, but down-regulated in the monocytes of 48% of SZ patients. Our approach shows that monocytes of SZ and BD patients overlap, but also differ in inflammatory gene expression. Our approach opens new avenues for nosological classifications of psychoses based on the inflammatory state of patients, enabling selection of those patients who might benefit from an anti-inflammatory treatment. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 7 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2010 Apr 34: 506-9 |
| PMID | 20144677 |
| Title | No association between EGR gene family polymorphisms and schizophrenia in the Chinese population. |
| Abstract | Early growth response (EGR) genes are thought to have a role in the pathogenesis of schizophrenia because of their conserved DNA binding domain and biologically activity in neuronal plasticity. This zinc-finger motif could influence gene post-translational modification and expression. The multigenetic association model, using markers in genes of similar or antagonistic biological effects within a signal pathway or gene family, might be more appropriate to this aspect of the schizophrenia hypothesis than the single gene strategy. In this study we investigated the role of EGR1, EGR2, EGR3 and EGR4 within the EGR family. Taqman technology was used to examine 12 single nucleotide polymorphisms (SNPs) covering these four genes in 2044 Chinese Han subjects. Case-control analyses were performed to detect association of these 4 genes with schizophrenia and multifactor dimensionality reduction (MDR) analysis was employed to examine their potential gene-gene interaction in schizophrenia. Neither allelic nor genotypic single-locus tests revealed any significant association between EGR1-4 and the risk of schizophrenia nor was any such association found with regard to interaction within EGR1-4 (p(min)=0.623, CV Consistency=10/10). We concluded that although multiple candidate genes are involved in schizophrenogenic development, the EGR family may not play a major role in schizophrenia susceptibility in the Chinese Han population. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 8 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2010 Oct 153B: 1355-60 |
| PMID | 20687139 |
| Title | EGR3 as a potential susceptibility gene for schizophrenia in Korea. |
| Abstract | Early growth response (EGR) genes play critical roles in signal transduction in the brain, which is involved in neuronal activation, brain development, and synaptic plasticity. EGR genes, including EGR2, EGR3, and EGR4, showed significant association with schizophrenia in Japanese schizophrenic pedigrees. In particular, EGR3, which resides at the chromosomal location 8p21.3, was suggested to be a potential susceptibility gene in schizophrenia based on a study of Japanese cases. However, this requires further replication with an independent sample set. We investigated the association of the EGR3 and EGR2 genes, which were suggested as potential susceptibility genes for schizophrenia supported by both genetic association and postmortem brain expression studies, with schizophrenia in Korean patients. Along with 350 healthy individuals, 244 schizophrenic patients were analyzed. Among the four examined single-nucleotide polymorphisms (SNPs) of EGR3 (rs1008949, rs7009708, rs35201266, and rs3750192), SNP rs35201266 in intron 1 of the EGR3 gene showed a significant association with schizophrenia (P?=?0.0008, ?(2)?=?11.156, OR?=?1.493), which withstands multiple testing correction. In addition, the "T-G-C-G" haplotype of EGR3 was under-represented in the patients with schizophrenia (P?=?0.0073, ?(2)?=?7.188, OR?=?0.697). However, an association between the SNPs of EGR2 (rs2295814 and rs2297488) and schizophrenia was not found. These findings are consistent with the previous genetic association of the EGR3 gene in Japanese cohorts, which is the first replication concerning the association of EGR3 with schizophrenia in an independent cohort. Taken together, EGR3 could be suggested as a compelling susceptibility gene in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 9 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2010 Oct 153B: 1355-60 |
| PMID | 20687139 |
| Title | EGR3 as a potential susceptibility gene for schizophrenia in Korea. |
| Abstract | Early growth response (EGR) genes play critical roles in signal transduction in the brain, which is involved in neuronal activation, brain development, and synaptic plasticity. EGR genes, including EGR2, EGR3, and EGR4, showed significant association with schizophrenia in Japanese schizophrenic pedigrees. In particular, EGR3, which resides at the chromosomal location 8p21.3, was suggested to be a potential susceptibility gene in schizophrenia based on a study of Japanese cases. However, this requires further replication with an independent sample set. We investigated the association of the EGR3 and EGR2 genes, which were suggested as potential susceptibility genes for schizophrenia supported by both genetic association and postmortem brain expression studies, with schizophrenia in Korean patients. Along with 350 healthy individuals, 244 schizophrenic patients were analyzed. Among the four examined single-nucleotide polymorphisms (SNPs) of EGR3 (rs1008949, rs7009708, rs35201266, and rs3750192), SNP rs35201266 in intron 1 of the EGR3 gene showed a significant association with schizophrenia (P?=?0.0008, ?(2)?=?11.156, OR?=?1.493), which withstands multiple testing correction. In addition, the "T-G-C-G" haplotype of EGR3 was under-represented in the patients with schizophrenia (P?=?0.0073, ?(2)?=?7.188, OR?=?0.697). However, an association between the SNPs of EGR2 (rs2295814 and rs2297488) and schizophrenia was not found. These findings are consistent with the previous genetic association of the EGR3 gene in Japanese cohorts, which is the first replication concerning the association of EGR3 with schizophrenia in an independent cohort. Taken together, EGR3 could be suggested as a compelling susceptibility gene in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 10 | BMC Syst Biol 2010 -1 4: 10 |
| PMID | 20156358 |
| Title | A novel microRNA and transcription factor mediated regulatory network in schizophrenia. |
| Abstract | schizophrenia is a complex brain disorder with molecular mechanisms that have yet to be elucidated. Previous studies have suggested that changes in gene expression may play an important role in the etiology of schizophrenia, and that microRNAs (miRNAs) and transcription factors (TFs) are primary regulators of this gene expression. So far, several miRNA-TF mediated regulatory modules have been verified. We hypothesized that miRNAs and TFs might play combinatory regulatory roles for schizophrenia genes and, thus, explored miRNA-TF regulatory networks in schizophrenia. We identified 32 feed-forward loops (FFLs) among our compiled schizophrenia-related miRNAs, TFs and genes. Our evaluation revealed that these observed FFLs were significantly enriched in schizophrenia genes. By converging the FFLs and mutual feedback loops, we constructed a novel miRNA-TF regulatory network for schizophrenia. Our analysis revealed EGR3 and hsa-miR-195 were core regulators in this regulatory network. We next proposed a model highlighting EGR3 and miRNAs involved in signaling pathways and regulatory networks in the nervous system. Finally, we suggested several single nucleotide polymorphisms (SNPs) located on miRNAs, their target sites, and TFBSs, which may have an effect in schizophrenia gene regulation. This study provides many insights on the regulatory mechanisms of genes involved in schizophrenia. It represents the first investigation of a miRNA-TF regulatory network for a complex disease, as demonstrated in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 11 | Brain Behav. Immun. 2011 Aug 25: 1162-9 |
| PMID | 21421043 |
| Title | TREM-1 and DAP12 expression in monocytes of patients with severe psychiatric disorders. EGR3, ATF3 and PU.1 as important transcription factors. |
| Abstract | Immune activation is a characteristic of schizophrenia (SCZ), bipolar disorder (BD) and unipolar major depressive disorder (MDD). The triggering receptor expressed on myeloid cells 1 (TREM-1), its' adaptor molecule DAP12 and their transcription factor (TF) PU.1 are important key genes in inflammation and expressed in activated monocytes and microglia. To test: (1) if the expressions of TREM-1, DAP12 and PU.1 are increased in monocytes of patients with severe psychiatric disorders and (2) if PU.1 and the TFs ATF3 and EGR3 (which have been found as prominent increased monocyte genes in previous studies) are involved in the regulation of TREM-1 and DAP12 expression. Using Q-PCR, we studied the gene expression of TREM-1, DAP12, PU.1, ATF3 and EGR3 in the monocytes of 73 patients with severe psychiatric disorders (27 recent onset SCZ patients, 22 BD patients and 24 MDD patients) and of 79 healthy controls (HC). Using in silico TF binding site prediction and in vivo chromatin immunoprecipitation (ChIP), we studied the actual binding of EGR3, ATF3 and PU.1 to the promoter regions of TREM-1 and DAP12. 1. TREM-1 gene expression was increased in the monocytes of SCZ and BD patients and tended to be increased in the monocytes of MDD patients. 2. DAP12 gene levels were neither increased in the monocytes of SCZ, BD, nor MDD patients. 3. PU.1 expression levels were increased in the monocytes of MDD patients, but not in those of SCZ and BD patients. 4. TREM-1 expression levels correlated in particular to ATF3 and EGR3 expression levels, DAP12 expression levels correlated in particular to PU.1 expression levels. 5. We found using binding site prediction and ChIP assays that the TFs EGR3 and ATF3 indeed bound to the TREM-1 promoter, PU.1 bound to both the TREM-1 and DAP12 promoter. In this study, we provide evidence that TREM-1 gene expression is significantly increased in monocytes of SCZ and BD patients and that the TREM-1 gene is a target gene of the TFs ATF3 and EGR3. In MDD patients, PU.1 gene expression was increased with a tendency for TREM-1 gene over expression. Our observations support the concept that monocytes are in a pro-inflammatory state in severe psychiatric conditions and suggest differences in monocyte inflammatory set points between SCZ, BD and MDD. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 12 | Psychiatry Res 2011 Jan 185: 16-9 |
| PMID | 20537399 |
| Title | Association of calcineurin A gamma subunit (PPP3CC) and early growth response 3 (EGR3) gene polymorphisms with susceptibility to schizophrenia in a Japanese population. |
| Abstract | To examine the association of PPP3CC (rs10108011 and rs2461491) and EGR3 (rs3750192) single-nucleotide polymorphisms (SNPs) with Japanese schizophrenia, we performed a case-control association study using 337 patients and 369 healthy controls. As a result, by our moderated cohort-size study, PPP3CC and EGR3 are not genetic risk factors for schizophrenia, whereas meta-analysis showed weak association of rs10108011 with schizophrenia in the Japanese population (odds ratio (OR)=1.12, P=0.01). |
| SCZ Keywords | schizophrenia, schizophrenic |
| 13 | Yi Chuan 2012 Mar 34: 307-14 |
| PMID | 22425949 |
| Title | [A family-based association study of the EGR3 gene polymorphisms and schizophrenia]. |
| Abstract | Previous studies showed that EGR3 gene located in chromosome 8p21.3 was involved in the etiology of schizophrenia. However, the finding failed to be replicated in several case-control studies. To investigate the genetic role of the EGR3 gene in Chinese psychiatric patients, we genotyped five single nucleotide polymorphisms (SNPs) in EGR3 gene locus using 93 nuclear families in Han Chinese, and performed transmission disequilibrium test (TDT). In this study, two SNPs (rs1996147 and rs3750192) showed significant association with schizophrenia (c2>4.40, P<0.05). In the linkage disequilibrium analysis, the significant association was also found in two- (rs3750192-rs35201266), three- (rs1877670- rs3750192-rs7009708) and four-SNP (rs1996147-rs1877670-rs3750192-rs7009708) tests of haplotype analyses (c2>7.10, global P<0.05). Overall, the results suggested that EGR3 gene may play an important role in schizophrenia susceptibility in the Han Chinese population, and further functional exploration of the EGR3 gene will contribute to the underlying molecular mechanism for schizophrenia pathogenesis. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 14 | Neuropsychopharmacology 2012 Sep 37: 2285-98 |
| PMID | 22692564 |
| Title | Reduced levels of serotonin 2A receptors underlie resistance of Egr3-deficient mice to locomotor suppression by clozapine. |
| Abstract | The immediate-early gene early growth response 3 (EGR3) is associated with schizophrenia and expressed at reduced levels in postmortem patients' brains. We have previously reported that EGR3-deficient (EGR3(-/-)) mice display reduced sensitivity to the sedating effects of clozapine compared with wild-type (WT) littermates, paralleling the heightened tolerance of schizophrenia patients to antipsychotic side effects. In this study, we have used a pharmacological dissection approach to identify a neurotransmitter receptor defect in EGR3(-/-) mice that may mediate their resistance to the locomotor suppressive effects of clozapine. We report that this response is specific to second-generation antipsychotic agents (SGAs), as first-generation medications suppress the locomotor activity of EGR3(-/-) and WT mice to a similar degree. Further, in contrast to the leading theory that sedation by clozapine results from anti-histaminergic effects, we show that H1 histamine receptors are not responsible for this effect in C57BL/6 mice. Instead, selective serotonin 2A receptor (5HT(2A)R) antagonists ketanserin and MDL-11939 replicate the effect of SGAs, repressing the activity in WT mice at a dosage that fails to suppress the activity of EGR3(-/-) mice. Radioligand binding revealed nearly 70% reduction in 5HT(2A)R expression in the prefrontal cortex of EGR3(-/-) mice compared with controls. EGR3(-/-) mice also exhibit a decreased head-twitch response to 5HT(2A)R agonist 1-(2,5-dimethoxy 4-iodophenyl)-2-amino propane (DOI). These findings provide a mechanism to explain the reduced sensitivity of EGR3(-/-) mice to the locomotor suppressive effects of SGAs, and suggest that 5HT(2A)Rs may also contribute to the sedating properties of these medications in humans. Moreover, as the deficit in cortical 5HT(2A)R in EGR3(-/-) mice aligns with numerous studies reporting decreased 5HT(2A)R levels in the brains of schizophrenia patients, and the gene encoding the 5HT(2A)R is itself a leading schizophrenia candidate gene, these findings suggest a potential mechanism by which putative dysfunction in EGR3 in humans may influence risk for schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 15 | PLoS ONE 2012 -1 7: e30237 |
| PMID | 22276163 |
| Title | Genetic evidence for the association between the early growth response 3 (EGR3) gene and schizophrenia. |
| Abstract | Recently, two genome scan meta-analysis studies have found strong evidence for the association of loci on chromosome 8p with schizophrenia. The early growth response 3 (EGR3) gene located in chromosome 8p21.3 was also found to be involved in the etiology of schizophrenia. However, subsequent studies failed to replicate this finding. To investigate the genetic role of EGR3 in Chinese patients, we genotyped four SNPs (average interval ?2.3 kb) in the chromosome region of EGR3 in 470 Chinese schizophrenia patients and 480 healthy control subjects. The SNP rs35201266 (located in intron 1 of EGR3) showed significant differences between cases and controls in both genotype frequency distribution (P?=?0.016) and allele frequency distribution (P?=?0.009). Analysis of the haplotype rs35201266-rs3750192 provided significant evidence for association with schizophrenia (P?=?0.0012); a significant difference was found for the common haplotype AG (P?=?0.0005). Furthermore, significant associations were also found in several other two-, and three-SNP tests of haplotype analyses. The meta-analysis revealed a statistically significant association between rs35201266 and schizophrenia (P?=?0.0001). In summary, our study supports the association of EGR3 with schizophrenia in our Han Chinese sample, and further functional exploration of the EGR3 gene will contribute to the molecular basis for the complex network underlying schizophrenia pathogenesis. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 16 | Neural Regen Res 2013 Sep 8: 2415-23 |
| PMID | 25206551 |
| Title | Hippocampal and thalamic neuronal metabolism in a putative rat model of schizophrenia. |
| Abstract | The transcription factor early growth response protein 3 (EGR3) is involved in schizophrenia. We developed a putative rat model of schizophrenia by transfecting lentiviral particles carrying the EGR3 gene into bilateral hippocampal dentate gyrus. We assessed spatial working memory using the Morris water maze test, and neuronal metabolite levels in bilateral hippocampus and thalamus were determined by 3.0 T proton magnetic resonance spectroscopy. Choline content was significantly greater in the hippocampus after transfection, while N-acetylaspartate and the ratio of N-acetylaspartate to creatine/phosphocreatine in the thalamus were lower than in controls. This study is the first to report evaluation of brain metabolites using 3.0 T proton magnetic resonance spectroscopy in rats transfected with EGR3, and reveals metabolic abnormalities in the hippocampus and thalamus in this putative model of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 17 | Neuroimage 2014 Jan 85 Pt 1: 527-34 |
| PMID | 23962955 |
| Title | Association of decreased prefrontal hemodynamic response during a verbal fluency task with EGR3 gene polymorphism in patients with schizophrenia and in healthy individuals. |
| Abstract | The early growth response 3 (EGR3) gene is an immediate early gene that is expressed throughout the brain and has been suggested as a potential susceptibility gene for schizophrenia (SZ). EGR3 impairment is associated with various neurodevelopmental dysfunctions, and some animal studies have reported a role for EGR3 function in the prefrontal cortex. Therefore, EGR3 genotype variation may be reflected in prefrontal function. By using multi-channel near-infrared spectroscopy (NIRS) in an imaging genetics approach, we tested for an association between the EGR3 gene polymorphism and prefrontal hemodynamic response during a cognitive task in patients with SZ. We assessed 73 chronic patients with SZ and 73 age-, gender-, and genotype-matched healthy controls (HC) who provided written informed consent. We used NIRS to measure changes in prefrontal oxygenated hemoglobin concentration (oxyHb) during the letter version of a verbal fluency task (VFT). Statistical comparisons were performed among EGR3 genotype subgroups (rs35201266, GG/GA/AA). The AA genotype group showed significantly smaller oxyHb increases in the left dorsolateral prefrontal cortex (DLPFC) during the VFT than the GG and GA genotype groups; this was true for both patients with SZ and HC. Our findings provide in vivo human evidence of a significant influence of EGR3 polymorphisms on prefrontal hemodynamic activation level in healthy adults and in patients with SZ. Genetic variation in EGR3 may affect prefrontal function through neurodevelopment. This study illustrates the usefulness of NIRS in imaging genetics investigations on psychiatric disorders. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 18 | ACS Chem Neurosci 2015 Jul 6: 1137-42 |
| PMID | 25857407 |
| Title | Htr2a Expression Responds Rapidly to Environmental Stimuli in an Egr3-Dependent Manner. |
| Abstract | Pharmacologic and genetic findings have implicated the serotonin 2A receptor (5-HT2AR) in the etiology of schizophrenia. Recent studies have shown reduced 5-HT2AR levels in schizophrenia patients, yet the cause of this difference is unknown. Environmental factors, such as stress, also influence schizophrenia risk, yet little is known about how environment may affect this receptor. To determine if acute stress alters 5-HT2AR expression, we examined the effect of sleep deprivation on cortical Htr2a mRNA in mice. We found that 6 h of sleep deprivation induces a twofold increase in Htr2a mRNA, a more rapid effect than has been previously reported. This effect requires the immediate early gene early growth response 3 (EGR3), as sleep deprivation failed to induce Htr2a expression in EGR3-/- mice. These findings provide a functional link between two schizophrenia candidate genes and an explanation of how environment may influence a genetic predisposition for schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 19 | Biochem. Biophys. Res. Commun. 2015 May 460: 678-83 |
| PMID | 25817788 |
| Title | Functional magnetic resonance imaging reveals abnormal brain connectivity in EGR3 gene transfected rat model of schizophrenia. |
| Abstract | schizophrenia is characterized by the disorder of "social brain". However, the alternation of connectivity density in brain areas of schizophrenia patients remains largely unknown. In this study, we successfully created a rat model of schizophrenia by the transfection of EGR3 gene into rat brain. We then investigated the connectivity density of schizophrenia susceptible regions in rat brain using functional magnetic resonance imaging (fMRI) in combination with multivariate Granger causality (GC) model. We found that the average signal strength in prefrontal lobe and hippocampus of schizophrenia model group was significantly higher than the control group. Bidirectional Granger causality connection was observed between hippocampus and thalamic in schizophrenia model group. Both connectivity density and Granger causality connection were changed in prefrontal lobe, hippocampus and thalamus after risperidone treatment. Our results indicated that fMRI in combination with GC connection analysis may be used as an important method in diagnosis of schizophrenia and evaluation the effect of antipsychotic treatment. These findings support the connectivity disorder hypothesis of schizophrenia and increase our understanding of the neural mechanisms of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 20 | J Biomed Mater Res A 2015 Feb 103: 746-61 |
| PMID | 24866321 |
| Title | Gene expression analysis of laminin-1-induced neurite outgrowth in human mesenchymal stem cells derived from bone marrow. |
| Abstract | The mechanisms underlying the differentiation of Mesenchymal stem cells (MSCs) toward neuronal cell type are not clearly understood. Earlier, we reported that laminin-1 induces neurite outgrowth in human MSCs via c-Jun/AP-1 activation through ERK, JNK, and Akt pathways. In this study, we demonstrate that laminin-1 increases the expression of proneural gene, neuroD1 and induces the expression of immediate-early biomarkers of neuronal cell-programming-Egr1, EGR3, PC3, and PC4. Gene expression profiling of MSCs cultured on laminin-1 and Poly-l-lysine for 12 h revealed differential regulation of 267 genes (>1.5 fold, p < 0.05), predominantly in the category of nervous system development and affected the pathways involved in TGF-?/TNF-? signaling, regulation of MAPK and JNK cascade. Data for 11 selected genes related to nervous system development was validated by real time PCR. Transcriptional regulatory network analysis revealed c-Jun as the key transcription factor regulating majority of differentially expressed genes and identified Disrupted in schizophrenia 1, as a novel target of c-Jun. Modeling and analysis of biological network showed selective induction of Growth Arrest and DNA damage 45 (GADD45B) and repression of NF-?B inhibitor A (NF?BIA). Collectively, our findings provide the basis for understanding the molecular mechanisms associated with laminin-1-induced neurogenic expression in MSCs. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 21 | PLoS ONE 2015 -1 10: e0135076 |
| PMID | 26474411 |
| Title | Association of SNPs in EGR3 and ARC with Schizophrenia Supports a Biological Pathway for Schizophrenia Risk. |
| Abstract | We have previously hypothesized a biological pathway of activity-dependent synaptic plasticity proteins that addresses the dual genetic and environmental contributions to schizophrenia. Accordingly, variations in the immediate early gene EGR3, and its target ARC, should influence schizophrenia susceptibility. We used a pooled Next-Generation Sequencing approach to identify variants across these genes in U.S. populations of European (EU) and African (AA) descent. Three EGR3 and one ARC SNP were selected and genotyped for validation, and three SNPs were tested for association in a replication cohort. In the EU group of 386 schizophrenia cases and 150 controls EGR3 SNP rs1877670 and ARC SNP rs35900184 showed significant associations (p = 0.0078 and p = 0.0275, respectively). In the AA group of 185 cases and 50 controls, only the ARC SNP revealed significant association (p = 0.0448). The ARC SNP did not show association in the Han Chinese (CH) population. However, combining the EU, AA, and CH groups revealed a highly significant association of ARC SNP rs35900184 (p = 2.353 x 10(-7); OR [95% CI] = 1.54 [1.310-1.820]). These findings support previously reported associations between EGR3 and schizophrenia. Moreover, this is the first report associating an ARC SNP with schizophrenia and supports recent large-scale GWAS findings implicating the ARC complex in schizophrenia risk. These results support the need for further investigation of the proposed pathway of environmentally responsive, synaptic plasticity-related, schizophrenia genes. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 22 | Neuropsychiatr Dis Treat 2015 -1 11: 1625-38 |
| PMID | 26170675 |
| Title | The reduction of volume and fiber bundle connections in the hippocampus of EGR3 transgenic schizophrenia rats. |
| Abstract | There is a growing consensus that schizophrenia is ultimately caused by abnormal communication between spatially disparate brain structures. White matter fasciculi represent the primary infrastructure for long distance communication in the brain. In this study, we aimed to investigate the white matter connection in schizophrenia susceptible brain regions of early growth response factor 3 (EGR3) expressing rats. A rat model of schizophrenia was created by the transfection of the EGR3 gene into rat hippocampus. All animals were placed in a fixation system using a commercial rat-dedicated coil. schizophrenia susceptible brain regions were scanned using in vivo diffusion tensor magnetic resonance imaging. The volume, quantity, average length of fiber bundles, fractional anisotropy, apparent diffusion coefficient, the relative heterosexual fraction, and volume ratio were collected in the whole brain and schizophrenia related brain areas (the hippocampus, thalamus, and prefrontal lobe). MedINRIA software was used for data processing of diffusion tensor and fiber bundles tracking. The fibronectin in relevant brain regions was also analyzed. There was a significant decrease in the volume of the fiber beam through the left hippocampus dentate in the schizophrenia model group in comparison to the control group and the risperidone treatment group (P<0.05). A significant reduction in the volume and number of the fiber bundles was also observed in left prefrontal-left hippocampus, left hippocampus-left thalamus, left prefrontal-left hippocampus-left thalamus areas in the model group (all P<0.05). The volume of hippocampus and the number of fiber bundles were reduced in EGR3 transgenic schizophrenia rats, and are the most sensitive indicators in schizophrenia. The diffusion tensor imaging technique plays an important role in the evaluation of patients with schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic |