| 1 | Psychiatry Res 2000 Feb 93: 41-54 |
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| PMID | 10699227 |
| Title | Smooth pursuit eye tracking and visual fixation in psychosis-prone individuals. |
| Abstract | Subjects identified by Perceptual Aberration-MAGical Ideation (Per-MAG) scores (n=97), Social Anhedonia (SocAnh) scores (n=45), and Physical Anhedonia (PhysAnh) scores (n=31) as well as normal controls (n=94), underwent psychophysiological and clinical assessment. This is the first published investigation of pursuit system functioning in three groups of questionnaire-identified at-risk individuals. Pursuit during a simple non-monitor tracking task was measured using root-mean-square error (RMSE) scores and pursuit gain scores. Fixation performance was measured in terms of number of saccades away from the central fixation point. The at-risk subjects were more likely to display aberrant smooth pursuit tracking than controls, though there were no significant differences between the at-risk subjects endorsing items relevant to positive-symptom schizotypy and those endorsing items pertaining to negative-symptom schizotypy. The groups did not differ significantly in their visual fixation performance. Participants were also evaluated for the presence of Axis I symptomatology and psychotic-like experiences. Neither the experimental subjects nor the control subjects displayed a significant association between ocular motor performance and psychotic-like experiences. These findings are consistent with prior evidence that pursuit tracking is a trait characteristic, independent of clinical status. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 2 | J. Neurosci. Res. 2004 Sep 77: 858-66 |
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| PMID | 15334603 |
| Title | Microarray analysis of postmortem temporal cortex from patients with schizophrenia. |
| Abstract | To examine molecular mechanisms associated with schizophrenia this study measured expression of approximately 12,000 genes in the middle temporal gyrus from 12 subjects with schizophrenia and 14 matched normal controls. Among the most consistent changes in genes with robust expression were significant decreases in the expression of myelination-related genes MAG, PLLP (TM4SF11), PLP1, ERBB3 in subjects with schizophrenia. There was also altered expression of genes regulating neurodevelopment (TRAF4, Neurod1, histone deacetylase 3), a circadian pacemaker (PER1), and several other genes involved in regulation of chromatin function and signaling mechanisms. These findings support the hypothesis that schizophrenia is associated with abnormalities in oligodendroglia and provide initial evidence suggesting a role for epigenetic mechanisms and altered circadian rhythms in this disorder. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 3 | J Appl Meas 2004 -1 5: 160-71 |
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| PMID | 15064535 |
| Title | A Rasch analysis of three of the Wisconsin Scales of Psychosis Proneness: measurement of schizotypy. |
| Abstract | Rasch analyses were conducted with data from 90 university students on three of the Wisconsin Scales of Psychosis Proneness--the MAGical Ideation (Eckblad & Chapman, 1983), Perceptual Aberration (Chapman, Chapman, & Raulin, 1978), and Revised Social Anhedonia Scales (Eckblad, Chapman, Chapman, & Mishlove, 1982). All of the items for each of the individual scales, plus all of the items from the combined Perceptual Aberration/MAGical Ideation (Per-MAG) Scale, showed satisfactory fit to the Rasch model. These results show that personality traits including these psychosis proneness, or schizotypy, traits can be measured on a theoretically sound quantitative interval scale. Rasch scale equivalents for raw scores are provided. Possible improvements to the MAGical Ideation, Perceptual Aberration, and Per-MAG scales are suggested by the item analysis. Advantages of Rasch scaling for clinical applications include detection of invalid test protocols, more meaningful interpretations of test scores, and direct comparison of scores from different tests of the same construct. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 4 | Mol. Psychiatry 2005 Mar 10: 309-22 |
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| PMID | 15303102 |
| Title | Transcriptional profiling reveals evidence for signaling and oligodendroglial abnormalities in the temporal cortex from patients with major depressive disorder. |
| Abstract | Major depressive disorder is one of the most common and devastating psychiatric disorders. To identify candidate mechanisms for major depressive disorder, we compared gene expression in the temporal cortex from 12 patients with major depressive disorder and 14 matched controls using Affymetrix HgU95A microarrays. Significant expression changes were revealed in families of genes involved in neurodevelopment, signal transduction and cell communication. Among these, the expression of 17 genes related to oligodendrocyte function was significantly (P < 0.05, fold change > 1.4) decreased in patients with major depressive disorder. Eight of these 17 genes encode structural components of myelin (CNP, MAG, MAL, MOG, MOBP, PMP22, PLLP, PLP1). Five other genes encode enzymes involved in the synthesis of myelin constituents (ASPA, UGT8), or are essential in regulation of myelin formation (ENPP2, EDG2, TF, KLK6). One gene, that is, SOX10, encodes a transcription factor regulating other myelination-related genes. OLIG2 is a transcription factor present exclusively in oligodendrocytes and oligodendrocyte precursors. Another gene, ERBB3, is involved in oligodendrocyte differentiation. In addition to myelination-related genes, there were significant changes in multiple genes involved in axonal growth/synaptic function. These findings suggest that major depressive disorder may be associated with changes in cell communication and signal transduction mechanisms that contribute to abnormalities in oligodendroglia and synaptic function. Taken together with other studies, these findings indicate that major depressive disorder may share common oligodendroglial abnormalities with schizophrenia and bipolar disorder. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 5 | Neurosci. Lett. 2005 Nov 388: 126-31 |
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| PMID | 16039057 |
| Title | Polymorphisms of myelin-associated glycoprotein gene are associated with schizophrenia in the Chinese Han population. |
| Abstract | Results of gene expression microarray and quantitative PCR studies have suggested abnormalities in the expression of myelin-related genes including myelin-associated glycoprotein (MAG) in schizophrenic patients. Research provides strong evidence for oligodendrocyte dysfunction in schizophrenics. In order to further assess the role of MAG in schizophrenia, we examined four single nucleotide polymorphisms (SNPs), namely rs2301600, rs3746248, rs720309 and rs720308, of this gene in Chinese schizophrenic patients (n=470) and healthy controls (n=470). The distribution of rs720309 T/A genotypes showed a strong association with schizophrenia (chi(2)=14.58, d.f.=2, P=0.0008). A haplotype constructed of rs720309-rs720308 also revealed a significant association with schizophrenia (chi(2)=11.914, d.f.=3, P=0.0084). Our findings of a significant associations between schizophrenia and the MAG gene suggest that this gene may be involved in susceptibility to schizophrenia in the Chinese Han population. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 6 | Neurosci. Lett. 2005 Nov 388: 126-31 |
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| PMID | 16039057 |
| Title | Polymorphisms of myelin-associated glycoprotein gene are associated with schizophrenia in the Chinese Han population. |
| Abstract | Results of gene expression microarray and quantitative PCR studies have suggested abnormalities in the expression of myelin-related genes including myelin-associated glycoprotein (MAG) in schizophrenic patients. Research provides strong evidence for oligodendrocyte dysfunction in schizophrenics. In order to further assess the role of MAG in schizophrenia, we examined four single nucleotide polymorphisms (SNPs), namely rs2301600, rs3746248, rs720309 and rs720308, of this gene in Chinese schizophrenic patients (n=470) and healthy controls (n=470). The distribution of rs720309 T/A genotypes showed a strong association with schizophrenia (chi(2)=14.58, d.f.=2, P=0.0008). A haplotype constructed of rs720309-rs720308 also revealed a significant association with schizophrenia (chi(2)=11.914, d.f.=3, P=0.0084). Our findings of a significant associations between schizophrenia and the MAG gene suggest that this gene may be involved in susceptibility to schizophrenia in the Chinese Han population. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 7 | Neurosci. Lett. 2005 Nov 388: 126-31 |
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| PMID | 16039057 |
| Title | Polymorphisms of myelin-associated glycoprotein gene are associated with schizophrenia in the Chinese Han population. |
| Abstract | Results of gene expression microarray and quantitative PCR studies have suggested abnormalities in the expression of myelin-related genes including myelin-associated glycoprotein (MAG) in schizophrenic patients. Research provides strong evidence for oligodendrocyte dysfunction in schizophrenics. In order to further assess the role of MAG in schizophrenia, we examined four single nucleotide polymorphisms (SNPs), namely rs2301600, rs3746248, rs720309 and rs720308, of this gene in Chinese schizophrenic patients (n=470) and healthy controls (n=470). The distribution of rs720309 T/A genotypes showed a strong association with schizophrenia (chi(2)=14.58, d.f.=2, P=0.0008). A haplotype constructed of rs720309-rs720308 also revealed a significant association with schizophrenia (chi(2)=11.914, d.f.=3, P=0.0084). Our findings of a significant associations between schizophrenia and the MAG gene suggest that this gene may be involved in susceptibility to schizophrenia in the Chinese Han population. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 8 | Schizophr. Res. 2005 Jun 75: 11-9 |
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| PMID | 15820319 |
| Title | Possible association of the MAG locus with schizophrenia in a Chinese Han cohort of family trios. |
| Abstract | Neurotransmitter-based hypotheses have so far led to only moderate success in predicting new pathogenetic findings in etiology of schizophrenia. On the other hand, the more recent oligodendroglia hypotheses of this disorder have been supported by an increasing body of evidence. For example, the expression level of the myelin associated glycoprotein (MAG) gene has been shown to be significantly lower in schizophrenia patient groups compared to control groups. Such an effect might be a result of genetic variations of the MAG gene. In order to test this hypothesis, we genotyped four markers within the MAG locus in 413 trios sample of the Han Chinese using allele-specific PCR. None of the four markers revealed noticeable allelic significance. However, the four-marker and two-marker haplotypes covering components rs720309 and rs720308 were observed to be significantly associated with schizophrenia (P < 0.0001) in this study. In addition, we identified one common risk haplotype TA (rs720309-rs720308, present in 78.5% of the general population) that showed increased evidence of overtransmission from parents to affected offspring (P = 0.0001). The results demonstrated MAG might play a role in genetic susceptibility to schizophrenia. Furthermore, our finding of a possible association between the MAG locus and schizophrenia is in agreement with the hypotheses of oligodendrltic and myelination dysfunction. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 9 | Neurobiol. Dis. 2006 Mar 21: 531-40 |
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| PMID | 16213148 |
| Title | Myelin-associated mRNA and protein expression deficits in the anterior cingulate cortex and hippocampus in elderly schizophrenia patients. |
| Abstract | Microarray and other studies have reported oligodendrocyte and myelin-related (OMR) deficits in schizophrenia. Here, we employed a quantitative approach to determine the MAGnitude of OMR gene expression deficits and their brain-region specificity. In addition, we examined how expression levels among the studied OMR genes are interrelated. mRNA of MAG, CNP, SOX10, CLDN11, and PMP22, but not MBP and MOBP, was reduced in the hippocampus and anterior cingulate cortex but not in the putamen of patients with schizophrenia. Expression of the only protein examined (CNP) was decreased in the hippocampus but not in the putamen. Correlation and factor analyses revealed that mRNA levels for genes that did exhibit differential expression in schizophrenia (MAG, CNP, SOX10, CLDN11, and PMP2), as opposed to those that did not (MOBP and MBP), loaded on separate factors. Thus, OMR gene and protein expression deficits in schizophrenia are brain-region specific, and the affected components may share regulatory elements. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 10 | Proc. Natl. Acad. Sci. U.S.A. 2006 May 103: 7482-7 |
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| PMID | 16641098 |
| Title | Human QKI, a potential regulator of mRNA expression of human oligodendrocyte-related genes involved in schizophrenia. |
| Abstract | The quaking viable mouse mutation (qk(v)) is a deletion including the 5' regulatory region of the quaking gene (Qki), which causes body tremor and severe dysmyelination in mouse. The function of the human quaking gene, called quaking homolog KH domain RNA-binding (mouse) (QKI), is not well known. We have previously shown that QKI is a new candidate gene for schizophrenia. Here we show that human QKI mRNA levels can account for a high proportion (47%) of normal interindividual mRNA expression variation (and covariation) of six oligodendrocyte-related genes (PLP1, MAG, MBP, TF, SOX10, and CDKN1B) in 55 human brain autopsy samples from individuals without psychiatric diagnoses. In addition, the tightly coexpressed myelin-related genes (PLP1, MAG, and TF) have decreased mRNA levels in 55 schizophrenic patients, as compared with 55 control individuals, and most of this difference (68-96%) can be explained by variation in the relative mRNA levels of QKI-7kb, the same QKI splice variant previously shown to be down-regulated in patients with schizophrenia. Taken together, our results suggest that QKI levels may regulate oligodendrocyte differentiation and maturation in human brain, in a similar way as in mouse. Moreover, we hypothesize that previously observed decreased activity of myelin-related genes in schizophrenia might be caused by disturbed QKI splicing. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 11 | Proc. Natl. Acad. Sci. U.S.A. 2006 May 103: 7482-7 |
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| PMID | 16641098 |
| Title | Human QKI, a potential regulator of mRNA expression of human oligodendrocyte-related genes involved in schizophrenia. |
| Abstract | The quaking viable mouse mutation (qk(v)) is a deletion including the 5' regulatory region of the quaking gene (Qki), which causes body tremor and severe dysmyelination in mouse. The function of the human quaking gene, called quaking homolog KH domain RNA-binding (mouse) (QKI), is not well known. We have previously shown that QKI is a new candidate gene for schizophrenia. Here we show that human QKI mRNA levels can account for a high proportion (47%) of normal interindividual mRNA expression variation (and covariation) of six oligodendrocyte-related genes (PLP1, MAG, MBP, TF, SOX10, and CDKN1B) in 55 human brain autopsy samples from individuals without psychiatric diagnoses. In addition, the tightly coexpressed myelin-related genes (PLP1, MAG, and TF) have decreased mRNA levels in 55 schizophrenic patients, as compared with 55 control individuals, and most of this difference (68-96%) can be explained by variation in the relative mRNA levels of QKI-7kb, the same QKI splice variant previously shown to be down-regulated in patients with schizophrenia. Taken together, our results suggest that QKI levels may regulate oligodendrocyte differentiation and maturation in human brain, in a similar way as in mouse. Moreover, we hypothesize that previously observed decreased activity of myelin-related genes in schizophrenia might be caused by disturbed QKI splicing. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 12 | Int. J. Neuropsychopharmacol. 2007 Aug 10: 547-55 |
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| PMID | 17291372 |
| Title | Oligodendroglial abnormalities in schizophrenia, mood disorders and substance abuse. Comorbidity, shared traits, or molecular phenocopies? |
| Abstract | The evidence implicating oligodendroglia in major mental disorders has grown significantly in the past few years. Microarray analysis revealed altered expression of oligodendroglia-related genes in multiple brain regions from several, clinically diverse groups of subjects with schizophrenia (SZ) as well as subjects with bipolar disorder (BD) and major depressive disorders (MDD), alcoholics and cocaine users. In line with gene expression findings, evidence for ultrastructural changes in white matter and altered oligodendroglia in these disorders were reported in neuroiMAGing and neuropathological studies. Changes in oligodendroglia-related genes reported in SZ, BD and MDD appear to display considerable similarities (particularly decreased expression of MAG, ERBB, TF, PLP1, MOG, MOBP, MOG), while changes in cocaine abuse and alcoholism are more diverse. Common oligodendroglial abnormalities might indicate aetiological or pathophysiological overlaps between different disorders. The possible mechanisms of oligodendroglial abnormalities may involve functional variations in oligodendroglia-related genes, epigenetic regulation of chromatin, DA system hyperactivity and other mechanisms. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 13 | Int. J. Neuropsychopharmacol. 2007 Aug 10: 503-11 |
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| PMID | 17291369 |
| Title | Oligodendrocyte pathophysiology: a new view of schizophrenia. |
| Abstract | A recent focus of schizophrenia research is disruption of white-matter integrity as a key facet of this complex disorder. This was spurred, partly, by new iMAGing modalities, MAGnetic transfer iMAGing and diffusion tensor iMAGing, which showed differences in white-matter integrity and tract coherence in persons with schizophrenia compared to controls. Oligodendrocytes, in particular, have been the subject of increased study after gene microarray analyses revealed that six myelin-related genes specific to oligodendrocytes have decreased expression levels in schizophrenia. Oligodendrocytes have also been shown to be decreased in number in the superior frontal gyrus of subjects with schizophrenia. The MAG knockout mouse, missing a myelin-related gene linked to schizophrenia, may prove to be a useful animal model for the dysmyelination observed in the human disease. Studies currently ongoing on this model have found changes in dendritic branching patterns of pyramidal cells in layer III of the prefrontal cortex. Further characterization of the pathology in these mice is underway. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 14 | J Neural Transm (Vienna) 2007 Feb 114: 249-54 |
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| PMID | 16897606 |
| Title | No association between the genetic polymorphisms in the RTN4R gene and schizophrenia in the Chinese population. |
| Abstract | The RTN4R gene is located in the 22q11 region and it encodes a subunit of the receptor complex (RTN4R-p75NTR) which results in neuronal growth inhibitory signals in response to Nogo-66, MAG or OMG signaling. Previous studies have suggested that RTN4R might act as a potential candidate for schizophrenia susceptibility loci. We genotyped four SNPs within the gene and conducted a case-control study and TDT analysis, involving 707 schizophrenic patients, 689 controls and 372 unrelated small nuclear families with schizophrenic offspring in the Chinese population. We examined allele and genotype frequencies and haplotype distributions in both family- and nonfamily-based samples. Our results suggest that there is no significant association between the genetic polymorphisms and schizophrenia in the Han Chinese population. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 15 | J Neural Transm (Vienna) 2007 Feb 114: 249-54 |
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| PMID | 16897606 |
| Title | No association between the genetic polymorphisms in the RTN4R gene and schizophrenia in the Chinese population. |
| Abstract | The RTN4R gene is located in the 22q11 region and it encodes a subunit of the receptor complex (RTN4R-p75NTR) which results in neuronal growth inhibitory signals in response to Nogo-66, MAG or OMG signaling. Previous studies have suggested that RTN4R might act as a potential candidate for schizophrenia susceptibility loci. We genotyped four SNPs within the gene and conducted a case-control study and TDT analysis, involving 707 schizophrenic patients, 689 controls and 372 unrelated small nuclear families with schizophrenic offspring in the Chinese population. We examined allele and genotype frequencies and haplotype distributions in both family- and nonfamily-based samples. Our results suggest that there is no significant association between the genetic polymorphisms and schizophrenia in the Han Chinese population. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 16 | Schizophr. Res. 2007 Feb 90: 15-27 |
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| PMID | 17223013 |
| Title | Expression of transcripts for myelination-related genes in the anterior cingulate cortex in schizophrenia. |
| Abstract | Several recent studies have found changes in the expression of genes functionally related to myelination and oligodendrocyte homeostasis in schizophrenia. These studies utilized microarrays and quantitative PCR (QPCR), methodologies which do not permit direct, unamplified examination of mRNA expression. In addition, these studies generally only examined transcript expression in homogenates of gray matter. In the present study, we examined the expression of myelination-related genes previously implicated in schizophrenia by microarray or QPCR. Using in situ hybridization, we measured transcript expression of 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNP), myelin-associated glycoprotein (MAG), transferrin (TF), quaking (QKI), gelsolin, myelin oligodendrocyte glycoprotein, v-erb-b2 erythroblastic leukemia viral oncogene homolog 3, erbb2 interacting protein, motility-related protein-1, SRY-box containing gene 10, oligodendrocyte transcription factor 2, peripheral myelin protein 22, and claudin-11 in both gray and white matter of the anterior cingulate cortex (ACC) in subjects with schizophrenia (n=41) and a comparison group (n=34). We found decreased expression of MAG, QKI, TF, and CNP transcripts in white matter. We did not find any differences in expression of these transcripts between medicated (n=31) and unmedicated (n=10) schizophrenics, suggesting that these changes are not secondary to treatment with antipsychotics. Finally, we found significant positive correlations between QKI and MAG or CNP mRNA expression, suggesting that the transcription factor QKI regulates MAG and CNP expression. Our results support the hypothesis that myelination and oligodendrocyte function are impaired in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 17 | Schizophr. Res. 2007 Feb 90: 15-27 |
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| PMID | 17223013 |
| Title | Expression of transcripts for myelination-related genes in the anterior cingulate cortex in schizophrenia. |
| Abstract | Several recent studies have found changes in the expression of genes functionally related to myelination and oligodendrocyte homeostasis in schizophrenia. These studies utilized microarrays and quantitative PCR (QPCR), methodologies which do not permit direct, unamplified examination of mRNA expression. In addition, these studies generally only examined transcript expression in homogenates of gray matter. In the present study, we examined the expression of myelination-related genes previously implicated in schizophrenia by microarray or QPCR. Using in situ hybridization, we measured transcript expression of 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNP), myelin-associated glycoprotein (MAG), transferrin (TF), quaking (QKI), gelsolin, myelin oligodendrocyte glycoprotein, v-erb-b2 erythroblastic leukemia viral oncogene homolog 3, erbb2 interacting protein, motility-related protein-1, SRY-box containing gene 10, oligodendrocyte transcription factor 2, peripheral myelin protein 22, and claudin-11 in both gray and white matter of the anterior cingulate cortex (ACC) in subjects with schizophrenia (n=41) and a comparison group (n=34). We found decreased expression of MAG, QKI, TF, and CNP transcripts in white matter. We did not find any differences in expression of these transcripts between medicated (n=31) and unmedicated (n=10) schizophrenics, suggesting that these changes are not secondary to treatment with antipsychotics. Finally, we found significant positive correlations between QKI and MAG or CNP mRNA expression, suggesting that the transcription factor QKI regulates MAG and CNP expression. Our results support the hypothesis that myelination and oligodendrocyte function are impaired in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 18 | Psychiatr. Genet. 2008 Jun 18: 143-6 |
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| PMID | 18496213 |
| Title | A family-based association study of the myelin-associated glycoprotein and 2',3'-cyclic nucleotide 3'-phosphodiesterase genes with schizophrenia. |
| Abstract | A recent surge of evidence implicating myelin abnormalities in the etiology of schizophrenia has been found. This study is a family-based genetic association analysis examining the myelin-associated glycoprotein (MAG) and 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNP) genes in schizophrenia. About 246 families of primarily European-Caucasian origin were genotyped for MAG rs2301600, rs720308, rs720309, rs756796, and CNP rs2070106 single nucleotide polymorphisms (SNPs). The FBAT program (v1.7.2) and Transmit were used to analyze individual SNPs and haplotypes, respectively. The CNP SNP (rs2070106) was potentially associated with schizophrenia (P=0.027). MAG variants were not associated with disease transmission based on single marker or haplotype analysis. A significant maternal parent-of-origin effect for the CNP risk allele for schizophrenia was found (P=0.003). No CNP-MAG gene-gene interaction conferred increased risk for schizophrenia. Our finding provides support for potential association of the CNP gene but not the MAG gene in schizophrenia in a Caucasian population. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 19 | Neuropsychopharmacology 2008 Nov 33: 2993-3009 |
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| PMID | 18322470 |
| Title | Abnormal indices of cell cycle activity in schizophrenia and their potential association with oligodendrocytes. |
| Abstract | The goal of this study was to determine what signaling pathways may elicit myelin-specific gene expression deficits in schizophrenia (SZ). Microarray analyses indicated that genes associated with canonical cell cycle pathways were significantly affected in the anterior cingulate gyrus (ACG), the region exhibiting the most profound myelin-specific gene expression changes, in persons with SZ (N=16) as compared with controls (N=19). Detected gene expression changes of key regulators of G1/S phase transition and genes central to oligodendrocyte differentiation were validated using qPCR in the ACG in an independent cohort (Ns=45/34). The relative abundance of phosphorylated retinoblastoma protein (pRb) was increased in the white matter underlying the ACG in SZ subjects (Ns=12). The upregulation of cyclin D1 gene expression and the downregulation of p57(Kip2), accompanied by increased cyclin D/CDK4-dependent phosphorylation of pRb, acting as a checkpoint for G1/S phase transition, suggest abnormal cell cycle re-entry in postmitotic oligodendrocytes in SZ. Furthermore, gene expression profiling of brain samples from myelin mutant animal models, quaking and myelin-associated glycoprotein (MAG) null mice, showed that cell cycle gene expression changes were not a necessary consequence of the reduced gene expression of structural myelin proteins, such as MAG. While, quaking, a known modulator of cell cycle activity during oligodendrocyte differentiation impairs the expression of multiple myelin genes, including those that are affected in SZ. These data suggest that the normal patterns of cell cycle gene and protein expression are disrupted in SZ and that this disruption may contribute to the oligodendroglial deficits observed in SZ. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 20 | Schizophr. Res. 2008 Jan 98: 118-28 |
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| PMID | 18029146 |
| Title | Schizophrenia and sex associated differences in the expression of neuronal and oligodendrocyte-specific genes in individual thalamic nuclei. |
| Abstract | Considerable evidence based on the study of postmortem brain tissue suggests deficits in both neuronal and myelin systems in schizophrenia (SZ). To date, the majority of the biochemical and molecular biological studies have focused on the cerebral cortex. Most information traveling to or from the cortex is relayed or synaptically gated through the thalamus, and numerous studies suggest structural and functional abnormalities in interconnected regions of the thalamus and cortex in SZ. The present study extends our gene expression studies of neuronal and myelin systems to the thalamus. Quantitative PCR was employed to assess the expression of 10 genes in 5 divisions of the thalamus which were precisely harvested using Laser Capture Microdissection. The divisions studied were present on coronal sections at the level of the centromedian nucleus (CMN) taken from 14 schizophrenic and 16 normal control postmortem brains. The genes examined were specific for oligodendrocytes (MAG, CNP, MBP), neurons (ENO2), glutamatergic neurons (VGlut1, VGlut2, PV, CB) or GABAergic neurons (GAD65, GAD67). Expression levels for each of these markers were quantitated and compared between diagnoses, between sexes, and across nuclei. CB was much more highly expressed in the CMN in SZs compared to NCs. No other diagnosis related differences in gene expression were observed. The expression levels of CNP and MAG, but not MBP, were highly correlated with one another and both, but not MBP, were much more highly expressed in females than in males in all thalamic divisions examined. All markers were differentially expressed across nuclei. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 21 | Schizophr. Res. 2008 Jan 98: 118-28 |
|---|
| PMID | 18029146 |
| Title | Schizophrenia and sex associated differences in the expression of neuronal and oligodendrocyte-specific genes in individual thalamic nuclei. |
| Abstract | Considerable evidence based on the study of postmortem brain tissue suggests deficits in both neuronal and myelin systems in schizophrenia (SZ). To date, the majority of the biochemical and molecular biological studies have focused on the cerebral cortex. Most information traveling to or from the cortex is relayed or synaptically gated through the thalamus, and numerous studies suggest structural and functional abnormalities in interconnected regions of the thalamus and cortex in SZ. The present study extends our gene expression studies of neuronal and myelin systems to the thalamus. Quantitative PCR was employed to assess the expression of 10 genes in 5 divisions of the thalamus which were precisely harvested using Laser Capture Microdissection. The divisions studied were present on coronal sections at the level of the centromedian nucleus (CMN) taken from 14 schizophrenic and 16 normal control postmortem brains. The genes examined were specific for oligodendrocytes (MAG, CNP, MBP), neurons (ENO2), glutamatergic neurons (VGlut1, VGlut2, PV, CB) or GABAergic neurons (GAD65, GAD67). Expression levels for each of these markers were quantitated and compared between diagnoses, between sexes, and across nuclei. CB was much more highly expressed in the CMN in SZs compared to NCs. No other diagnosis related differences in gene expression were observed. The expression levels of CNP and MAG, but not MBP, were highly correlated with one another and both, but not MBP, were much more highly expressed in females than in males in all thalamic divisions examined. All markers were differentially expressed across nuclei. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 22 | Schizophr. Res. 2008 Jan 98: 129-38 |
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| PMID | 17964117 |
| Title | Expression of oligodendrocyte-associated genes in dorsolateral prefrontal cortex of patients with schizophrenia. |
| Abstract | Prior studies have found decreased mRNA expression of oligodendrocyte-associated genes in the dorsolateral prefrontal cortex (DLPFC) of patients with schizophrenia. However, it is unclear which specific genes are affected and whether the changes occur in the cortical white or grey matter. We assessed the mRNA expression levels of four oligodendrocyte-related genes: myelin-associated basic protein (MOBP), myelin-associated glycoprotein (MAG), 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNP) and oligodendrocyte-lineage transcription factor 2 (OLIG2) in DLPFC white and grey matter using quantitative-PCR (approximately 70 controls and approximately 30 patients with schizophrenia). We also examined the effects of high-risk polymorphisms in CNP and OLIG2 on mRNA levels of these genes. We found that genetic polymorphisms in CNP (rs2070106) and OLIG2 (rs1059004 and rs9653711), previously associated with schizophrenia, predicted low expression of these genes. Expression of MAG, CNP and OLIG2 did not differ between patients with schizophrenia and controls in the grey or white matter but MOBP mRNA levels were increased in the DLPFC white matter in patients with a history of substance abuse. MOBP and CNP protein in the white matter was not altered. Although previously reported reductions in the expression of myelin-related genes in the DLPFC were not detected, we show that individuals carrying risk-associated alleles in oligodendrocyte-related genes had relatively lower transcript levels. These data illustrate the importance of genetic background in gene expression studies in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 23 | Schizophr. Res. 2009 Jul 112: 54-64 |
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| PMID | 19447584 |
| Title | Subcortical oligodendrocyte- and astrocyte-associated gene expression in subjects with schizophrenia, major depression and bipolar disorder. |
| Abstract | Deficits in the expression of oligodendrocyte and myelin genes have been described in numerous cortical regions in schizophrenia and affective disorders; however, relatively little attention has been paid to subcortical structures. Here we employed quantitative real time PCR to examine the mRNA expression of 17 genes that are expressed by oligodendrocyte precursors (OLPs) and their derivatives, including astrocytes. Four subcortical regions were examined (the anteroventral (AV) and mediodorsal thalamic nuclei (MDN), internal capsule (IC) and putamen (Put)) in postmortem material from subjects (age 25-68 at time of death) with no known psychiatric history (NCs) as well as in subjects with schizophrenia (SZ), major depressive disorder (MDD), and bipolar disorder (BPD). In all regions examined, genes expressed after the terminal differentiation of oligodendrocytes tended to have lower levels of mRNA expression in subjects with SZ compared to NCs. These differences were statistically significant across regions for four genes (CNP, GALC, MAG and MOG) and approached significance for TF. No genes were under expressed in MDD. Only TF was under expressed in BPD and only in the IC. In contrast, two astrocyte-associated genes (GFAP and ALDH1L1) had higher mean expression levels across regions in all psychiatric groups relative to NCs. These differences reached statistical significance for SZ and MDD relative to NCs. There were no age by diagnosis interactions. The majority of age regressions had negative slopes for the expression of oligodendrocyte-associated genes. GFAP but not ALDH1L1 expression was significantly and positively correlated with age in the MDN, AV and Put. Across subject groups the expression of both astrocyte genes was highly correlated with cumulative neuroleptic exposure in all regions except the Put. Significant positive correlations were also observed in some regions between cumulative neuroleptic exposure and the expression of genes associated with mature oligodendrocytes as well as with bipotential OLPs. Multiple negative correlations were observed between the mRNA expression of astrocyte genes and genes expressed by terminally differentiated oligodendrocytes. These data are discussed in the context of myelin turnover and potential effects of psychiatric illness as well as medications on the developmental fate of OLPs. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 24 | Schizophr. Res. 2009 Jul 112: 46-53 |
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| PMID | 19487109 |
| Title | Abnormal expression of myelination genes and alterations in white matter fractional anisotropy following prenatal viral influenza infection at E16 in mice. |
| Abstract | Prenatal viral infection has been associated with the development of schizophrenia and autism. Our laboratory has previously shown that viral infection causes deleterious effects on brain structure and function in mouse offspring following late first trimester (E9) and late second trimester (E18) administration of influenza virus. We hypothesized that middle second trimester infection (E16) in mice may lead to a different pattern of brain gene expression and structural defects in the developing offspring. C57BL6 mice were infected on E16 with a sublethal dose of human influenza virus or sham-infected using vehicle solution. Male offspring of the infected mice were collected at P0, P14, P35, and P56, their brains removed and cerebella dissected and flash frozen. Microarray, DTI and MRI scanning, as well as qRT-PCR and SDS-PAGE and western blotting analyses were performed to detect differences in gene expression and brain atrophy. Expression of several genes associated with myelination, including Mbp, MAG, and Plp1 were found to be altered, as were protein levels of Mbp, MAG, and DM20. Brain iMAGing revealed significant atrophy in cerebellum at P14, reduced fractional anisotropy in white matter of the right internal capsule at P0, and increased fractional anisotropy in white matter in corpus callosum at P14 and right middle cerebellar peduncle at P56. We propose that maternal infection in mouse impacts myelination genes. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 25 | Brain Res. 2010 Jun 1336: 22-9 |
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| PMID | 20380825 |
| Title | Expression of the tyrosine kinase discoidin domain receptor 1 (DDR1) in human central nervous system myelin. |
| Abstract | During development of the mouse brain, the protein kinase discoidin domain receptor 1 (DDR1) is present prenatally in neurons of the proliferative areas, and postnatally, DDR1 expression is no longer detected in neurons, but a spatial-temporal expression pattern in oligodendrocytes that overlaps with the dynamics of the myelination process is detected. Notably, oligodendrocytic DDR1 expression is upregulated in mice during experimentally induced remyelination. Recently, we demonstrated that DDR1 expression is high in human brain and that there is an association between the gene and schizophrenia in a case-control study. However, data regarding expression of DDR1 in the human brain are scarce. Here, we describe the expression pattern of DDR1 in the human adult cerebral cortex. Using several immunohistological techniques and in situ hybridization, we identified DDR1 in the following: a) myelin, b) capillary endothelial cells in the gray as well as white matter, and c) in the soma of some oligodendrocytes and astrocytes in the white matter. The most important overall finding in this study was that DDR1 is present in myelin and is expressed by oligodendrocyte cells. We detected the presence of DDR1 mRNA and protein in myelin and observed that DDR1 co-localized with the classical myelin basic protein (MBP). Moreover, we found a strong positive correlation between expression levels of DDR1 and two myelin-associated genes, myelin-associated glycoprotein (MAG) and oligodendrocyte transcription factor 2 (OLIG2). These observations suggest that DDR1 could be an important constituent of myelin. Because defects in myelination are linked to several mental disorders such as schizophrenia, the function of DDR1 in the process of myelination warrants further investigation. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 26 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2011 Jul 156B: 581-92 |
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| PMID | 21563301 |
| Title | Association study of Nogo-related genes with schizophrenia in a Japanese case-control sample. |
| Abstract | Many studies have suggested that myelin dysfunction may be causally involved in the pathogenesis of schizophrenia. Nogo (RTN4), myelin-associated glycoprotein (MAG) and oligodendrocyte myelin glycoprotein (OMG) all bind to the common receptor, Nogo-66 receptor 1 (RTN4R). We examined 68 single nucleotide polymorphisms (SNPs) (51 with genotyping and 17 with imputation analysis) from these four genes for genetic association with schizophrenia, using a 2,120 case-control sample from the Japanese population. Allelic tests showed nominally significant association of two RTN4 SNPs (P = 0.047 and 0.037 for rs11894868 and rs2968804, respectively) and two MAG SNPs (P = 0.034 and 0.029 for rs7249617 and rs16970218, respectively) with schizophrenia. The MAG SNP rs7249617 also showed nominal significance in a genotypic test (P = 0.017). In haplotype analysis, the MAG haplotype block including rs7249617 and rs16970218 showed nominal significance (P = 0.008). These associations did not remain significant after correction for multiple testing, possibly due to their small genetic effect. In the imputation analysis of RTN4, the untyped SNP rs2972090 showed nominally significant association (P = 0.032) and several imputed SNPs showed marginal associations. Moreover, in silico analysis (PolyPhen) of a missense variant (rs11677099: Asp357Val), which is in strong linkage disequilibrium with rs11894868, predicted a deleterious effect on Nogo protein function. Despite a failure to detect robust associations in this Japanese cohort, our nominally positive signals, taken together with previously reported biological and genetic findings, add further support to the "disturbed myelin system theory of schizophrenia" across different populations. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 27 | Psychiatry Res 2011 May 187: 89-93 |
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| PMID | 21176970 |
| Title | Going beyond students: an association between mixed-hand preference and schizotypy subscales in a general population. |
| Abstract | Research on the sub-clinical condition of schizotypy suggests that it is associated with mixed handedness. To date, however, this research has focussed on undergraduate populations. If the association between schizotypy and mixed-handedness is the result of an underlying neurological trait, it is important to demonstrate that the effect extends to the general population. With this in mind, 699 participants were drawn from a wide community sample. schizotypy was measured using the Psychosis Proneness Questionnaire and handedness was assessed using the Annett inventory. To avoid the sometimes arbitrary definitions of left-, right- and mixed-handed, regression analyses were used to explore the data. There was no evidence of a difference in schizotypy between individuals with a left- or right-hand preference. People with a mixed-hand preference, however, had higher scores on PER-MAG (Perceptual Aberration and MAGical Ideation) and HYP-IMP (Hypomania and Impulsive Non-Conformity) scales (positive traits). No effect was observed for the SAN (Social Anhedonia) and PAN (Physical Anhedonia) scales (negative traits). The nature of the association between schizotypy and handedness observed in the current study is similar to that reported for student populations. The possibility that the association is related to response biases or a biological mechanism is discussed. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 28 | Front Psychiatry 2012 -1 3: 40 |
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| PMID | 22563322 |
| Title | Myelin-associated glycoprotein gene and brain morphometry in schizophrenia. |
| Abstract | Myelin and oligodendrocyte disruption may be a core feature of schizophrenia pathophysiology. The purpose of the present study was to localize the effects of previously identified risk variants in the myelin-associated glycoprotein (MAG) gene on brain morphometry in schizophrenia patients and healthy controls. Forty-five schizophrenia patients and 47 matched healthy controls underwent clinical, structural MAGnetic resonance iMAGing, and genetics procedures. Gray and white matter cortical lobe volumes along with hippocampal volumes were calculated from T1-weighted MRI scans. Each subject was also genotyped for the two disease-associated MAG single nucleotide polymorphisms (rs720308 and rs720309). Repeated measures general linear model (GLM) analysis found significant region by genotype and region by genotype by diagnosis interactions for the effects of MAG risk variants on lobar gray matter volumes. No significant associations were found with lobar white matter volumes or hippocampal volumes. Follow-up univariate GLMs found the AA genotype of rs720308 predisposed schizophrenia patients to left temporal and parietal gray matter volume deficits. These results suggest that the effects of the MAG gene on cortical gray matter volume in schizophrenia patients can be localized to temporal and parietal cortices. Our results support a role for MAG gene variation in brain morphometry in schizophrenia, align with other lines of evidence implicating MAG in schizophrenia, and provide genetically based insight into the heterogeneity of brain iMAGing findings in this disorder. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |