| 1. |
- Jiang, Lin, et al.
(författare)
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Haloperidol changes mRNA expression of a QKI splice variant in human astrocytoma cells.
- 2009
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Ingår i: BMC pharmacology. - : Springer Science and Business Media LLC. - 1471-2210. ; 9, s. 6-
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The quaking homolog, KH domain RNA binding (mouse) (QKI) is a candidate gene for schizophrenia. Disturbed QKI mRNA expression is observed in the prefrontal cortex of patients, and some of these changes correlate to treatment with antipsychotic drugs.To test if low doses of antipsychotic drugs can modify QKI mRNA expression, human astrocytoma (U343) and oligodendroglioma (HOG) cell lines were treated with five different antipsychotic drugs including Haloperidol, Aripiprazole, Clozapine, Olanzapine and Risperidone. Messenger RNA expression levels of splice variants QKI-5, QKI-6 and QKI-7 were measured by Real-Time PCR. RESULTS: Haloperidol treatment (0.2 microM) doubled QKI-7 mRNA levels in U343 cells after 6 hours (p-value < 0.02). The effect was dose dependent, and cells treated with ten times higher concentration (2 microM) responded with a five-fold and three-fold increase in QKI-7, 6 and 24 hours after treatment, respectively (p-values < 0.0001). CONCLUSION: The results in U343 cells suggest that QKI-7 mRNA expression in human astrocytes is induced by Haloperidol, at concentrations similar to plasma levels relevant to clinical treatment of schizophrenia. The molecular mechanism of action of antipsychotic drugs after binding to receptors is not well known. We hypothesize that QKI regulation is involved in this mechanism.
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| 2. |
- Jiang, Lin, et al.
(författare)
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QKI-7 regulates expression of interferon-related genes in human astrocyte glioma cells
- 2010
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Ingår i: PloS one. - : Public Library of Science (PLoS). - 1932-6203. ; 5:9, s. e13079-
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The human QKI gene, called quaking homolog, KH domain RNA binding (mouse), is a candidate gene for schizophrenia encoding an RNA-binding protein. This gene was shown to be essential for myelination in oligodendrocytes. QKI is also highly expressed in astrocytes, but its function in these cells is not known. METHODS/PRINCIPAL FINDINGS: We studied the effect of small interference RNA (siRNA)-mediated QKI depletion on global gene expression in human astrocyte glioma cells. Microarray measurements were confirmed with real-time quantitative polymerase chain reaction (qPCR). The presence of QKI binding sites (QRE) was assessed by a bioinformatic approach. Viability and cell morphology were also studied. The most significant alteration after QKI silencing was the decreased expression of genes involved in interferon (IFN) induction (P = 6.3E-10), including IFIT1, IFIT2, MX1, MX2, G1P2, G1P3, GBP1 and IFIH1. All eight genes were down-regulated after silencing of the splice variant QKI-7, but were not affected by QKI-5 silencing. Interestingly, four of them were up-regulated after treatment with the antipsychotic agent haloperidol that also resulted in increased QKI-7 mRNA levels. CONCLUSIONS/SIGNIFICANCE: The coordinated expression of QKI-7 splice variant and IFN-related genes supports the idea that this particular splice variant has specific functions in astrocytes. Furthermore, a role of QKI-7 as a regulator of an inflammatory gene pathway in astrocytes is suggested. This hypothesis is well in line with growing experimental evidence on the role of inflammatory components in schizophrenia.
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| 3. |
- Just, David, et al.
(författare)
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Exploring autoantibody signatures in brain tissue from patients with severe mental illness
- 2020
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Ingår i: Translational Psychiatry. - : Springer Nature. - 2158-3188. ; 10:1
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Tidskriftsartikel (refereegranskat)abstract
- In recent years, studies have shown higher prevalence of autoantibodies in patients with schizophrenia compared to healthy individuals. This study applies an untargeted and a targeted affinity proteomics approach to explore and characterize the autoantibody repertoire in brain tissues from 73 subjects diagnosed with schizophrenia and 52 control subjects with no psychiatric or neurological disorders. Selected brain tissue lysates were first explored for IgG reactivity on planar microarrays composed of 11,520 protein fragments representing 10,820 unique proteins. Based on these results of ours and other previous studies of autoantibodies related to psychosis, we selected 226 fragments with an average length of 80 amino acids, representing 127 unique proteins. Tissue-based analysis of IgG reactivities using antigen suspension bead arrays was performed in a multiplex and parallel fashion for all 125 subjects. Among the detected autoantigens, higher IgG reactivity in subjects with schizophrenia, as compared to psychiatrically healthy subjects, was found against the glutamate ionotropic receptor NMDA type subunit 2D (anti-GluN2D). In a separate cohort with serum samples from 395 young adults with a wider spectrum of psychiatric disorders, higher levels of serum autoantibodies targeting GluN2D were found when compared to 102 control individuals. By further validating GluN2D and additional potential autoantigens, we will seek insights into how these are associated with severe mental illnesses.
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| 4. |
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| 5. |
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| 6. |
- Lindholm Carlström, Eva, et al.
(författare)
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Linkage and exome analysis implicate multiple genes in non-syndromic intellectual disability in a large Swedish family
- 2019
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Ingår i: BMC Medical Genomics. - : Springer Science and Business Media LLC. - 1755-8794. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundNon-syndromic intellectual disability is genetically heterogeneous with dominant, recessive and complex forms of inheritance. We have performed detailed genetic studies in a large multi-generational Swedish family, including several members diagnosed with non-syndromic intellectual disability. Linkage analysis was performed on 22 family members, nine affected with mild to moderate intellectual disability and 13 unaffected family members.Methods Family members were analyzed with Affymetrix Genome-Wide Human SNP Array 6.0 and the genetic data was used to detect copy number variation and to perform genome wide linkage analysis with the SNP High Throughput Linkage analysis system and the Merlin software. For the exome sequencing, the samples were prepared using the Sure Select Human All Exon Kit (Agilent Technologies, Santa Clara, CA, USA) and sequenced using the Ion Proton (TM) System. Validation of identified variants was performed with Sanger sequencing.ResultsThe linkage analysis results indicate that intellectual disability in this family is genetically heterogeneous, with suggestive linkage found on chromosomes 1q31-q41, 4q32-q35, 6p25 and 14q24-q31 (LOD scores of 2.4, simulated p-value of 0.000003 and a simulated genome-wide p-value of 0.06). Exome sequencing was then performed in 14 family members and 7 unrelated individuals from the same region. The analysis of coding variation revealed a pathogenic and candidate variants in different branches of the family. In three patients we find a known homozygous pathogenic mutation in the Homo sapiens solute carrier family 17 member 5 (SLC17A5), causing Salla disease. We also identify a deletion overlapping KDM3B and a duplication overlapping MAP3K4 and AGPAT4, both overlapping variants previously reported in developmental disorders.Conclusions DNA samples from the large family analyzed in this study were initially collected based on a hypothesis that affected members shared a major genetic risk factor. Our results show that a complex phenotype such as mild intellectual disability in large families from genetically isolated populations may show considerable genetic heterogeneity.
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| 7. |
- Lindholm Carlström, Eva, et al.
(författare)
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Transcriptome analysis of post-mortem brain tissue reveals up-regulation of the complement cascade in a subgroup of schizophrenia patients
- 2021
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Ingår i: Genes. - : MDPI. - 2073-4425. ; 12:8
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Tidskriftsartikel (refereegranskat)abstract
- Schizophrenia is a genetically complex neuropsychiatric disorder with largely unresolved mechanisms of pathology. Identification of genes and pathways associated with schizophrenia is important for understanding the development, progression and treatment of schizophrenia. In this study, pathways associated with schizophrenia were explored at the level of gene expression. The study included post-mortem brain tissue samples from 68 schizophrenia patients and 44 age and sex-matched control subjects. Whole transcriptome poly-A selected paired-end RNA sequencing was performed on tissue from the prefrontal cortex and orbitofrontal cortex. RNA expression differences were detected between case and control individuals, focusing both on single genes and pathways. The results were validated with RT-qPCR. Significant differential expression between patient and controls groups was found for 71 genes. Gene ontology analysis of differentially expressed genes revealed an up-regulation of multiple genes in immune response among the patients (corrected p-value = 0.004). Several genes in the category belong to the complement system, including C1R, C1S, C7, FCN3, SERPING1, C4A and CFI. The increased complement expression is primarily driven by a subgroup of patients with increased expression of immune/inflammatory response genes, pointing to important differences in disease etiology within the patient group. Weighted gene co-expression network analysis highlighted networks associated with both synaptic transmission and activation of the immune response. Our results demonstrate the importance of immune-related pathways in schizophrenia and provide evidence for elevated expression of the complement cascade as an important pathway in schizophrenia pathology.
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| 8. |
- Moghadam, Behrooz Torabi, et al.
(författare)
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Analyzing DNA methylation patterns in subjects diagnosed with schizophrenia using machine learning methods
- 2019
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Ingår i: Journal of Psychiatric Research. - : PERGAMON-ELSEVIER SCIENCE LTD. - 0022-3956 .- 1879-1379. ; 114, s. 41-47
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Tidskriftsartikel (refereegranskat)abstract
- Schizophrenia is a common mental disorder with high heritability. It is genetically complex and to date more than a hundred risk loci have been identified. Association of environmental factors and schizophrenia has also been reported, while epigenetic analyses have yielded ambiguous and sometimes conflicting results. Here, we analyzed fresh frozen post-mortem brain tissue from a cohort of 73 subjects diagnosed with schizophrenia and 52 control samples, using the Illumina Infinium HumanMethylation450 Bead Chip, to investigate genome-wide DNA methylation patterns in the two groups. Analysis of differential methylation was performed with the Bioconductor Minfi package and modern machine-learning and visualization techniques, which were shown previously to be successful in detecting and highlighting differentially methylated patterns in case-control studies. In this dataset, however, these methods did not uncover any significant signals discerning the patient group and healthy controls, suggesting that if there are methylation changes associated with schizophrenia, they are heterogeneous and complex with small effect.
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| 9. |
- Radomska, Katarzyna J., et al.
(författare)
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RNA-binding protein QKI regulates Glial fibrillary acidic protein expression in human astrocytes
- 2013
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 22:7, s. 1373-1382
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Tidskriftsartikel (refereegranskat)abstract
- Linkage, association and expression studies previously pointed to the human QKI, KH domain containing, RNA-binding (QKI) as a candidate gene for schizophrenia. Functional studies of the mouse orthologue Qk focused mainly on its role in oligodendrocyte development and myelination, while its function in astroglia remained unexplored. Here, we show that QKI is highly expressed in human primary astrocytes and that its splice forms encode proteins targeting different subcellular localizations. Uncovering the role of QKI in astrocytes is of interest in light of growing evidence implicating astrocyte dysfunction in the pathogenesis of several disorders of the central nervous system. We selectively silenced QKI splice variants in human primary astrocytes and used RNA sequencing to identify differential expression and splice variant composition at the genome-wide level. We found that an mRNA expression of Glial fibrillary acidic protein (GFAP), encoding a major component of astrocyte intermediate filaments, was down-regulated after QKI7 splice variant silencing. Moreover, we identified a potential QKI-binding site within the 3 untranslated region of human GFAP. This sequence was not conserved between mice and humans, raising the possibility that GFAP is a target for QKI in humans but not rodents. Haloperidol treatment of primary astrocytes resulted in coordinated increases in QKI7 and GFAP expression. Taken together, our results provide the first link between QKI and GFAP, two genes with alterations previously observed independently in schizophrenic patients. Our findings for QKI, together with its well-known role in myelination, suggest that QKI is a hub regulator of glia function in humans.
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| 10. |
- Torabi Moghadam, Behrooz, et al.
(författare)
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Analyzing DNA methylation patterns in Schizophrenic patients using machine learning methods
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Schizophrenia is common mental disorder with known genetic component involved. Since the association of environmental factors and schizophrenia has been reported, we analyzed a cohort of 75 schizophrenic and 50 control samples to investigate DNA methylation patterns, as one of the key players of epigenetic gene regulation.Here we applied machine-learning and visualization methods, which were shown previously to be successful in detecting and highlighting differentially methylated patterns between cases and controls. On this data set, however, these methods did not uncover any signal discerning schizophrenia patients and healthy controls, suggesting that if a link exists, it is heterogeneous and complex.
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