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Article ; Online: Transcriptome Analysis of Post-Mortem Brain Tissue Reveals Up-Regulation of the Complement Cascade in a Subgroup of Schizophrenia Patients.

Lindholm Carlström, Eva / Niazi, Adnan / Etemadikhah, Mitra / Halvardson, Jonatan / Enroth, Stefan / Stockmeier, Craig A / Rajkowska, Grazyna / Nilsson, Bo / Feuk, Lars

Genes

2021 Volume 12, Issue 8

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 ...

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
MeSH term(s)	Adult ; Aged ; Complement System Proteins/metabolism ; Female ; Gene Expression Profiling ; Gene Ontology ; Humans ; Male ; Middle Aged ; Postmortem Changes ; Schizophrenia/genetics ; Schizophrenia/metabolism ; Schizophrenia/pathology ; Up-Regulation
Chemical Substances	Complement System Proteins (9007-36-7)
Language	English
Publishing date	2021-08-13
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2527218-4
ISSN	2073-4425 ; 2073-4425
ISSN (online)	2073-4425
ISSN	2073-4425
DOI	10.3390/genes12081242
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Linkage and exome analysis implicate multiple genes in non-syndromic intellectual disability in a large Swedish family.

Lindholm Carlström, Eva / Halvardson, Jonatan / Etemadikhah, Mitra / Wetterberg, Lennart / Gustavson, Karl-Henrik / Feuk, Lars

BMC medical genomics

2019 Volume 12, Issue 1, Page(s) 156

Abstract: Background: Non-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 ... ...

Abstract	Background: Non-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™ System. Validation of identified variants was performed with Sanger sequencing. Results: The 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.
MeSH term(s)	1-Acylglycerol-3-Phosphate O-Acyltransferase/genetics ; DNA Copy Number Variations ; Exome/genetics ; Genetic Linkage ; Humans ; Intellectual Disability/genetics ; Intellectual Disability/pathology ; Jumonji Domain-Containing Histone Demethylases/genetics ; Karyotyping ; MAP Kinase Kinase Kinase 4/genetics ; Organic Anion Transporters/genetics ; Pedigree ; Polymorphism, Single Nucleotide ; Sweden ; Symporters/genetics ; Whole Exome Sequencing
Chemical Substances	Organic Anion Transporters ; Symporters ; sialic acid transport proteins ; Jumonji Domain-Containing Histone Demethylases (EC 1.14.11.-) ; KDM3B protein, human (EC 1.14.11.-) ; 1-Acylglycerol-3-Phosphate O-Acyltransferase (EC 2.3.1.51) ; MAP Kinase Kinase Kinase 4 (EC 2.7.11.25) ; MAP3K4 protein, human (EC 2.7.11.25)
Language	English
Publishing date	2019-11-06
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1755-8794
ISSN (online)	1755-8794
DOI	10.1186/s12920-019-0606-4
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Transcriptome Analysis of Post-Mortem Brain Tissue Reveals Up-Regulation of the Complement Cascade in a Subgroup of Schizophrenia Patients

Lindholm Carlström, Eva / Niazi, Adnan / Etemadikhah, Mitra / Halvardson, Jonatan / Enroth, Stefan / Stockmeier, Craig A. / Rajkowska, Grazyna / Nilsson, Bo / Feuk, Lars

Genes. 2021 Aug. 13, v. 12, no. 8

2021

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.
Keywords	RNA ; complement ; etiology ; gene expression ; gene expression regulation ; gene ontology ; genes ; immune response ; inflammation ; patients ; prefrontal cortex ; schizophrenia ; synaptic transmission ; transcriptome ; transcriptomics
Language	English
Dates of publication	2021-0813
Publishing place	Multidisciplinary Digital Publishing Institute
Document type	Article
ZDB-ID	2527218-4
ISSN	2073-4425
ISSN	2073-4425
DOI	10.3390/genes12081242
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: QKI-7 regulates expression of interferon-related genes in human astrocyte glioma cells.

Jiang, Lin / Saetre, Peter / Radomska, Katarzyna J / Jazin, Elena / Lindholm Carlström, Eva

PloS one

2010 Volume 5, Issue 9

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 ... ...

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.
MeSH term(s)	Astrocytes/metabolism ; Cell Line ; Down-Regulation ; Gene Expression Regulation, Neoplastic ; Glioma/genetics ; Glioma/metabolism ; Humans ; Interferons/genetics ; Interferons/metabolism ; Protein Binding ; RNA-Binding Proteins/genetics ; RNA-Binding Proteins/metabolism
Chemical Substances	QKI protein, human ; RNA-Binding Proteins ; Interferons (9008-11-1)
Language	English
Publishing date	2010-09-29
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2267670-3
ISSN	1932-6203 ; 1932-6203
ISSN (online)	1932-6203
ISSN	1932-6203
DOI	10.1371/journal.pone.0013079
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: RNA-binding protein QKI regulates Glial fibrillary acidic protein expression in human astrocytes.

Radomska, Katarzyna J / Halvardson, Jonatan / Reinius, Björn / Lindholm Carlström, Eva / Emilsson, Lina / Feuk, Lars / Jazin, Elena

Human molecular genetics

2013 Volume 22, Issue 7, Page(s) 1373–1382

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 ... ...

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.
MeSH term(s)	Amino Acid Sequence ; Antipsychotic Agents/pharmacology ; Astrocytes/metabolism ; Cells, Cultured ; Gene Expression/drug effects ; Gene Expression Regulation ; Gene Knockdown Techniques ; Glial Fibrillary Acidic Protein/genetics ; Glial Fibrillary Acidic Protein/metabolism ; Haloperidol/pharmacology ; Humans ; Molecular Sequence Data ; Primary Cell Culture ; Protein Interaction Domains and Motifs ; Protein Isoforms/physiology ; Protein Transport ; RNA, Messenger/genetics ; RNA, Messenger/metabolism ; RNA, Small Interfering/genetics ; RNA-Binding Proteins/chemistry ; RNA-Binding Proteins/physiology ; Schizophrenia/metabolism ; Sequence Analysis, RNA ; Transcriptome
Chemical Substances	Antipsychotic Agents ; Glial Fibrillary Acidic Protein ; Protein Isoforms ; QKI protein, human ; RNA, Messenger ; RNA, Small Interfering ; RNA-Binding Proteins ; Haloperidol (J6292F8L3D)
Language	English
Publishing date	2013-04-01
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1108742-0
ISSN	1460-2083 ; 0964-6906
ISSN (online)	1460-2083
ISSN	0964-6906
DOI	10.1093/hmg/dds553
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Article ; Online: Association between a genetic variant in the serotonin transporter gene ( SLC6A4 ) and suicidal behavior in patients with schizophrenia

Lindholm Carlström Eva / Saetre Peter / Rosengren Anders / Thygesen Johan H / Djurovic Srdjan / Melle Ingrid / Andreassen Ole A / Werge Thomas / Agartz Ingrid / Hall Håkan / Terenius Lars / Jönsson Erik G

Behavioral and Brain Functions, Vol 8, Iss 1, p

2012 Volume 24

Abstract: Abstract Background The serotonin (5-hydroxytryptamin; 5-HT) system has a central role in the circuitry of cognition and emotions. Multiple lines of evidence suggest that genetic variation in the serotonin transporter gene ( SLC6A4 ... 5-HTT ) is ... ...

Abstract	Abstract Background The serotonin (5-hydroxytryptamin; 5-HT) system has a central role in the circuitry of cognition and emotions. Multiple lines of evidence suggest that genetic variation in the serotonin transporter gene ( SLC6A4 5-HTT ) is associated with schizophrenia and suicidal behavior. In this study, we wanted to elucidate whether SLC6A4 variations is involved in attempted suicide among patients with schizophrenia in a Scandinavian case–control sample. Methods Patients diagnosed with schizophrenia from three Scandinavian samples were assessed for presence or absence of suicide attempts, based on record reviews and interview data. Seven SLC6A4 single nucleotide polymorphisms (SNPs) were genotyped in 837 schizophrenia patients and 1,473 control individuals. Association analyses and statistical evaluations were performed with the program UNPHASED (version 3.0.9). Results We observed an allele association between the SNP rs16965628, located in intron one of SLC6A4 , and attempted suicide (adjusted p-value 0.01), among patients with schizophrenia. No association was found to a diagnosis of schizophrenia, when patients were compared to healthy control individuals. Conclusion The gene SLC6A4 appears to be involved in suicidal ideation among patients with schizophrenia. Independent replication is needed before more firm conclusions can be drawn.
Keywords	Suicide ideation ; Serotonin transporter gene ; Association ; Schizophrenia ; Neurology. Diseases of the nervous system ; RC346-429 ; Neurosciences. Biological psychiatry. Neuropsychiatry ; RC321-571 ; Internal medicine ; RC31-1245 ; Medicine ; R ; DOAJ:Neurology ; DOAJ:Medicine (General) ; DOAJ:Health Sciences
Subject code	150
Language	English
Publishing date	2012-05-01T00:00:00Z
Publisher	BioMed Central
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Association between a genetic variant in the serotonin transporter gene (SLC6A4) and suicidal behavior in patients with schizophrenia.

Lindholm Carlström, Eva / Saetre, Peter / Rosengren, Anders / Thygesen, Johan H / Djurovic, Srdjan / Melle, Ingrid / Andreassen, Ole A / Werge, Thomas / Agartz, Ingrid / Hall, Håkan / Terenius, Lars / Jönsson, Erik G

Behavioral and brain functions : BBF

2012 Volume 8, Page(s) 24

Abstract: Background: The serotonin (5-hydroxytryptamin; 5-HT) system has a central role in the circuitry of cognition and emotions. Multiple lines of evidence suggest that genetic variation in the serotonin transporter gene (SLC6A4; 5-HTT) is associated with ... ...

Abstract	Background: The serotonin (5-hydroxytryptamin; 5-HT) system has a central role in the circuitry of cognition and emotions. Multiple lines of evidence suggest that genetic variation in the serotonin transporter gene (SLC6A4; 5-HTT) is associated with schizophrenia and suicidal behavior. In this study, we wanted to elucidate whether SLC6A4 variations is involved in attempted suicide among patients with schizophrenia in a Scandinavian case-control sample. Methods: Patients diagnosed with schizophrenia from three Scandinavian samples were assessed for presence or absence of suicide attempts, based on record reviews and interview data. Seven SLC6A4 single nucleotide polymorphisms (SNPs) were genotyped in 837 schizophrenia patients and 1,473 control individuals. Association analyses and statistical evaluations were performed with the program UNPHASED (version 3.0.9). Results: We observed an allele association between the SNP rs16965628, located in intron one of SLC6A4, and attempted suicide (adjusted p-value 0.01), among patients with schizophrenia. No association was found to a diagnosis of schizophrenia, when patients were compared to healthy control individuals. Conclusion: The gene SLC6A4 appears to be involved in suicidal ideation among patients with schizophrenia. Independent replication is needed before more firm conclusions can be drawn.
MeSH term(s)	Adult ; Alleles ; Female ; Genetic Association Studies ; Genetic Predisposition to Disease ; Genotype ; Haplotypes ; Humans ; Male ; Middle Aged ; Polymorphism, Single Nucleotide ; Schizophrenia/genetics ; Schizophrenic Psychology ; Serotonin Plasma Membrane Transport Proteins/genetics ; Suicidal Ideation ; Suicide/psychology
Chemical Substances	Serotonin Plasma Membrane Transport Proteins
Language	English
Publishing date	2012-05-17
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1744-9081
ISSN (online)	1744-9081
DOI	10.1186/1744-9081-8-24
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Article ; Online: Transcriptome Analysis of Post-Mortem Brain Tissue Reveals Up-Regulation of the Complement Cascade in a Subgroup of Schizophrenia Patients.

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Article ; Online: Linkage and exome analysis implicate multiple genes in non-syndromic intellectual disability in a large Swedish family.

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Article: Transcriptome Analysis of Post-Mortem Brain Tissue Reveals Up-Regulation of the Complement Cascade in a Subgroup of Schizophrenia Patients

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Article ; Online: QKI-7 regulates expression of interferon-related genes in human astrocyte glioma cells.

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Article ; Online: RNA-binding protein QKI regulates Glial fibrillary acidic protein expression in human astrocytes.

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Article ; Online: Association between a genetic variant in the serotonin transporter gene ( SLC6A4 ) and suicidal behavior in patients with schizophrenia

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Article ; Online: Association between a genetic variant in the serotonin transporter gene (SLC6A4) and suicidal behavior in patients with schizophrenia.

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