Publications by authors named "Jing Qin Wu"

35 Publications

A Chromosome-Scale Assembly of the Wheat Leaf Rust Pathogen Provides Insights Into Structural Variations and Genetic Relationships With Haplotype Resolution.

Front Microbiol 2021 29;12:704253. Epub 2021 Jul 29.

Plant Breeding Institute, School of Life and Environmental Sciences, Faculty of Science, The University of Sydney, Sydney, NSW, Australia.

Despite the global economic importance of the wheat leaf rust pathogen (), genomic resources for are limited and chromosome-level assemblies of are lacking. Here, we present a complete haplotype-resolved genome assembly at a chromosome-scale for using the Australian pathotype 64-(6),(7),(10),11 (Pt64; North American race LBBQB) built upon the newly developed technologies of PacBio and Hi-C sequencing. PacBio reads with ∼200-fold coverage (29.8 Gb data) were assembled by Falcon and Falcon-unzip and subsequently scaffolded with Hi-C data using Falcon-phase and Proximo. This approach allowed us to construct 18 chromosome pseudomolecules ranging from 3.5 to 12.3 Mb in size for each haplotype of the dikaryotic genome of Pt64. Each haplotype had a total length of ∼147 Mb, scaffold of ∼9.4 Mb, and was ∼93% complete for BUSCOs. Each haplotype had ∼29,800 predicted genes, of which ∼2,000 were predicted as secreted proteins (SPs). The investigation of structural variants (SVs) between haplotypes A and B revealed that 10% of the total genome was spanned by SVs, highlighting variations previously undetected by short-read based assemblies. For the first time, the mating type (MAT) genes on each haplotype of Pt64 were identified, which showed that MAT loci and are located on two chromosomes (chromosomes 7 and 14), representing a tetrapolar type. Furthermore, the Pt64 assembly enabled haplotype-based evolutionary analyses for 21 Australian isolates, which highlighted the importance of a haplotype resolved reference when inferring genetic relationships using whole genome SNPs. This Pt64 assembly at chromosome-scale with full phase information provides an invaluable resource for genomic and evolutionary research, which will accelerate the understanding of molecular mechanisms underlying -wheat interactions and facilitate the development of durable resistance to leaf rust in wheat and sustainable control of rust disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fmicb.2021.704253DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8358450PMC
July 2021

Sex-Dependent Shared and Nonshared Genetic Architecture Across Mood and Psychotic Disorders.

Biol Psychiatry 2021 Mar 23. Epub 2021 Mar 23.

Department of Psychiatry and Behavioral Neuroscience, University of Chicago, Chicago, Illinois; Department of Psychiatry and Behavioral Sciences, North Shore University Health System, Evanston, Illinois.

Background: Sex differences in incidence and/or presentation of schizophrenia (SCZ), major depressive disorder (MDD), and bipolar disorder (BIP) are pervasive. Previous evidence for shared genetic risk and sex differences in brain abnormalities across disorders suggest possible shared sex-dependent genetic risk.

Methods: We conducted the largest to date genome-wide genotype-by-sex (G×S) interaction of risk for these disorders using 85,735 cases (33,403 SCZ, 19,924 BIP, and 32,408 MDD) and 109,946 controls from the PGC (Psychiatric Genomics Consortium) and iPSYCH.

Results: Across disorders, genome-wide significant single nucleotide polymorphism-by-sex interaction was detected for a locus encompassing NKAIN2 (rs117780815, p = 3.2 × 10), which interacts with sodium/potassium-transporting ATPase (adenosine triphosphatase) enzymes, implicating neuronal excitability. Three additional loci showed evidence (p < 1 × 10) for cross-disorder G×S interaction (rs7302529, p = 1.6 × 10; rs73033497, p = 8.8 × 10; rs7914279, p = 6.4 × 10), implicating various functions. Gene-based analyses identified G×S interaction across disorders (p = 8.97 × 10) with transcriptional inhibitor SLTM. Most significant in SCZ was a MOCOS gene locus (rs11665282, p = 1.5 × 10), implicating vascular endothelial cells. Secondary analysis of the PGC-SCZ dataset detected an interaction (rs13265509, p = 1.1 × 10) in a locus containing IDO2, a kynurenine pathway enzyme with immunoregulatory functions implicated in SCZ, BIP, and MDD. Pathway enrichment analysis detected significant G×S interaction of genes regulating vascular endothelial growth factor receptor signaling in MDD (false discovery rate-corrected p < .05).

Conclusions: In the largest genome-wide G×S analysis of mood and psychotic disorders to date, there was substantial genetic overlap between the sexes. However, significant sex-dependent effects were enriched for genes related to neuronal development and immune and vascular functions across and within SCZ, BIP, and MDD at the variant, gene, and pathway levels.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.biopsych.2021.02.972DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8458480PMC
March 2021

Integrated Analysis of Gene Expression, SNP, InDel, and CNV Identifies Candidate Avirulence Genes in Australian Isolates of the Wheat Leaf Rust Pathogen .

Genes (Basel) 2020 09 21;11(9). Epub 2020 Sep 21.

Plant Breeding Institute, School of Life and Environmental Science, Faculty of Science, The University of Sydney, Sydney, NSW 2006, Australia.

The leaf rust pathogen, (), threatens global wheat production. The deployment of leaf rust () resistance (R) genes in wheat varieties is often followed by the development of matching virulence in due to presumed changes in avirulence (Avr) genes in . Identifying such Avr genes is a crucial step to understand the mechanisms of wheat-rust interactions. This study is the first to develop and apply an integrated framework of gene expression, single nucleotide polymorphism (SNP), insertion/deletion (InDel), and copy number variation (CNV) analysis in a rust fungus and identify candidate avirulence genes. Using a long-read based genome assembly of an isolate of ('Pt104') as the reference, whole-genome resequencing data of 12 pathotypes derived from three lineages Pt104, Pt53, and Pt76 were analyzed. Candidate avirulence genes were identified by correlating virulence profiles with small variants (SNP and InDel) and CNV, and RNA-seq data of an additional three isolates to validate expression of genes encoding secreted proteins (SPs). Out of the annotated 29,043 genes, 2392 genes were selected as SP genes with detectable expression levels. Small variant comparisons between the isolates identified 27-40 candidates and CNV analysis identified 14-31 candidates for each Avr gene, which when combined, yielded the final 40, 64, and 69 candidates for , and , respectively. Taken together, our results will facilitate future work on experimental validation and cloning of Avr genes. In addition, the integrated framework of data analysis that we have developed and reported provides a more comprehensive approach for Avr gene mining than is currently available.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/genes11091107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7564353PMC
September 2020

Long-Read-Based Genome Assembly and Comparative Genomics of the Wheat Leaf Rust Pathogen Identifies Candidates for Three Avirulence Genes.

Front Genet 2020 4;11:521. Epub 2020 Jun 4.

Plant Breeding Institute, School of Life and Environmental Sciences, Faculty of Science, The University of Sydney, Sydney, NSW, Australia.

Leaf rust, caused by (), is one of the most devastating diseases of wheat, affecting production in nearly all wheat-growing regions worldwide. Despite its economic importance, genomic resources for are very limited. In the present study, we have used long-read sequencing (LRS) and the pipeline of FALCON and FALCON-Unzip (v4.1.0) to carry out the first LRS-based genome assembly for . Using 22.4-Gb data with an average read length of 11.6 kb and average coverage of 150-fold, we generated a genome assembly for Pt104 [strain 104-2,3,(6),(7),11; isolate S423], considered to be the founding isolate of a clonal lineage of in Australia. The Pt104 genome contains 162 contigs with a total length of 140.5 Mb and N of 2 Mb, with the associated haplotigs providing haplotype information for 91% of the genome. This represents the best quality of genome assembly to date, which reduces the contig number by 91-fold and improves the N by 4-fold as compared to the previous race1 assembly. An annotation pipeline that combined multiple lines of evidence including the transcriptome assemblies derived from RNA-Seq, previously identified expressed sequence tags and race 1 protein sequences predicted 29,043 genes for Pt104 genome. Based on the presence of a signal peptide, no transmembrane segment, and no target location to mitochondria, 2,178 genes were identified as secreted proteins (SPs). Whole-genome sequencing (Illumina paired-end) was performed for Pt104 and six additional strains with differential virulence profile on the wheat leaf rust resistance genes , , and . To identify candidates for the corresponding avirulence genes , , and , genetic variation within each strain was first identified by mapping to the Pt104 genome. Variants within predicted SP genes between the strains were then correlated to the virulence profiles, identifying 38, 31, and 37 candidates for , , and , respectively. The identification of these candidate genes lays a good foundation for future studies on isolating these avirulence genes, investigating the molecular mechanisms underlying host-pathogen interactions, and the development of new diagnostic tools for pathogen monitoring.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fgene.2020.00521DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7287177PMC
June 2020

The genetic architecture of the human cerebral cortex.

Science 2020 03;367(6484)

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1126/science.aay6690DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7295264PMC
March 2020

Wnt receptor gene was associated with schizophrenia in genome-wide SNP analysis of the Australian Schizophrenia Research Bank cohort.

Aust N Z J Psychiatry 2020 09 16;54(9):902-908. Epub 2019 Nov 16.

School of Biomedical Sciences and Pharmacy, The University of Newcastle, Callaghan, NSW, Australia.

Objectives: Large-scale genetic analysis of common variation in schizophrenia has been a powerful approach to understanding this complex but highly heritable psychotic disorder. To further investigate loci, genes and pathways associated more specifically in the well-characterized Australian Schizophrenia Research Bank cohort, we applied genome-wide single-nucleotide polymorphism analysis in these three annotation categories.

Methods: We performed a case-control genome-wide association study in 429 schizophrenia samples and 255 controls. Post-genome-wide association study analyses were then integrated with genomic annotations to explore the enrichment of variation at the gene and pathway level. We also examine candidate single-nucleotide polymorphisms with potential function within expression quantitative trait loci and investigate overall enrichment of variation within tissue-specific functional regulatory domains of the genome.

Results: The strongest finding ( = 2.01 × 10, odds ratio = 1.82, 95% confidence interval = [1.42, 2.33]) in genome-wide association study was with rs10252923 at 7q21.13, downstream of (frizzled class receptor 1). While this did not stand alone after correction, the involvement of was supported by gene-based analysis, which exceeded the threshold for genome-wide significance ( = 2.78 × 10).

Conclusion: The identification of , as an independent association signal at the gene level, supports the hypothesis that the Wnt signalling pathway is altered in the pathogenesis of schizophrenia and may be an important target for therapeutic development.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/0004867419885443DOI Listing
September 2020

Elevated triglyceride levels are associated with cognitive impairments among patients with major depressive disorder.

Compr Psychiatry 2017 05 14;75:103-109. Epub 2017 Mar 14.

First School of Clinical Medicine, Wenzhou Medical University, Wenzhou, Zhejiang, PR China; Suzhou Psychiatric Hospital, Suzhou, Jiangsu, PR China; Institute of Mental Health, Suzhou Psychiatric Hospital, The Affiliated Guangji Hospital of Soochow University, Suzhou, Jiangsu, PR China; Wenzhou Kangning Hospital, Kangning Hospital attached to Wenzhou Medical University, Wenzhou, Zhejiang, PR China. Electronic address:

Background: Cognitive deficits have been identified as one of core clinical symptoms of major depressive disorder (MDD). Accumulating evidence indicated that triglycerides (TG) might be associated with MDD and cognitive decline.

Objective: This study examined whether patients with MDD had poorer cognitive functions than healthy controls, and further investigate whether TG levels were involved in MDD, and its cognitive impairments in a Han Chinese population.

Method: 115 patients with MDD and 119 healthy controls were enrolled. Cognitive functions were assessed by the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), and serum TG levels were examined using enzymatic colorimetry.

Results: TG levels were higher in patients with MDD than healthy controls after controlling for the variables. Cognitive test scores were lower in patients with MDD than healthy controls except for visuospatial/constructional index after controlling for the variables. TG levels were negatively correlated with visuospatial/constructional score, delayed memory score and RBANS total score of MDD. Further multivariate regression analysis showed that TG levels were negatively associated with visuospatial/constructional score, attention score, delayed memory score and RBANS total score of MDD.

Conclusions: Our findings supported that serum TG levels might be involved in MDD, and play an important role in cognitive impairments of MDD, especially in delayed memory. Moreover, patients with MDD experienced greater cognitive impairments than healthy controls except for visuospatial/constructional index.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.comppsych.2017.03.007DOI Listing
May 2017

Comparative Genomics Integrated with Association Analysis Identifies Candidate Effector Genes Corresponding to in Phenotype-Paired Isolates from Australia.

Front Plant Sci 2017 9;8:148. Epub 2017 Feb 9.

Faculty of Agriculture and Environment, Plant Breeding Institute, The University of Sydney Narellan, NSW, Australia.

Leaf rust is one of the most common and damaging diseases of wheat, and is caused by an obligate biotrophic basidiomycete, (). In the present study, 20 isolates from Australia, comprising 10 phenotype-matched pairs with contrasting pathogenicity for , were analyzed using whole genome sequencing. Compared to the reference genome of the American isolate 1-1 BBBD Race 1, an average of 404,690 single nucleotide polymorphisms (SNPs) per isolate was found and the proportion of heterozygous SNPs was above 87% in the majority of the isolates, demonstrating a high level of polymorphism and a high rate of heterozygosity. From the genome-wide SNPs, a phylogenetic tree was inferred, which consisted of a large clade of 15 isolates representing diverse presumed clonal lineages including 14 closely related isolates and the more diverged isolate 670028, and a small clade of five isolates characterized by lower heterozygosity level. Principle component analysis detected three distinct clusters, corresponding exactly to the two major subsets of the small clade and the large clade comprising all 15 isolates without further separation of isolate 670028. While genome-wide association analysis identified 302 genes harboring at least one SNP associated with virulence ( < 0.05), a Wilcoxon rank sum test revealed that 36 and 68 genes had significant ( < 0.05) and marginally significant ( < 0.1) differences in the counts of non-synonymous mutations between avirulent and virulent groups, respectively. Twenty of these genes were predicted to have a signal peptide without a transmembrane segment, and hence identified as candidate effector genes corresponding to . SNP analysis also implicated the potential involvement of epigenetics and small RNA in pathogenicity. Future studies are thus warranted to investigate the biological functions of the candidate effectors as well as the gene regulation mechanisms at epigenetic and post-transcription levels. Our study is the first to integrate phenotype-genotype association with effector prediction in genomes, an approach that may circumvent some of the technical difficulties in working with obligate rust fungi and accelerate avirulence gene identification.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fpls.2017.00148DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5298990PMC
February 2017

Contribution of copy number variants to schizophrenia from a genome-wide study of 41,321 subjects.

Nat Genet 2017 01 21;49(1):27-35. Epub 2016 Nov 21.

Department of Psychiatry, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.

Copy number variants (CNVs) have been strongly implicated in the genetic etiology of schizophrenia (SCZ). However, genome-wide investigation of the contribution of CNV to risk has been hampered by limited sample sizes. We sought to address this obstacle by applying a centralized analysis pipeline to a SCZ cohort of 21,094 cases and 20,227 controls. A global enrichment of CNV burden was observed in cases (odds ratio (OR) = 1.11, P = 5.7 × 10), which persisted after excluding loci implicated in previous studies (OR = 1.07, P = 1.7 × 10). CNV burden was enriched for genes associated with synaptic function (OR = 1.68, P = 2.8 × 10) and neurobehavioral phenotypes in mouse (OR = 1.18, P = 7.3 × 10). Genome-wide significant evidence was obtained for eight loci, including 1q21.1, 2p16.3 (NRXN1), 3q29, 7q11.2, 15q13.3, distal 16p11.2, proximal 16p11.2 and 22q11.2. Suggestive support was found for eight additional candidate susceptibility and protective loci, which consisted predominantly of CNVs mediated by nonallelic homologous recombination.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/ng.3725DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5737772PMC
January 2017

Ginkgo biloba and vitamin E ameliorate haloperidol-induced vacuous chewingmovement and brain-derived neurotrophic factor expression in a rat tardive dyskinesia model.

Pharmacol Biochem Behav 2016 09 3;148:53-8. Epub 2016 Jun 3.

Psychiatry Research Center, Beijing HuiLongGuan Hospital, Peking University, Beijing, China; Department of Chinese Integrative Medicine, Beijing HuiLongGuan Hospital, Peking University, Beijing, China; Department of Psychiatry and Behavioral Sciences, The University of Texas Health Science Center at Houston, Houston, TX, USA. Electronic address:

Neurodegeneration may be involved in the development of tardive dyskinesia (TD), and low levels of brain-derived neurotrophic factor (BDNF) may play a role. Ginkgo biloba (EGb761), a potent antioxidant, may have neuroprotective effects. We hypothesized that there would be decreased BDNF expression in TD, but that treatment with EGb761 would increase BDNF expression and reduce TD manifestations in a rat model. Forty rats were treated with haloperidol (2mg/kg/day via intraperitoneal injections) for 5weeks. EGb761 (50mg/kg/day) and vitamin E (20mg/kg/day) were then administered by oral gavage for another 5weeks, and we compared the effects of treatment with EGb761 or vitamin E on haloperidol-induced vacuous chewing movements (VCMs) and BDNF expression in four brain regions: prefrontal cortex (PFC), striatum (ST), substantia nigra (SNR), and globus pallidus (GP). Our results showed that haloperidol administration led to a progressive increase in VCMs, but both EGb761 and vitamin E significantly decreased VCMs. Haloperidol also decreased BDNF expression in all four brain regions, but both EGb761 and vitamin E administration significantly increased BDNF expression. Our results showed that both EGb761 and VE treatments exerted similar positive effects in a rat model of TD and increased BDNF expression levels in the four tested brain regions, suggesting that both EGb761 and vitamin E improve TD symptoms, possibly by enhancing BDNF in the brain and/or via their free radical-scavenging actions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.pbb.2016.06.003DOI Listing
September 2016

Cognitive impairments in first-episode drug-naive and chronic medicated schizophrenia: MATRICS consensus cognitive battery in a Chinese Han population.

Psychiatry Res 2016 04 18;238:196-202. Epub 2016 Feb 18.

Psychiatry Research Center, Beijing HuiLongGuan Hospital, Peking University, Beijing, China; Department of Psychiatry and Behavioral Sciences, The University of Texas Health Science Center at Houston, Houston, TX, USA. Electronic address:

Cognitive deficits are a core feature of schizophrenia and we examined the cognitive profile of first-episode and chronic schizophrenia in a Chinese Han population using the MATRICS Consensus Cognitive Battery (MCCB). We recruited 79 first-episode drug-naïve (FEDN) schizophrenia, 132 chronic medicated schizophrenia inpatients and 124 healthy controls. We assessed patient psychopathology using the Positive and Negative Syndrome Scale (PANSS). MCCB total score (p<0.01) and index scores of category fluency, trail making A, digital sequence, Hopkins Verbal Learning Test (HVLT), mazes, and Mayer-Salovey-Caruso Emotional Intelligence Test (MSCEIT) were significantly higher in FEDN than in chronic patients (all p<0.05). FEDN exhibited relative weakness in continuous performance, whereas chronic patients exhibited relative weakness in mazes. Multiple regression analysis confirmed that in FEDN and chronic patients, total score and negative symptom of PANSS were independent contributors to MCCB total score, respectively. Our results not only demonstrate the applicability of the MCCB as a sensitive measure of cognitive impairment for schizophrenia patients in a Chinese Han population, but also suggest that the compromised cognition is present in the early stage of schizophrenia, some of which could be more severe in the chronic stage of illness.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.psychres.2016.02.042DOI Listing
April 2016

Evidence for Genetic Overlap Between Schizophrenia and Age at First Birth in Women.

JAMA Psychiatry 2016 05;73(5):497-505

CIBERSAM, University Hospital Marqués de Valdecilla, University of Cantabria-IDIVAL, Department of Psychiatry, Santander, Spain28 Centro Investigación Biomédica en Red Salud Mental, Madrid, Spain.

Importance: A recently published study of national data by McGrath et al in 2014 showed increased risk of schizophrenia (SCZ) in offspring associated with both early and delayed parental age, consistent with a U-shaped relationship. However, it remains unclear if the risk to the child is due to psychosocial factors associated with parental age or if those at higher risk for SCZ tend to have children at an earlier or later age.

Objective: To determine if there is a genetic association between SCZ and age at first birth (AFB) using genetically informative but independently ascertained data sets.

Design, Setting, And Participants: This investigation used multiple independent genome-wide association study data sets. The SCZ sample comprised 18 957 SCZ cases and 22 673 controls in a genome-wide association study from the second phase of the Psychiatric Genomics Consortium, and the AFB sample comprised 12 247 genotyped women measured for AFB from the following 4 community cohorts: Estonia (Estonian Genome Center Biobank, University of Tartu), the Netherlands (LifeLines Cohort Study), Sweden (Swedish Twin Registry), and the United Kingdom (TwinsUK). Schizophrenia genetic risk for each woman in the AFB community sample was estimated using genetic effects inferred from the SCZ genome-wide association study.

Main Outcomes And Measures: We tested if SCZ genetic risk was a significant predictor of response variables based on published polynomial functions that described the relationship between maternal age and SCZ risk in offspring in Denmark. We substituted AFB for maternal age in these functions, one of which was corrected for the age of the father, and found that the fit was superior for the model without adjustment for the father's age.

Results: We observed a U-shaped relationship between SCZ risk and AFB in the community cohorts, consistent with the previously reported relationship between SCZ risk in offspring and maternal age when not adjusted for the age of the father. We confirmed that SCZ risk profile scores significantly predicted the response variables (coefficient of determination R2 = 1.1E-03, P = 4.1E-04), reflecting the published relationship between maternal age and SCZ risk in offspring by McGrath et al in 2014.

Conclusions And Relevance: This study provides evidence for a significant overlap between genetic factors associated with risk of SCZ and genetic factors associated with AFB. It has been reported that SCZ risk associated with increased maternal age is explained by the age of the father and that de novo mutations that occur more frequently in the germline of older men are the underlying causal mechanism. This explanation may need to be revised if, as suggested herein and if replicated in future studies, there is also increased genetic risk of SCZ in older mothers.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jamapsychiatry.2016.0129DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5785705PMC
May 2016

Altered interleukin-18 levels are associated with cognitive impairment in chronic schizophrenia.

J Psychiatr Res 2016 05 29;76:9-15. Epub 2016 Jan 29.

Psychiatry Research Center, Beijing HuiLongGuan Hospital, Peking University, Beijing, China; Department of Psychiatry and Behavioral Sciences, The University of Texas Health Science Center at Houston, Houston, TX, USA. Electronic address:

The pathophysiology of cognitive deficits in schizophrenia may involve the neuroinflammation mediated by cytokines. This study examined the IL-18 levels, the cognitive function, and their association in schizophrenia. We recruited 70 chronic patients and 75 normal controls and examined the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and IL-18 levels. Positive and Negative Syndrome Scale (PANSS) was assessed in chronic patients. IL-18 levels were increased in chronic patients as compared to normal controls (p < 0.01). RBANS total score and the subscales of immediate memory and delayed memory were lower in patients than controls (all p < 0.001). In patients, IL-18 levels were positively associated with RBANS total score and the subscales of immediate and delayed memory (all p < 0.05). Multiple regression analysis further confirmed that IL-18 was an independent contributor to RBANS total score and the aforementioned two indexes (all p < 0.05). Our data demonstrate that immune responses may play an important role in cognitive deficits in schizophrenia and the abnormal levels of IL-18 reflecting the disturbed balance of proinflammatory and anti-inflammatory mechanisms may be relevant to cognitive deficits of this disorder.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jpsychires.2016.01.013DOI Listing
May 2016

Altered neural signaling and immune pathways in peripheral blood mononuclear cells of schizophrenia patients with cognitive impairment: A transcriptome analysis.

Brain Behav Immun 2016 Mar 14;53:194-206. Epub 2015 Dec 14.

School of Biomedical Sciences and Pharmacy, Faculty of Health, The University of Newcastle, University Drive, Callaghan, NSW 2308, Australia; Schizophrenia Research Institute, Sydney, Australia; Centre for Translational Neuroscience and Mental Health, Hunter Medical Research Institute, Newcastle, NSW 2305, Australia. Electronic address:

Cognitive deficits are a core feature of schizophrenia and contribute significantly to functional disability. We investigated the molecular pathways associated with schizophrenia (SZ; n=47) cases representing both 'cognitive deficit' (CD; n=22) and 'cognitively spared' (CS; n=25) subtypes of schizophrenia (based on latent class analysis of 9 cognitive performance indicators), compared with 49 healthy controls displaying 'normal' cognition. This was accomplished using gene-set analysis of transcriptome data derived from peripheral blood mononuclear cells (PBMCs). We detected 27 significantly altered pathways (19 pathways up-regulated and 8 down-regulated) in the combined SZ group and a further 6 pathways up-regulated in the CS group and 5 altered pathways (4 down-regulated and 1 up-regulated) in the CD group. The transcriptome profiling in SZ and cognitive subtypes were characterized by the up-regulated pathways involved in immune dysfunction (e.g., antigen presentation in SZ), energy metabolism (e.g., oxidative phosphorylation), and down-regulation of the pathways involved in neuronal signaling (e.g., WNT in SZ/CD and ERBB in SZ). When we looked for pathways that differentiated the two cognitive subtypes we found that the WNT signaling was significantly down-regulated (FDR<0.05) in the CD group in accordance with the combined SZ cohort, whereas it was unaffected in the CS group. This suggested suppression of WNT signaling was a defining feature of cognitive decline in schizophrenia. The WNT pathway plays a role in both the development/function of the central nervous system and peripheral tissues, therefore its alteration in PBMCs may be indicative of an important genomic axis relevant to cognition in the neuropathology of schizophrenia.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbi.2015.12.010DOI Listing
March 2016

TCF4 gene polymorphism is associated with cognition in patients with schizophrenia and healthy controls.

J Psychiatr Res 2015 Oct 22;69:95-101. Epub 2015 Jul 22.

Biological Psychiatry Center, Beijing HuiLongGuan Hospital, Peking University, Beijing, PR China; Department of Psychiatry and Behavioral Sciences, Harris County Psychiatric Center, The University of Texas Health Science Center at Houston, Houston, TX, USA. Electronic address:

Background: Cognitive deficits have been identified as an important core feature of schizophrenia. Single nucleotide polymorphisms in the transcription factor 4 (TCF4) gene have been reported to be involved in the susceptibility to schizophrenia and be significantly related to cognitive deficits of schizophrenia and controls. This study examines whether the TCF4 rs2958182 polymorphism influences cognitive functions in chronic schizophrenia and controls.

Methods: The presence of the TCF4 rs2958182 was determined in 976 patients and 420 controls using a case-control design. We assessed all the patients' psychopathology using the Positive and Negative Syndrome Scale (PANSS). Cognition was assessed in 777 patients and 399 controls by using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS).

Results: There were marginally significant differences in the TCF4 rs2958182 allelic and genotypic distributions between patients and controls (χ2 = 3.48, p = 0.062 and χ2 = 0.036, p = 0.036, respectively). Cognitive test scores were significantly lower in patients than in controls on all scales (all p < 0.001) except for the visuospatial/constructional index (p > 0.05). There were significant genotype effects on delayed memory score (p = 0.013), the RBANS total score (p = 0.028) and language score (p = 0.034). Further analysis showed that the language score significantly differed according to the genotypic groups (A/A+T/A group versus T/T group) (p = 0.007) in patients but not in controls (p > 0.05), and the delayed memory score also significantly differed according to the genotypic groups (A/A+T/A group versus T/T group) (p = 0.021) in controls but not in patients (p > 0.05).

Conclusions: This study found that the A allele of the TCF4 rs2958182 polymorphism was the risk allele of schizophrenia, and was associated with lower cognitive performance in language in schizophrenia and delayed memory in controls. In contrast, the T allele of this polymorphism was found to be the schizophrenia risk allele in another study in Han Chinese people.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jpsychires.2015.07.022DOI Listing
October 2015

Association of angiotensin-converting enzyme gene polymorphism with schizophrenia and depressive symptom severity in a Chinese population.

Hum Psychopharmacol 2015 Mar 19;30(2):100-7. Epub 2015 Feb 19.

Institute of Kangning Mental Health, Wenzhou Kangning Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China.

Background: Depressive symptoms are frequently observed in schizophrenia patients. Angiotensin-converting enzyme (ACE), a key enzyme of renin-angiotensin system, can catalyze the degradation of neuropeptides and modulate dopaminergic and serotonergic neurotransmission. Previous studies have revealed the association of the ACE gene insertion/deletion polymorphism with depressive disorder and its treatment response but not with the depressive symptoms in schizophrenia.

Objective: The aim of this study is to examine whether this polymorphism was associated with susceptibility to schizophrenia and with its psychopathological symptoms, especially depressive symptoms in a Han Chinese population.

Methods: This polymorphism was genotyped in 382 chronic patients and 538 healthy controls. Psychopathology was characterised using the positive and negative syndrome scale.

Results: The allelic and genotypic frequencies of this polymorphism significantly differed between patients and controls (both p < 0.001). A significant difference in the positive and negative syndrome scale depressive symptom score was observed among the three genotypes (p < 0.03), with higher score in patients with insertion/insertion (I/I) than with deletion/deletion (D/D) genotypes (p < 0.05). Furthermore, there was a significant linear correlation between the number of I alleles and the depressive symptom score (p < 0.05).

Conclusions: The ACE gene insertion/deletion polymorphism may play a role in susceptibility to schizophrenia and also in its depressive symptom severity in a Han Chinese population.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/hup.2460DOI Listing
March 2015

Differential regulation of cytotoxicity pathway discriminating between HIV, HCV mono- and co-infection identified by transcriptome profiling of PBMCs.

Virol J 2015 Jan 27;12. Epub 2015 Jan 27.

Retroviral Genetics Division, Center for Virus Research, Westmead Millennium Institute & Westmead Hospital, University of Sydney, Westmead, Sydney, NSW, 2145, Australia.

Background: Despite the easy accessibility and diagnostic utility of PBMCs and their potential to show distinct expression patterns associated with the accelerated disease progression in HIV/HCV co-infection, there has not been a systematic study focusing on the global dysregulations of the biological pathways in PBMCs from HIV, HCV mono- and co-infected individuals. This study aimed at identifying the transcriptome distinctions of PBMCs between these patient groups.

Methods: Genome-wide transcriptomes of PBMCs from 10 HIV/HCV co-infected patients, 7 HIV+ patients, 5 HCV+ patients, and 5 HIV/HCV sero-negative healthy controls were analyzed using Illumina microarray. Pairwise comparisons were performed to identify differentially expressed genes (DEGs), followed by gene set enrichment analysis (GSEA) to detect the global dysregulations of the biological pathways between HIV, HCV mono- and co-infection.

Results: Forty-one, 262, and 44 DEGs with fold change > 1.5 and FDR (false discovery rate) <0.05 for the comparisons of HCV versus co-infection, HIV versus co-infection, and HIV versus HCV were identified, respectively. Significantly altered pathways (FDR < 0.05), featured by those involved in immune system, signaling transduction, and cell cycle, were detected. Notably, the differential regulation of cytotoxicity pathway discriminated between HIV, HCV mono- and co-infection (up-regulated in the former versus the latter group: co-infection versus HIV or HCV, HIV versus HCV; FDR <0.001 ~ 0.019). Conversely, the cytokine-cytokine receptor interaction pathway was down-regulated in co-infection versus either HCV (FDR = 0.003) or HIV (FDR = 0.028). For the comparison of HIV versus HCV, the cell cycle (FDR = 0.016) and WNT signaling (FDR = 0.006) pathways were up- and down-regulated in HIV, respectively.

Conclusions: Our study is the first to identify the differential regulation of cytotoxicity pathway discriminating between HIV, HCV mono- and co-infection, which may reflect the distinct patterns of virus-host cell interactions underlying disease progression. Further inspection of cytotoxicity pathway has pinned down to the expression of the KIR genes to be associated with specific patterns of particular virus-host interactions. Between HIV and HCV, the altered cell cycle and WNT signaling pathways may suggest the different impact of HIV and HCV on cell proliferation and differentiation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12985-014-0236-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4312599PMC
January 2015

Altered IL-2, IL-6 and IL-8 serum levels in schizophrenia patients with tardive dyskinesia.

Schizophr Res 2015 Mar 15;162(1-3):261-8. Epub 2015 Jan 15.

Beijing HuiLongGuan Hospital, Peking University, Beijing, China; Department of Psychiatry and Behavioral Sciences, Harris County Psychiatric Center, The University of Texas Health Science Center at Houston, Houston, TX, USA. Electronic address:

Immune deregulation has been postulated to be one of the mechanisms underlying the pathogenesis of tardive dyskinesia (TD). We hypothesized that interleukins would have a link with TD in schizophrenia patients. In this study, the serum IL-2, IL-6 and IL-8 levels were examined by enzyme-linked immunosorbent assay (ELISA) in schizophrenia patients with TD (n=48) and without TD (n=45), and healthy controls (n=44). The psychopathological symptoms of schizophrenia were assessed by the Positive and Negative Syndrome Scale (PANSS). The severity of TD was evaluated using Abnormal Involuntary Movement Scale (AIMS). The results showed that serum IL-2, IL-6 and IL-8 levels were significantly different among schizophrenia patients with TD and without TD and normal controls. Moreover, IL-2 level was significantly correlated with PANSS positive subscale and general subscale in patients with TD and without TD. In addition, IL-2 level was positively correlated with AIMS score in TD patients. The results supported that immune disturbance is related to the schizophrenia patients, especially to the patients with TD and ILs might play an important role in the pathophysiology of schizophrenia patients with TD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.schres.2014.12.037DOI Listing
March 2015

Mn-superoxide dismutase activity is associated with orofacial involuntary movements in schizophrenia patients with tardive dyskinesia.

Hum Psychopharmacol 2015 Jan;30(1):57-63

School of Biomedical Sciences and Pharmacy, Faculty of Health, The University of Newcastle, Newcastle, New South Wales, Australia; Schizophrenia Research Institute, Sydney, Australia; Psychiatry Research Center, Beijing HuiLongGuan Hospital, Peking University, Beijing, China.

Background: Oxidative stress-induced damage may be involved in tardive dyskinesia (TD) development. Superoxide dismutase (SOD), the key antioxidant enzyme, was found abnormal in TD.

Objective: We examined the role of oxidative stress in relation to TD and TD subtypes in schizophrenia using manganese SOD (MnSOD) as the biomarker.

Methods: We recruited 152 male chronic patients with (n = 76) and without TD (n = 76) meeting Diagnostic and Statistical Manual of Mental Disorders-IV criteria for schizophrenia and 75 male control subjects. We examined the MnSOD activity for all subjects. Positive and Negative Syndrome Scale and the Abnormal Involuntary Movement Scale (AIMS) were assessed in the patients.

Results: Manganese SOD activity was lower in patients with TD than non-TD (p < 0.05). In the patients with TD, orofacial and total scores of AIMS were positively associated with MnSOD levels (both p < 0.05). Multiple regression analysis further confirmed that MnSOD was an independent contributor to both the orofacial and the total scores of AIMS (both p < 0.05).

Conclusions: Oxidative stress reflected by compromised oxidative defense may play a role in the development and severity of TD. There may be an etiologic relationship between increased SOD level and dyskinetic movements associated with TD. In particular, MnSOD activity may have a specific role in orofacial TD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/hup.2453DOI Listing
January 2015

Association of altered CuZn superoxide dismutase and cognitive impairment in schizophrenia patients with tardive dyskinesia.

J Psychiatr Res 2014 Nov 8;58:167-74. Epub 2014 Aug 8.

Psychiatry Research Center, Beijing HuiLongGuan Hospital, Peking University, Beijing, China; Department of Psychiatry and Behavioral Sciences, Harris County Psychiatric Center, The University of Texas Health Science Center at Houston, Houston, TX, USA. Electronic address:

Free radical-mediated abnormalities may contribute to the development of tardive dyskinesia (TD) and specific aspects of schizophrenia symptomatology such as cognitive deficits. Superoxide dismutase (SOD), a critical enzyme in the detoxification of superoxide radicals, was found to be abnormal in TD. While most of previous studies focused on the manganese isoform located in mitochondria, this study investigated the activities of isoform CuZnSOD present in the plasma. We recruited 113 male chronic patients with TD (n = 43) and without TD (n = 70) meeting DSM-IV criteria for schizophrenia, and 84 male control subjects. We examined the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), CuZnSOD activity for both the patient and control groups along with total antioxidant status (TAS) and malondialdehyde (MDA) levels in a subset of the cohort. Positive and Negative Symptom Scale (PANSS) and the Abnormal Involuntary Movement Scale (AIMS) were assessed in the patient group. Our results showed lower CuZnSOD activity and TAS levels, but higher MDA levels in patients with TD than those without TD (all p < 0.05). Patients with TD had lower RBANS subscales of Visuospatial/Constructional (p < 0.05) and attention (p < 0.01) than those without TD. Multiple regression analysis showed that in either TD or non-TD group, CuZnSOD was an independent contributor to the attention index of RBANS (both p < 0.05). These results implicated that TD patients suffered greater oxidative stress and cognitive dysfunction than non-TD patients. Oxidative stress could contribute to both TD development and cognitive impairment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jpsychires.2014.07.028DOI Listing
November 2014

Altered BDNF is correlated to cognition impairment in schizophrenia patients with tardive dyskinesia.

Psychopharmacology (Berl) 2015 Jan 4;232(1):223-32. Epub 2014 Jul 4.

School of Biomedical Sciences and Pharmacy, Faculty of Health, The University of Newcastle, University Drive, Callaghan, NSW, 2308, Australia.

Background: Long-term antipsychotic treatment for schizophrenia is often associated with the emergence of tardive dyskinesia (TD), which is linked to greater cognitive impairment. Brain-derived neurotrophic factor (BDNF) plays a critical role in cognitive function, and schizophrenia patients with TD have lower BDNF levels than those without TD.

Objective: This study examines the BDNF levels, the cognitive function, and the association of BDNF with cognitive function in schizophrenia patients with or without TD.

Methods: We recruited 83 male chronic patients with (n=35) and without TD (n=48) meeting DSM-IV criteria for schizophrenia and 52 male control subjects. We examined the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and BDNF levels for all subjects. Positive and Negative Symptom Scale (PANSS) and the Abnormal Involuntary Movement Scale (AIMS) were assessed in patients.

Results: BDNF levels were lower in patients with than those without TD (p<0.05). RBANS total score (p<0.01) and subscales of immediate memory, visuospatial/constructional performance, and attention were lower in patients with than those without TD (all p<0.05). BDNF levels were positively associated with immediate memory in patients without TD, but negatively in TD patients (both p<0.05). Multiple regression analysis confirmed that in either TD or non-TD group, BDNF was an independent contributor to immediate memory (both p<0.05).

Conclusions: BDNF may be involved in the pathophysiology of TD. While the associations between BDNF and cognition in both TD and non-TD patients suggest a close relationship between BDNF and cognition, the different directions may implicate distinct mechanisms between TD and non-TD patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00213-014-3660-9DOI Listing
January 2015

Association between the angiotensin-converting enzyme gene insertion/deletion polymorphism and first-episode patients with schizophrenia in a Chinese Han population.

Hum Psychopharmacol 2014 May 11;29(3):274-9. Epub 2014 Mar 11.

Institute of Kangning Mental Health, Wenzhou Kangning Hospital, Wenzhou, China; Research Center for Genomic Medicine and MH Radiobiology Research Unit, School of Public Health, Jilin University, Changchun, China.

Background: Angiotensin-converting enzyme (ACE), a key enzyme of the renin-angiotensin system, can modulate dopamine turnover in the midbrain. Previous studies have revealed an association between ACE gene insertion/deletion (I/D) polymorphism and chronic schizophrenia, yet results are conflicting.

Objective: The primary objective of this study was to examine whether the ACE gene I/D polymorphism is associated with first-episode patients with schizophrenia (FEP) in a Chinese Han population.

Methods: The presence of the polymorphism was determined in 220 FEP and 538 healthy controls using a case-control design. We assessed the psychopathology in 212 FEP using the Positive and Negative Syndrome Scale (PANSS).

Results: The allelic and genotypic frequencies of the ACE gene I/D polymorphism did not significantly differ between FEP and healthy controls (both p>0.05). However, the negative PANSS symptom was significantly higher in FEP with the D/D genotype than those with I/D and I/I genotypes (all p<0.05) even after Bonferroni corrections (all p<0.05). Furthermore, the D allele of the ACE gene was associated with higher negative PANSS symptom score in FEP.

Conclusions: Our results indicated that even though the ACE gene I/D polymorphism did not associate with FEP, it may play a role in susceptibility to the negative PANSS symptom of FEP in a Chinese Han population.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/hup.2396DOI Listing
May 2014

Transcriptome analysis of primary monocytes from HIV-positive patients with differential responses to antiretroviral therapy.

Virol J 2013 Dec 27;10:361. Epub 2013 Dec 27.

Retroviral Genetics Division, Center for Virus Research, Westmead Millennium Institute & Westmead Hospital, University of Sydney, Westmead, Sydney, NSW, 2145, Australia.

Background: Despite the significant contributions of monocytes to HIV persistence, the HIV-monocyte interaction remains elusive. For patients on antiretroviral therapy, previous studies observed a virological suppression rate of >70% and suggested complete viral suppression as the primary goal. Although some studies have reported genetic dysregulations associated with HIV disease progression, research on ex vivo-derived monocytic transcriptomes from HIV+ patients with differential responses to therapy is limited. This study investigated the monocytic transcriptome distinctions between patients with sustained virus suppression and those with virological failure during highly active antiretroviral therapy (HAART).

Methods: Genome-wide transcriptomes of primary monocytes from five HIV+ patients on HAART who sustainably controlled HIV to below detection level (BDL), five HIV+ patients on HAART who consecutively experienced viremia, and four healthy HIV sero-negative controls were analyzed using Illumina microarray. Pairwise comparisons were performed to identify differentially expressed genes followed by quantitative PCR validation. Gene set enrichment analysis was used to check the consistency of our dataset with previous studies, as well as to detect the global dysregulations of the biological pathways in monocytes between viremic patients and BDLs.

Results: Pairwise comparisons including viremic patients versus controls, BDL versus controls, and viremic patients versus BDLs identified 473, 76, and 59 differentially expressed genes (fold change > 2 and FDR < 0.05), respectively. The reliability of our dataset was confirmed by gene set enrichment analysis showing that 6 out of 10 published gene lists were significantly enriched (FDR < 0.01) in at least one of the three pairwise comparisons. In the comparison of viremic patients versus BDLs, gene set enrichment analysis revealed that the pathways characterizing the primary functions of monocytes including antigen processing and presentation, FcγR mediated phagocytosis, and chemokine signaling were significantly up-regulated in viremic patients.

Conclusions: This study revealed the first transcriptome distinctions in monocytes between viremic patients and BDLs on HAART. Our results reflected the outcome balanced between the subversion of the monocyte transcriptome by HIV and the compensatory effect adapted by host cells. The up-regulation of antigen presentation pathway in viremic patients particularly highlighted the role of the interface between innate and adaptive immunity in HIV disease progression.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/1743-422X-10-361DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3877975PMC
December 2013

Preliminary evidence of an interaction between the FOXP2 gene and childhood emotional abuse predicting likelihood of auditory verbal hallucinations in schizophrenia.

J Psychiatr Res 2014 Mar 7;50:66-72. Epub 2013 Dec 7.

School of Psychiatry, Faculty of Medicine, University of New South Wales, NSW, Australia; Schizophrenia Research Institute, Sydney, NSW, Australia.

Objective: The FOXP2 gene is involved in the development of speech and language. As some single nucleotide polymorphisms (SNPs) of FOXP2 have been found to be associated with auditory verbal hallucinations (AVHs) at trend levels, this study set out to undertake the first examination into whether interactions between candidate FOXP2 SNPs and environmental factors (specifically, child abuse) predict the likelihood of AVHs.

Method: Data on parental child abuse and FOXP2 SNPs previously linked to AVHs (rs1456031, rs2396753, rs2253478) were obtained from the Australian Schizophrenia Research Bank for people with schizophrenia-spectrum disorders, both with (n = 211) and without (n = 122) a lifetime history of AVHs.

Results: Genotypic frequencies did not differ between the two groups; however, logistic regression found that childhood parental emotional abuse (CPEA) interacted with rs1456031 to predict lifetime experience of AVH. CPEA was only associated with significantly higher levels of AVHs in people with CC genotypes (odds ratio = 4.25), yet in the absence of CPEA, people with TT genotypes had significantly higher levels of AVHs than people with CC genotypes (odds ratio = 4.90). This interaction was specific to auditory verbal hallucinations, and did not predict the likelihood of non-verbal auditory hallucinations.

Conclusions: Our findings offer tentative evidence that FOXP2 may be a susceptibility gene for AVHs, influencing the probability people experience AVHs in the presence and absence of CPEA. However, these findings are in need of replication in a larger study that addresses the methodological limitations of the present investigation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jpsychires.2013.11.012DOI Listing
March 2014

Cognition impairment in schizophrenia patients with tardive dyskinesia: association with plasma superoxide dismutase activity.

Schizophr Res 2014 Jan 8;152(1):210-6. Epub 2013 Dec 8.

Biological Psychiatry Center, Beijing HuiLongGuan Hospital, Peking University, Beijing, China; Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, TX, USA. Electronic address:

Long-term antipsychotic treatment for schizophrenia is often associated with the emergence of tardive dyskinesia (TD), and TD presence is also accompanied by more severe cognitive impairment. Oxidative stress-induced damage may be involved in the development of TD and contribute to cognitive deficits in schizophrenia. We examined the role of oxidative stress in relation to TD and cognitive deficits in schizophrenia using plasma manganese superoxide dismutase (MnSOD) as a biomarker. We recruited 83 male chronic patients with (n=32) and without TD (n=51) meeting DSM-IV criteria for schizophrenia, and 58 male control subjects. We examined the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and MnSOD activity for all subjects. Positive and Negative Symptom Scale (PANSS) and the Abnormal Involuntary Movement Scale (AIMS) were assessed in the patients. MnSOD activity was lower in patients with TD than non-TD, and either TD or non-TD group had lower MnSOD levels than controls (all p<0.05). Patients with TD had lower RBANS total (p<0.05) and Visuospatial/Constructional subscale scores than non-TD patients (p<0.01), and either TD or non-TD group scored lower than the controls on all RBANS subscales (all p<0.001) except for the Visuospatial/Constructional index. Multiple regression analysis showed that in either TD or non-TD group, MnSOD was an independent contributor to the RBANS total score (both p<0.05). These findings suggest that TD patients suffered oxidative stress and cognition impairment at a more severe level than non-TD patients. Oxidative stress might serve as a functionally linking node between TD development and cognition dysfunction in schizophrenia.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.schres.2013.11.010DOI Listing
January 2014

Tardive dyskinesia is associated with greater cognitive impairment in schizophrenia.

Prog Neuropsychopharmacol Biol Psychiatry 2013 Oct 1;46:71-7. Epub 2013 Jul 1.

School of Biomedical Sciences and Pharmacy, Faculty of Health, The University of Newcastle, University Drive, Callaghan, NSW 2308, Australia; Schizophrenia Research Institute, Sydney, Australia; Psychiatry Research Center, Beijing HuiLongGuan Hospital, Peking University, Beijing, China.

Objective: Schizophrenia is a psychiatric disorder diagnosed by the presence of a number of symptoms with cognitive impairment as a core feature. Long-term antipsychotic treatment is often associated with the emergence of tardive dyskinesia (TD) and the presence of TD is linked to cognitive impairment. This study examined the relationship between TD and cognitive deficits in Chinese patients with schizophrenia.

Methods: We recruited 206 chronic patients with TD (n=102) and without TD (n=104) meeting DSM-IV criteria for schizophrenia and 104 control subjects who were matched on age, gender, and education. All the patients completed the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), Positive and Negative Symptom Scale (PANSS), and the Abnormal Involuntary Movement Scale (AIMS).

Results: The PANSS total score (p=0.01), N subscore (p=0.006), and AIMS total score (p<0.001) were significantly higher in patients with TD compared to patients without TD. Patients with TD scored lower for visuospatial/constructional, attention, and total index scores (all p<0.001) on the RBANS. AIMS orofacial scores were identified as an independent contributor to RBANS total scores and attention index (p<0.05), whereas AIMS limb and truncal scores were an independent determinant to the visuospatial/constructional index of RBANS (p<0.05).

Conclusion: TD was associated with greater cognitive impairment in patients with schizophrenia compared to those without TD. The orofacial and limb-trunk TD specifically appeared to be a risk factor or contributor to the different aspects of cognitive deficits in schizophrenia. The association between schizophrenia and TD may be explained in part by oxidative stress.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.pnpbp.2013.06.013DOI Listing
October 2013

Free radicals, antioxidant defense systems, and schizophrenia.

Prog Neuropsychopharmacol Biol Psychiatry 2013 Oct 5;46:200-6. Epub 2013 Mar 5.

School of Biomedical Sciences and Pharmacy, Faculty of Health, The University of Newcastle, University Drive, Callaghan, NSW 2308, Australia; Schizophrenia Research Institute, Sydney, Australia; Psychiatry Research Center, Beijing Hui Long Guan Hospital, Peking University, Beijing 100096, China.

The etiopathogenic mechanisms of schizophrenia are to date unknown, although several hypotheses have been suggested. Accumulating evidence suggests that excessive free radical production or oxidative stress may be involved in the pathophysiology of schizophrenia as evidenced by increased production of reactive oxygen or decreased antioxidant protection in schizophrenic patients. This review aims to summarize the basic molecular mechanisms of free radical metabolism, the impaired antioxidant defense system and membrane pathology in schizophrenia, their interrelationships with the characteristic clinical symptoms and the implications for antipsychotic treatments. In schizophrenia, there is accumulating evidence of altered antioxidant enzyme activities and increased levels of lipid peroxidation, as well as altered levels of plasma antioxidants. Moreover, free radical-mediated abnormalities may contribute to specific aspects of schizophrenic symptomatology and complications of its treatment with antipsychotic drugs, as well as the development of tardive dyskinesia (TD). Finally, the potential therapeutic strategies implicated by the accumulating data on oxidative stress mechanisms for the treatment of schizophrenia are discussed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.pnpbp.2013.02.015DOI Listing
October 2013

Transcriptome analysis of primary monocytes shows global down-regulation of genetic networks in HIV viremic patients versus long-term non-progressors.

Virology 2013 Jan 13;435(2):308-19. Epub 2012 Nov 13.

School of Biomedical Sciences and Pharmacy, Faculty of Health, The University of Newcastle, University Drive, Callaghan, NSW 2308, Australia.

Despite significant contributions of monocytes to HIV persistence, the genomic basis of HIV-infection of monocytes and its association with plasma viremia remain elusive. To understand HIV interactions with monocytes during disease progression, monocytic transcriptomes from long-term non-progressors (LTNP), HIV+ patients with viral load <1000, with viral load >1000, and seronegative controls were analyzed using Illumina microarray. Differentially expressed genes were identified (fold change >2; adjusted p<0.05) and GSEA between HIV+ groups demonstrated that the down-regulation of the pathways including Toll-like receptor (TLR) signaling, cytokine-cytokine receptor interaction, cell cycle and apoptosis was significantly associated with the viremic groups, whereas their up-regulation with the LTNP group. The down-regulation of TLR pathway in the viremic patients was exemplified by the decreased expression of TLR with the subsequent tuning down of MAPK, NF-κB, JAK-STAT, and IRF cascades. These data provide the first transcriptomic distinction between HIV+ progressors and LTNPs based on primary monocytes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.virol.2012.10.026DOI Listing
January 2013

Transcriptome sequencing revealed significant alteration of cortical promoter usage and splicing in schizophrenia.

PLoS One 2012 27;7(4):e36351. Epub 2012 Apr 27.

Schizophrenia Research Institute, Sydney, Australia.

Background: While hybridization based analysis of the cortical transcriptome has provided important insight into the neuropathology of schizophrenia, it represents a restricted view of disease-associated gene activity based on predetermined probes. By contrast, sequencing technology can provide un-biased analysis of transcription at nucleotide resolution. Here we use this approach to investigate schizophrenia-associated cortical gene expression.

Methodology/principal Findings: The data was generated from 76 bp reads of RNA-Seq, aligned to the reference genome and assembled into transcripts for quantification of exons, splice variants and alternative promoters in postmortem superior temporal gyrus (STG/BA22) from 9 male subjects with schizophrenia and 9 matched non-psychiatric controls. Differentially expressed genes were then subjected to further sequence and functional group analysis. The output, amounting to more than 38 Gb of sequence, revealed significant alteration of gene expression including many previously shown to be associated with schizophrenia. Gene ontology enrichment analysis followed by functional map construction identified three functional clusters highly relevant to schizophrenia including neurotransmission related functions, synaptic vesicle trafficking, and neural development. Significantly, more than 2000 genes displayed schizophrenia-associated alternative promoter usage and more than 1000 genes showed differential splicing (FDR<0.05). Both types of transcriptional isoforms were exemplified by reads aligned to the neurodevelopmentally significant doublecortin-like kinase 1 (DCLK1) gene.

Conclusions: This study provided the first deep and un-biased analysis of schizophrenia-associated transcriptional diversity within the STG, and revealed variants with important implications for the complex pathophysiology of schizophrenia.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0036351PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3338678PMC
September 2012

Genome-wide analysis of primary CD4+ and CD8+ T cell transcriptomes shows evidence for a network of enriched pathways associated with HIV disease.

Retrovirology 2011 Mar 16;8:18. Epub 2011 Mar 16.

Retroviral Genetics Division, Center for Virus Research, Westmead Millennium Institute, University of Sydney, Darcy Road, Westmead, NSW 2145, Australia.

Background: HIV preferentially infects CD4+ T cells, and the functional impairment and numerical decline of CD4+ and CD8+ T cells characterize HIV disease. The numerical decline of CD4+ and CD8+ T cells affects the optimal ratio between the two cell types necessary for immune regulation. Therefore, this work aimed to define the genomic basis of HIV interactions with the cellular transcriptome of both CD4+ and CD8+ T cells.

Results: Genome-wide transcriptomes of primary CD4+ and CD8+ T cells from HIV+ patients were analyzed at different stages of HIV disease using Illumina microarray. For each cell subset, pairwise comparisons were performed and differentially expressed (DE) genes were identified (fold change >2 and B-statistic >0) followed by quantitative PCR validation. Gene ontology (GO) analysis of DE genes revealed enriched categories of complement activation, actin filament, proteasome core and proton-transporting ATPase complex. By gene set enrichment analysis (GSEA), a network of enriched pathways functionally connected by mitochondria was identified in both T cell subsets as a transcriptional signature of HIV disease progression. These pathways ranged from metabolism and energy production (TCA cycle and OXPHOS) to mitochondria meditated cell apoptosis and cell cycle dysregulation. The most unique and significant feature of our work was that the non-progressing status in HIV+ long-term non-progressors was associated with MAPK, WNT, and AKT pathways contributing to cell survival and anti-viral responses.

Conclusions: These data offer new comparative insights into HIV disease progression from the aspect of HIV-host interactions at the transcriptomic level, which will facilitate the understanding of the genetic basis of transcriptomic interaction of HIV in vivo and how HIV subverts the human gene machinery at the individual cell type level.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/1742-4690-8-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3068086PMC
March 2011
-->