ORCID Profile
0000-0003-2490-2538
Current Organisation
Faculty of Health and Medicine, University of Newcastle Australia
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Publisher: Springer Science and Business Media LLC
Date: 21-11-2016
DOI: 10.1038/NG.3725
Publisher: Springer Science and Business Media LLC
Date: 23-07-2021
Publisher: Springer Science and Business Media LLC
Date: 02-2016
DOI: 10.1038/NN.4228
Publisher: Elsevier BV
Date: 09-2015
Publisher: Oxford University Press (OUP)
Date: 09-01-2008
DOI: 10.1093/HMG/DDN005
Abstract: Analysis of global microRNA (miRNA) expression in postmortem cortical grey matter from the superior temporal gyrus, revealed significant up-regulation of miR-181b expression in schizophrenia. This finding was supported by quantitative real-time RT-PCR analysis of miRNA expression in a cohort of 21 matched pairs of schizophrenia and non-psychiatric controls. The implications of this finding are substantial, as this miRNA is predicted to regulate many target genes with potential significance to the development of schizophrenia. They include the calcium sensor gene visinin-like 1 (VSNL1) and the ionotropic AMPA glutamate receptor subunit (GRIA2), which were found to be down-regulated in the same cortical tissue from the schizophrenia group. Both of these genes were also suppressed in miR-181b transfected cells and shown to contain functional miR-181b miRNA recognition elements by reporter gene assay. This study suggests altered miRNA levels could be a significant factor in the dysregulation of cortical gene expression in schizophrenia.
Publisher: Springer Science and Business Media LLC
Date: 22-02-2019
DOI: 10.1038/S41598-019-38860-9
Abstract: Circular RNAs (circRNAs) are covalently closed structural isoforms of linear mRNA which have been observed across a broad range of species and tissues. Here, we provide a comprehensive circRNAs expression catalogue for the rat including 8 organs of both sexes during 4 developmental stages using a public RNAseq dataset. These analyses revealed thousands of circular RNA species, many expressed in an organ-specific manner along with their host genes which were enriched with tissue-specific biological functions. A large number of circRNAs also displayed a developmental-dependent expression pattern and are accumulated during ageing. CircRNAs also displayed some sexually dimorphic expression, with gender associated differences observed in various tissues and developmental stages. These observations suggest that circRNAs are dynamically expressed in a spatial-, temporal- and gender-specific manner in mammals, and may have important biological function in differentiation, development and aging.
Publisher: Oxford University Press (OUP)
Date: 24-06-2023
Abstract: Schizophrenia is highly heritable, with a polygenic effect of many genes conferring risk. Evidence on whether cumulative risk also predicts alterations in brain morphology and function is inconsistent. This systematic review examined evidence for schizophrenia polygenic risk score (sczPRS) associations with commonly used magnetic resonance imaging (MRI) measures. We expected consistent evidence to emerge for significant sczPRS associations with variation in structure and function, specifically in frontal, temporal, and insula cortices that are commonly implicated in schizophrenia pathophysiology. In accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we searched MEDLINE, Embase, and PsycINFO for peer-reviewed studies published between January 2013 and March 2022. Studies were screened against predetermined criteria and National Institutes of Health (NIH) quality assessment tools. In total, 57 studies of T1-weighted structural, diffusion, and functional MRI were included (age range = 9–80 years, Nrange = 64–76 644). We observed moderate, albeit preliminary, evidence for higher sczPRS predicting global reductions in cortical thickness and widespread variation in functional connectivity, and to a lesser extent, region-specific reductions in frontal and temporal volume and thickness. Conversely, sczPRS does not predict whole-brain surface area or gray/white matter volume. Limited evidence emerged for sczPRS associations with diffusion tensor measures of white matter microstructure in a large community s le and smaller cohorts of children and young adults. These findings were broadly consistent across community and clinical populations. Our review supports the hypothesis that schizophrenia is a disorder of disrupted within and between-region brain connectivity, and points to specific whole-brain and regional MRI metrics that may provide useful intermediate phenotypes.
Publisher: Elsevier BV
Date: 08-2010
DOI: 10.1016/J.JINORGBIO.2010.03.011
Abstract: Three platinum complexes in which substituted (7-OMe, 9-NH(2) 7-F, 9-NH(2) and 7-H, 9-NH(CH(2))(2)OH) 9-aminoacridine-4-carboxamides were tethered to a platinum(II)diamine moiety were synthesised and characterised at the chemical and biological level. These variants showed a decrease in cytotoxicity, as measured by IC(50) values in HeLa cells, when compared with the parent 7-H, 9-NH(2) compound. The 7-F and 9-NH(CH(2))(2)OH substituents gave rise to a small decrease in cytotoxicity, and the 7-OMe substituent resulted in a larger decrease in cytotoxicity. Their binding to purified pUC19 plasmid DNA was investigated and it was found that the addition of 7-F, 9-NH(CH(2))(2)OH and especially the 7-OMe substituents, resulted in reduced DNA binding. This correlated well with the IC(50) cytotoxicity values. However, the DNA sequence selectivity was unaffected by the addition of these moieties.
Publisher: Springer Science and Business Media LLC
Date: 13-09-2020
DOI: 10.1038/S41386-020-00847-W
Abstract: Data from observational studies have suggested an involvement of abnormal glycaemic regulation in the pathophysiology of psychiatric illness. This may be an attractive target for clinical intervention as glycaemia can be modulated by both lifestyle factors and pharmacological agents. However, observational studies are inherently confounded, and therefore, causal relationships cannot be reliably established. We employed genetic variants rigorously associated with three glycaemic traits (fasting glucose, fasting insulin, and glycated haemoglobin) as instrumental variables in a two-s le Mendelian randomisation analysis to investigate the causal effect of these measures on the risk for eight psychiatric disorders. A significant protective effect of a natural log transformed pmol/L increase in fasting insulin levels was observed for anorexia nervosa after the application of multiple testing correction (OR = 0.48 [95% CI: 0.33-0.71]—inverse-variance weighted estimate). There was no consistently strong evidence for a causal effect of glycaemic factors on the other seven psychiatric disorders considered. The relationship between fasting insulin and anorexia nervosa was supported by a suite of sensitivity analyses, with no statistical evidence of instrument heterogeneity or horizontal pleiotropy. Further investigation is required to explore the relationship between insulin levels and anorexia.
Publisher: Wiley
Date: 13-06-2017
DOI: 10.1111/ADB.12520
Abstract: MicroRNAs (miRNAs) within the ventral and dorsal striatum have been shown to regulate addiction-relevant behaviours. However, it is unclear how cocaine experience alone can alter the expression of addiction-relevant miRNAs within striatal subregions. Further, it is not known whether differential expression of miRNAs in the striatum contributes to in idual differences in addiction vulnerability. We first examined the effect of cocaine self-administration on the expression of miR-101b, miR-137, miR-212 and miR-132 in nucleus accumbens core and nucleus accumbens shell (NAcSh), as well as dorsomedial striatum and dorsolateral striatum (DLS). We then examined the expression of these same miRNAs in striatal subregions of animals identified as being 'addiction-prone', either immediately following self-administration training or following extinction and relapse testing. Cocaine self-administration was associated with changes in miRNA expression in a regionally discrete manner within the striatum, with the most marked changes occurring in the nucleus accumbens core. When we examined the miRNA profile of addiction-prone rats following self-administration, we observed increased levels of miR-212 in the dorsomedial striatum. After extinction and relapse testing, addiction-prone rats showed significant increases in the expression of miR-101b, miR-137, miR-212 and miR-132 in NAcSh, and miR-137 in the DLS. This study identifies temporally specific changes in miRNA expression consistent with the engagement of distinct striatal subregions across the course of the addiction cycle. Increased dysregulation of miRNA expression in NAcSh and DLS at late stages of the addiction cycle may underlie habitual drug seeking, and may therefore aid in the identification of targets designed to treat addiction.
Publisher: Cold Spring Harbor Laboratory
Date: 28-09-2023
Publisher: eLife Sciences Publications, Ltd
Date: 05-01-2021
Publisher: Elsevier BV
Date: 08-2015
DOI: 10.1016/J.BIOPSYCH.2014.12.009
Abstract: Psychiatric syndromes, including schizophrenia, mood disorders, and autism spectrum disorders, are characterized by a complex range of symptoms, including psychosis, depression, mania, and cognitive deficits. Although the mechanisms driving pathophysiology are complex and remain largely unknown, advances in the understanding of gene association and gene networks are providing significant clues to their etiology. In recent years, small noncoding RNA molecules known as microRNA (miRNA) have emerged as potential players in the pathophysiology of mental illness. These small RNAs regulate hundreds of target transcripts by modifying their stability and translation on a broad scale, influencing entire gene networks in the process. There is evidence to suggest that numerous miRNAs are dysregulated in postmortem neuropathology of neuropsychiatric disorders, and there is strong genetic support for association of miRNA genes and their targets with these conditions. This review presents the accumulated evidence linking miRNA dysregulation and dysfunction with schizophrenia, bipolar disorder, major depressive disorder, and autism spectrum disorders and the potential of miRNAs as biomarkers or therapeutics for these disorders. We further assess the functional roles of some outstanding miRNAs associated with these conditions and how they may be influencing the development of psychiatric symptoms.
Publisher: Springer Science and Business Media LLC
Date: 19-02-2013
DOI: 10.1038/TP.2013.3
Publisher: Oxford University Press (OUP)
Date: 07-12-2018
DOI: 10.1093/NAR/GKY1235
Publisher: Oxford University Press (OUP)
Date: 28-01-2013
DOI: 10.1093/JMCB/MJT004
Abstract: Since their discovery, microRNAs (miRNA) have been implicated in a vast array of biological processes in animals, from fundamental developmental functions including cellular proliferation and differentiation, to more complex and specialized roles such as long-term potentiation and synapse-specific modifications in neurons. This review recounts the history behind this paradigm shift, which has seen small non-coding RNA molecules coming to the forefront of molecular biology, and introduces their role in establishing developmental complexity in animals. The fundamental mechanisms of miRNA biogenesis and function are then considered, leading into a discussion of recent discoveries transforming our understanding of how these molecules regulate gene network behaviour throughout developmental and pathophysiological processes. The emerging complexity of this mechanism is also examined with respect to the influence of cellular context on miRNA function. This discussion highlights the absolute imperative for experimental designs to appreciate the significance of context-specific factors when determining what genes are regulated by a particular miRNA. Moreover, by establishing the timing, location, and mechanism of these regulatory events, we may ultimately understand the true biological function of a specific miRNA in a given cellular environment.
Publisher: Elsevier BV
Date: 03-2018
DOI: 10.1016/J.PNPBP.2017.12.007
Abstract: The single nucleotide polymorphism (SNP) rs1344706 [A>C] within intron 2 of the zinc finger protein 804A gene (ZNF804A) is associated with schizophrenia at the genome-wide level, but its function in relation to the development of psychotic disorders, including its influence on brain morphology remains unclear. Using both univariate (voxel-based morphometry, VBM cortical thickness) and multivariate (source-based morphometry, SBM) approaches, we examined the effects of variation of the rs1344706 polymorphism on grey matter integrity in 214 Caucasian schizophrenia cases and 94 Caucasian healthy in iduals selected from the Australian Schizophrenia Research Bank. Neither univariate nor multivariate analyses showed any associations between indices of grey matter and rs1344706 variation in schizophrenia or healthy participants. This was revealed in the context of the typical pattern of decreased grey matter integrity in schizophrenia compared to healthy in iduals, including: (1) large grey matter volume reductions in the orbitofrontal and anterior cingulate cortices and the left fusiform/inferior temporal gyri (2) decreased cortical thickness in the left inferior temporal and fusiform gyri, the left orbitofrontal gyrus, as well as in the right pars opercularis recentral gyrus and (3) decreased covariation of grey matter concentration in frontal and limbic brain regions emerging from the SBM analyses. Contrary to some - but not all - previous findings, this study of a large s le of schizophrenia cases and healthy controls reveals no evidence for association between grey matter alterations and variation in rs1344706 (ZNF804A). Differences in s le sizes and ethnicities may account for discrepant findings between the present and previous studies.
Publisher: Cold Spring Harbor Laboratory
Date: 26-01-2021
DOI: 10.1101/2021.01.24.21250424
Abstract: Pneumonia remains one of the leading causes of death worldwide, particularly amongst the elderly and young children. We performed a genome-wide meta-analysis of lifetime pneumonia diagnosis (N=266,277), that encompassed the largest collection of cases published to date. Genome-wide significant associations with pneumonia were uncovered for the first time beyond the major histocompatibility complex region, with three novel loci, including a signal fine-mapped to a cluster of mucin genes. Moreover, we demonstrated evidence of a polygenic effect of common and low frequency pneumonia associated variation impacting several other mucin genes and O -glycosylation, further suggesting a role for these processes in pneumonia pathophysiology. The pneumonia GWAS was then leveraged to identify drug repurposing opportunities, including evidence that supports the use of lipid modifying agents in the prevention and treatment of the disorder. We also propose how polygenic risk could be utilised for precision drug repurposing through pneumonia risk scores constructed using variants mapped to pathways with known drug targets. In summary, we provide novel insights into the genetic architecture of pneumonia susceptibility, with future study warranted to functionally interrogate novel association signals and evaluate the suitability of the compounds prioritised by this study as repositioning candidates.
Publisher: Elsevier BV
Date: 02-2014
DOI: 10.1016/J.JPSYCHIRES.2013.10.018
Abstract: The interaction of genetic and environmental factors may affect the course and development of psychotic disorders. We examined whether the effects of childhood trauma on cognition and symptoms in schizophrenia were moderated by the Catechol-O-methyltransferase (COMT) Val(158)Met polymorphism, a common genetic variant known to affect cognition and prefrontal dopamine levels. Participants were 429 schizophrenia/schizoaffective cases from the Australian Schizophrenia Research Bank (ASRB). Cognitive performance was assessed using the Repeatable Battery for Assessment of Neuropsychological Status (RBANS), Controlled Oral Word Association Test (COWAT), Letter Number Sequencing (LNS) test, and the Wechsler Test of Adult Reading (WTAR). Hierarchical regression was used to test the main effects and additive interaction effects of genotype and childhood trauma in the domains of physical abuse, emotional abuse, and emotional neglect, on cognition and symptom profiles of clinical cases. Consistent with previous findings, COMT Val homozygotes performed worse on cognitive measures in the absence of childhood adversity. In addition, a significant interaction between COMT genotype and physical abuse was associated with better executive function in Val homozygotes, relative to those of the same genotype with no history of abuse. Finally, the severity of positive symptoms was greater in Met carriers who had experienced physical abuse, and the severity of negative symptoms in Met carriers was greater in the presence of emotional neglect. These results suggest that the possible epigenetic modulation of the expression of the COMT Val(158)Met polymorphism and consequent effects on cognition and symptoms in schizophrenia, with worse outcomes associated with adverse childhood experiences in Met carriers.
Publisher: SAGE Publications
Date: 16-11-2020
Abstract: 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. We performed a case–control genome-wide association study in 429 schizophrenia s les 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. The strongest finding ( p = 2.01 × 10 −6 , odds ratio = 1.82, 95% confidence interval = [1.42, 2.33]) in genome-wide association study was with rs10252923 at 7q21.13, downstream of FZD1 (frizzled class receptor 1). While this did not stand alone after correction, the involvement of FZD1 was supported by gene-based analysis, which exceeded the threshold for genome-wide significance ( p = 2.78 × 10 −6 ). The identification of FZD1, 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.
Publisher: Springer Science and Business Media LLC
Date: 10-02-2022
DOI: 10.1038/S41380-022-01460-7
Abstract: Brain morphology differs markedly between in iduals with schizophrenia, but the cellular and genetic basis of this heterogeneity is poorly understood. Here, we sought to determine whether cortical thickness (CTh) heterogeneity in schizophrenia relates to interregional variation in distinct neural cell types, as inferred from established gene expression data and person-specific genomic variation. This study comprised 1849 participants in total, including a discovery (140 cases and 1267 controls) and a validation cohort (335 cases and 185 controls). To characterize CTh heterogeneity, normative ranges were established for 34 cortical regions and the extent of deviation from these ranges was measured for each in idual with schizophrenia. CTh deviations were explained by interregional gene expression levels of five out of seven neural cell types examined: (1) astrocytes (2) endothelial cells (3) oligodendrocyte progenitor cells (OPCs) (4) excitatory neurons and (5) inhibitory neurons. Regional alignment between CTh alterations with cell type transcriptional maps distinguished broad patient subtypes, which were validated against genomic data drawn from the same in iduals. In a predominantly neuronal/endothelial subtype (22% of patients), CTh deviations covaried with polygenic risk for schizophrenia (sczPRS) calculated specifically from genes marking neuronal and endothelial cells ( r = −0.40, p = 0.010). Whereas, in a predominantly glia/OPC subtype (43% of patients), CTh deviations covaried with sczPRS calculated from glia and OPC-linked genes ( r = −0.30, p = 0.028). This multi-scale analysis of genomic, transcriptomic, and brain phenotypic data may indicate that CTh heterogeneity in schizophrenia relates to inter-in idual variation in cell-type specific functions. Decomposing heterogeneity in relation to cortical cell types enables prioritization of schizophrenia subsets for future disease modeling efforts.
Publisher: Springer Science and Business Media LLC
Date: 30-09-2014
DOI: 10.1038/TP.2014.99
Publisher: Elsevier BV
Date: 06-2004
Publisher: Springer Science and Business Media LLC
Date: 02-02-2015
DOI: 10.1038/NG.3211
Publisher: Oxford University Press (OUP)
Date: 14-11-2019
DOI: 10.1093/NAR/GKZ1038
Abstract: Gene expression is precisely controlled in a stage and cell-type-specific manner, largely through the interaction between cis-regulatory elements and their associated trans-acting factors. Where these components aggregate in promoters and enhancers, they are able to cooperate to modulate chromatin structure and support the engagement in long-range 3D superstructures that shape the dynamics of a cell's genomic architecture. Recently, the term ‘super-enhancer’ has been introduced to describe a hyper-active regulatory domain comprising a complex array of sequence elements that work together to control the key gene networks involved in cell identity. Here, we survey the unique characteristics of super-enhancers compared to other enhancer types and summarize the recent advances in our understanding of their biological role in gene regulation. In particular, we discuss their capacity to attract the formation of phase-separated condensates, and capacity to generate three-dimensional genome structures that precisely activate their target genes. We also propose a multi-stage transition model to explain the evolutionary pressure driving the development of super-enhancers in complex organisms, and highlight the potential for involvement in tumorigenesis. Finally, we discuss more broadly the role of super-enhancers in human health disorders and related potential in therapeutic interventions.
Publisher: Oxford University Press (OUP)
Date: 22-11-2012
DOI: 10.1093/BIB/BBS075
Publisher: Springer Science and Business Media LLC
Date: 05-07-2012
DOI: 10.1038/MP.2011.78
Publisher: Elsevier BV
Date: 08-2016
DOI: 10.1016/J.BBI.2016.02.021
Abstract: Maternal immune activation (MIA) and adolescent cannabinoid exposure (ACE) have both been identified as major environmental risk factors for schizophrenia. We examined the effects of these two risk factors alone, and in combination, on gene expression during late adolescence. Pregnant rats were exposed to the viral infection mimic polyriboinosinic-polyribocytidylic acid (poly I:C) on gestational day (GD) 15. Adolescent offspring received daily injections of the cannabinoid HU210 for 14days starting on postnatal day (PND) 35. Gene expression was examined in the left entorhinal cortex (EC) using mRNA microarrays. We found prenatal treatment with poly I:C alone, or HU210 alone, produced relatively minor changes in gene expression. However, following combined treatments, offspring displayed significant changes in transcription. This dramatic and persistent alteration of transcriptional networks enriched with genes involved in neurotransmission, cellular signalling and schizophrenia, was associated with a corresponding perturbation in the expression of small non-coding microRNA (miRNA). These results suggest that a combination of environmental exposures during development leads to significant genomic remodeling that disrupts maturation of the EC and its associated circuitry with important implications as the potential antecedents of memory and learning deficits in schizophrenia and other neuropsychiatric disorders.
Publisher: Springer Science and Business Media LLC
Date: 04-2018
Publisher: Elsevier BV
Date: 08-2016
Publisher: Elsevier
Date: 2017
Publisher: eLife Sciences Publications, Ltd
Date: 15-03-2021
DOI: 10.7554/ELIFE.63115
Abstract: Measures of lung function are heritable, and thus, we sought to utilise genetics to propose drug-repurposing candidates that could improve respiratory outcomes. Lung function measures were found to be genetically correlated with seven druggable biochemical traits, with further evidence of a causal relationship between increased fasting glucose and diminished lung function. Moreover, we developed polygenic scores for lung function specifically within pathways with known drug targets and investigated their relationship with pulmonary phenotypes and gene expression in independent cohorts to prioritise in iduals who may benefit from particular drug-repurposing opportunities. A transcriptome-wide association study (TWAS) of lung function was then performed which identified several drug–gene interactions with predicted lung function increasing modes of action. Drugs that regulate blood glucose were uncovered through both polygenic scoring and TWAS methodologies. In summary, we provided genetic justification for a number of novel drug-repurposing opportunities that could improve lung function.
Publisher: Cold Spring Harbor Laboratory
Date: 17-08-2020
DOI: 10.1101/2020.08.13.249813
Abstract: 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. We conducted the largest to date genome-wide genotype–by–sex (GxS) interaction of risk for these disorders, using 85,735 cases (33,403 SCZ, 19,924 BIP, 32,408 MDD) and 109,946 controls from the Psychiatric Genomics Consortium (PGC) and iPSYCH. Across disorders, genome-wide significant SNP-by-sex interaction was detected for a locus encompassing NKAIN2 (rs117780815 p =3.2×10 −8 ), that interacts with sodium otassium-transporting ATPase enzymes implicating neuronal excitability. Three additional loci showed evidence ( p ×10 −6 ) for cross-disorder GxS interaction (rs7302529, p =1.6×10 −7 rs73033497, p =8.8×10 −7 rs7914279, p =6.4×10 −7 ) implicating various functions. Gene-based analyses identified GxS interaction across disorders ( p =8.97×10 −7 ) with transcriptional inhibitor SLTM . Most significant in SCZ was a MOCOS gene locus (rs11665282 p =1.5×10 −7 ), implicating vascular endothelial cells. Secondary analysis of the PGC-SCZ dataset detected an interaction (rs13265509 p =1.1×10 −7 ) in a locus containing IDO2 , a kynurenine pathway enzyme with immunoregulatory functions implicated in SCZ, BIP, and MDD. Pathway enrichment analysis detected significant GxS of genes regulating vascular endothelial growth factor (VEGF) receptor signaling in MDD ( p FDR .05). In the largest genome-wide GxS 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, immune and vascular functions across and within SCZ, BIP, and MDD at the variant, gene, and pathway enrichment levels.
Publisher: Cold Spring Harbor Laboratory
Date: 10-08-2023
DOI: 10.1101/2023.08.07.23293796
Abstract: Retinol is a fat-soluble vitamin that plays an essential role in many biological processes throughout the human lifespan. Previous work has characterised genetic influences on circulating retinol however, small s le sizes have limited our ability to fully appreciate the genetic architecture of this trait. In this study, we performed the largest genome-wide association study (GWAS) of retinol to date in up to 22,274 participants. We identified eight common variant loci associated with retinol, as well as a rare-variant signal. An integrative gene prioritisation pipeline supported novel retinol-associated genes outside of the main retinol transport complex ( RBP4 : TTR ) related to lipid biology, energy homeostasis, and endocrine signalling. Genetic proxies of circulating retinol were then used to estimate causal relationships with almost 20,000 clinical phenotypes via a phenome-wide Mendelian randomisation study (MR-pheWAS). The MR-pheWAS suggested that retinol may exert causal effects on inflammation, adiposity, ocular measures, the microbiome, and MRI-derived brain phenotypes, amongst several others. Conversely, circulating retinol may be causally influenced by factors including lipids and renal function. Finally, we demonstrated how a retinol polygenic score could identify in iduals who are more likely to fall outside of the normative range of circulating retinol for a given age. In summary, this study provides a comprehensive evaluation of the genetics of circulating retinol, as well as revealing traits which should be prioritised for further clinical investigation with respect to retinol related therapies or nutritional intervention.
Publisher: American Association for Cancer Research (AACR)
Date: 10-2014
DOI: 10.1158/1538-7445.AM2014-4364
Abstract: Rationale The tetraspanins CD151 & CD9 are known to play a prominent role in cancer progression by modulating cell adhesion and migration/invasion. CD151 is commonly overexpressed (metastasis enhancer) and tends to predict poor prognosis in many solid malignancies, whereas the metastasis suppressor CD9 is typically down-regulated which correlates with poor patient outcomes. However, progress in developing CD151 and CD9 as prognostic biomarkers & therapeutic targets has been h ered by a lack of understanding of how they are regulated in normal cells and how they are deregulated in cancers. Objective Many micro-RNAs are deregulated in prostate and breast cancers. Bio-informatic analysis has identified 250 miRNAs that potentially regulate CD151 or CD9. Therefore, we investigated whether miRNAs regulate CD151 and CD9 in a range of normal and cancerous breast and prostate cell lines in vitro. Methods & Results A dual luciferase reporter assay using the 3′UTR of CD151 and CD9 provided evidence that breast & prostate cancer cell lines endogenously express miRNA that regulate tetraspanins and that the extent of regulation varies across the cell lines. Analysis of miRNA expression in normal and cancer cell lines using miRNA arrays and qPCR has confirmed that some miRNAs which are predicted to target CD9, are up-regulated in many prostate and/or breast cancer cell lines compared to non-tumourigenic cells. Furthermore, miRNAs were identified with altered expression that were predicted to target CD151. These miRNA have also been shown to directly regulate CD151 or CD9 using the dual luciferase 3′UTR reporter assay with miRNA mimics. Conclusion Altered miRNA expression may contribute to prostate and breast cancers by manipulating tetraspanins to allow cancer progression and metastasis. Therefore, miRNA may be effective prognostic and/or therapeutic targets for prostate and breast cancers in the future. Citation Format: Danielle R. Bond, Crystal Passfield, Murray Cairns, Leonie K. Ashman, Judith Weidenhofer. Posttranscriptional regulation of tetraspanins CD151 & CD9 in breast & prostate cancers. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research 2014 Apr 5-9 San Diego, CA. Philadelphia (PA): AACR Cancer Res 2014 (19 Suppl):Abstract nr 4364. doi:10.1158/1538-7445.AM2014-4364
Publisher: Elsevier BV
Date: 04-2012
Publisher: Elsevier BV
Date: 06-2013
Abstract: MicroRNAs (miRNAs) are small noncoding RNA molecules that act as sequence specificity guides to direct post-transcriptional gene silencing. In doing so, miRNAs regulate many critical developmental processes, including cellular proliferation, differentiation, migration, and apoptosis, as well as more specialized biological functions such as dendritic spine development and synaptogenesis. Interactions between miRNAs and their miRNA recognition elements occur via partial complementarity, rendering tremendous redundancy in targeting such that miRNAs are predicted to regulate 60% of the genome, with each miRNA estimated to regulate more than 200 genes. Because these predictions are prone to false positives and false negatives, there is an ever present need to provide material support to these assertions to firmly establish the biological function of specific miRNAs in both normal and pathophysiological contexts. Using schizophrenia-associated miR-181b as an ex le, we present detailed guidelines and novel insights for the rapid establishment of a streamlined miRNA-reporter gene assay and explore various design concepts for miRNA-reporter gene applications, including bidirectional miRNA modulation. In exemplifying this approach, we report seven novel miR-181b target sites for five schizophrenia candidate genes (DISC1, BDNF, ENKUR, GRIA1, and GRIK1) and dissect a number of vital concepts regarding future developments for miRNA-reporter gene assays and the interpretation of their results.
Publisher: MDPI AG
Date: 28-04-2022
DOI: 10.3390/IJMS23094923
Abstract: Although genomes from many edible mushrooms are sequenced, studies on fungal micro RNAs (miRNAs) are scarce. Most of the bioinformatic tools are designed for plants or animals, but the processing and expression of fungal miRNAs share similarities and differences with both kingdoms. Moreover, since mushroom species such as Agaricus bisporus (A. bisporus, white button mushroom) are frequently consumed as food, controversial discussions are still evaluating whether their miRNAs might or might not be assimilated, perhaps within extracellular vesicles (i.e., exosomes). Therefore, the A. bisporus RNA-seq was studied in order to identify potential de novo miRNA-like small RNAs (milRNAs) that might allow their later detection in diet. Results pointed to 1 already known and 37 de novo milRNAs. Three milRNAs were selected for RT-qPCR experiments. Precursors and mature milRNAs were found in the edible parts (caps and stipes), validating the predictions carried out in silico. When their potential gene targets were investigated, results pointed that most were involved in primary and secondary metabolic regulation. However, when the human transcriptome is used as the target, the results suggest that they might interfere with important biological processes related with cancer, infection and neurodegenerative diseases.
Publisher: Elsevier BV
Date: 04-2012
Publisher: Elsevier BV
Date: 10-2016
Publisher: Springer Science and Business Media LLC
Date: 07-08-2012
DOI: 10.1038/MP.2012.110
Abstract: Upregulation of the immune response may be involved in the pathogenesis of schizophrenia with changes occurring in both peripheral blood and brain tissue. To date, microarray technology has provided a limited view of specific inflammatory transcripts in brain perhaps due to sensitivity issues. Here we used SOLiD Next Generation Sequencing to quantify neuroimmune mRNA expression levels in the dorsolateral prefrontal cortex of 20 in iduals with schizophrenia and their matched controls. We detected 798 differentially regulated transcripts present in people with schizophrenia compared with controls. Ingenuity pathway analysis identified the inflammatory response as a key change. Using quantitative real-time PCR we confirmed the changes in candidate cytokines and immune modulators, including interleukin (IL)-6, IL-8, IL-1β and SERPINA3. The density of major histocompatibility complex-II-positive cells morphologically resembling microglia was significantly increased in schizophrenia and correlated with IL-1β expression. A group of in iduals, most of whom had schizophrenia, were found to have increased inflammatory mRNA expression. In summary, we have demonstrated changes in an inflammatory response pathway that are present in ∼40% of people diagnosed with schizophrenia. This suggests that therapies aimed at immune system attenuation in schizophrenia may be of direct benefit in the brain.
Publisher: Elsevier BV
Date: 04-2014
Publisher: Morressier
Date: 14-08-2019
Publisher: MDPI AG
Date: 02-12-2020
DOI: 10.3390/IJMS21239182
Abstract: Prenatal environmental exposures that have been shown to induce oxidative stress (OS) during pregnancy, such as smoking and alcohol consumption, are risk factors for the onset of schizophrenia and other neurodevelopmental disorders (NDDs). While the OS role in the etiology of neurodegenerative diseases is well known, its contribution to the genomic dysregulation associated with psychiatric disorders is less well defined. In this study we used the SH-SY5Y cell line and applied RNA-sequencing to explore transcriptomic changes in response to OS before or during neural differentiation. We observed differential expression of many genes, most of which localised to the synapse and were involved in neuronal differentiation. These genes were enriched in schizophrenia-associated signalling pathways, including PI3K/Akt, axon guidance, and signalling by retinoic acid. Interestingly, circulatory system development was affected by both treatments, which is concordant with observations of increased prevalence of cardiovascular disease in patients with NDDs. We also observed a very significant increase in the expression of immunity-related genes, supporting current hypotheses of immune system involvement in psychiatric disorders. While further investigation of this influence in other cell and animal models is warranted, our data suggest that early life exposure to OS has a disruptive influence on neuronal gene expression that may perturb normal differentiation and neurodevelopment, thereby contributing towards overall risk for developing psychiatric diseases.
Publisher: Springer Science and Business Media LLC
Date: 03-02-2015
DOI: 10.1038/TP.2014.144
Publisher: Elsevier BV
Date: 2014
Publisher: Springer Netherlands
Date: 19-12-2012
DOI: 10.1007/978-94-007-5590-1_14
Abstract: microRNAs (miRNAs) are small non-coding RNAs that cause mRNA degradation and translation inhibition. They are pivotal regulators of development and cellular homeostasis through their control of erse processes. Recently, great efforts have been made to elucidate many targets that are affected by miRNAs, but the functions of most miRNAs and their precise regulatory mechanisms remain elusive. With more and more matched expression profiles of miRNAs and mRNAs having been made available, it is of great interest to utilize both expression profiles and sequence information to discover the functional regulatory networks of miRNAs and their target mRNAs for potential biological processes that they may participate in. In this chapter, we first briefly review the computational methods for discovering miRNA targets and miRNA-mRNA regulatory modules, and then focus on a method of identifying functional miRNA-mRNA regulatory modules by integrating multiple data sets from different sources.
Publisher: Elsevier BV
Date: 11-2015
DOI: 10.1016/J.JPSYCHIRES.2015.07.019
Abstract: Common variants of the FK506 binding protein 5 (FKBP5) gene are implicated in psychotic and other disorders, via their role in regulating glucocorticoid receptor (GR) receptor sensitivity and effects on the broader function of the HPA system in response to stress. In this study, the effects of four FKBP5 polymorphisms (rs1360780, rs9470080, rs4713902, rs9394309) on IQ and eight other cognitive domains were examined in the context of exposure to childhood maltreatment in 444 cases with schizophrenia and 292 healthy controls (from a total s le of 617 cases and 659 controls obtained from the Australian Schizophrenia Research Bank ASRB). Participants subjected to any kind of maltreatment (including physical, emotional, or sexual abuse or physical or emotional neglect) in childhood were classified as 'exposed' cognitive functioning was measured with Repeatable Battery for the Assessment of Neuropsychological Status, the Controlled Oral Word Association Test, and IQ was estimated with the Weschler Test of Adult Reading. Hierarchical regressions were used to test the main effects of genotype and childhood maltreatment, and their additive interactive effects, on cognitive function. For rs1360870, there were significant main effects of genotype and childhood maltreatment, and a significant interaction of genotype with childhood trauma affecting attention in both schizophrenia and healthy participants (C-homozygotes in both groups showed worse attention in the context of maltreatment) in SZ, this SNP also affected global neuropsychological function regardless of exposure to childhood trauma, with T-homozygotes showing worse cognition than other genotypes. The mechanisms of trauma-dependent effects of FKBP5 following early life trauma deserve further exploration in healthy and psychotic s les, in the context of epigenetic effects and perhaps epistasis with other genes. Study of these processes may be particularly informative in subgroups exposed to various other forms of early life adversity (i.e., birth complications, immigration).
Publisher: American Psychiatric Association Publishing
Date: 11-2015
Publisher: Springer Science and Business Media LLC
Date: 15-01-2013
Publisher: Bentham Science Publishers Ltd.
Date: 06-2008
Publisher: American Medical Association (AMA)
Date: 05-2016
Publisher: Wiley
Date: 14-07-2023
DOI: 10.1111/ADB.13313
Abstract: Cannabis use disorder (CUD) remains a significant public health issue globally, affecting up to one in five adults who use cannabis. Despite extensive research into the molecular underpinnings of the condition, there are no effective pharmacological treatment options available. Therefore, we sought to further explore genetic analyses to prioritise opportunities to repurpose existing drugs for CUD. Specifically, we aimed to identify druggable genes associated with the disorder, integrate transcriptomic roteomic data and estimate genetic relationships with clinically actionable biochemical traits. Aggregating variants to genes based on genomic position, prioritised the phosphodiesterase gene PDE4B as an interesting target for drug repurposing in CUD. Credible causal PDE4B variants revealed by probabilistic finemapping in and around this locus demonstrated an association with inflammatory and other substance use phenotypes. Gene and protein expression data integrated with the GWAS data revealed a novel CUD associated gene, NPTX1 , in whole blood and supported a role for hyaluronidase, a key enzyme in the extracellular matrix in the brain and other tissues. Finally, genetic correlation with biochemical traits revealed a genetic overlap between CUD and immune‐related markers such as lymphocyte count, as well as serum triglycerides.
Publisher: Springer Science and Business Media LLC
Date: 22-01-2018
DOI: 10.1038/S41398-017-0052-Z
Abstract: Brain white matter abnormalities are evident in in iduals with schizophrenia, and also their first-degree relatives, suggesting that some alterations may relate to underlying genetic risk. The ST8 alpha-N-acetyl-neuraminide alpha-2,8-sialyltransferase 2 ( ST8SIA2) gene, which encodes the alpha-2,8-sialyltransferase 8B enzyme that aids neuronal migration and synaptic plasticity, was previously implicated as a schizophrenia susceptibility gene. This study examined the extent to which specific haplotypes in ST8SIA2 influence white matter microstructure using diffusion-weighted imaging of in iduals with schizophrenia ( n = 281) and healthy controls ( n = 172), recruited across five Australian sites. Interactions between diagnostic status and the number of haplotype copies (0 or ≥1) were tested across all white matter voxels with cluster-based statistics. Fractional anisotropy (FA) in the right parietal lobe was found to show a significant interaction between diagnosis and ST8SIA2 protective haplotype ( p 0.05, family-wise error rate (FWER) cluster-corrected). The protective haplotype was associated with increased FA in controls, but this effect was reversed in people with schizophrenia. White matter fiber tracking revealed that the region-of-interest was traversed by portions of the superior longitudinal fasciculus, corona radiata, and posterior limb of internal capsule. Post hoc analysis revealed that reduced FA in this regional juncture correlated with reduced IQ in people with schizophrenia. The ST8SIA2 risk haplotype copy number did not show any differential effects on white matter. This study provides a link between a common disease-associated haplotype and specific changes in white matter microstructure, which may relate to resilience or risk for mental illness, providing further compelling evidence for involvement of ST8SIA2 in the pathophysiology of schizophrenia.
Publisher: American Chemical Society (ACS)
Date: 1996
DOI: 10.1021/BI9600207
Publisher: Public Library of Science (PLoS)
Date: 06-09-2012
Publisher: Oxford University Press (OUP)
Date: 31-01-2014
Publisher: Elsevier BV
Date: 08-1994
DOI: 10.1016/0167-4781(94)90183-X
Abstract: The N7 of guanine is thought to be the primary target for adduct and crosslink formation between cisplatin and DNA. However, reactive sites in DNA other than the N7 of guanine may also participate in the formation of adducts with cisplatin. The possibility that these interactions arise and form DNA polymerase blocking lesions was investigated by primer extension reactions with Taq DNA polymerase. To differentiate between damage produced at relatively weak sites from those formed at the N7 of guanine, a modified DNA template was synthesised with the N7 of guanine replaced with a carbon atom. This was achieved in a PCR designed to incorporate 7-deazaguanine instead of normal guanine. The sequence specificity of cisplatin damage in the modified and unmodified DNA substrates was compared (after linear lification) by DNA sequencing gel analysis. For concentrations of cisplatin (1 to 5 microM) that induce blocking lesions in normal DNA, no significant damage was observed in the modified DNA. This confirmed that the N7 of guanine is the major site of adduct formation in normal DNA. At higher concentrations of cisplatin (50 microM and 100 microM), lesions were found at AA dinucleotides and other novel sites in the modified DNA. These results indicate that the N7 of guanine is not required in the formation of some cisplatin adducts.
Publisher: Elsevier BV
Date: 06-2018
Publisher: Springer Science and Business Media LLC
Date: 20-02-2019
Publisher: Elsevier BV
Date: 03-2014
DOI: 10.1016/J.BBI.2013.12.010
Abstract: Microglia are unique cells within the central nervous system because of their biophysical independence. As a result of this unusual property the cells must undergo significant structural remodelling in order to engage and connect with other elements within the central nervous system. Efficient remodelling is required for all activities that microglia are involved in ranging from monitoring synaptic information flow through to phagocytosis of tissue debris. Despite the fact that morphological remodelling is a pre-requisite to all microglial activities, relatively little research has been undertaken on the topic. This review examines what is known about how microglia transform themselves during development, under physiological conditions in response to changes in neuronal activity, and under pathological circumstances. Specific attention is given to exploring a variety of models that have been proposed to account for microglial transformation as well as the signals that are known to trigger these transformations.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 08-04-2022
Abstract: There is a long-standing interest in exploring the relationship between blood-based biomarkers and psychiatric disorders, despite their causal role being difficult to resolve in observational studies. In this study, we leverage genome-wide association study data for a large panel of heritable serum biochemical traits to refine our understanding of causal effect in biochemical-psychiatric trait pairings. We observed widespread positive and negative genetic correlation between psychiatric disorders and biochemical traits. Causal inference was then implemented to distinguish causation from correlation, with strong evidence that C-reactive protein (CRP) exerts a causal effect on psychiatric disorders. Notably, CRP demonstrated both protective and risk-increasing effects on different disorders. Multivariable models that conditioned CRP effects on interleukin-6 signaling and body mass index supported that the CRP-schizophrenia relationship was not driven by these factors. Collectively, these data suggest that there are shared pathways that influence both biochemical traits and psychiatric illness.
Publisher: Cold Spring Harbor Laboratory
Date: 03-06-2019
DOI: 10.1101/655001
Abstract: In iduals with complex disorders typically have a heritable burden of common variation that can be expressed as a polygenic risk score (PRS). While PRS has some predictive utility, it lacks the molecular specificity to be directly informative for clinical interventions. We therefore sought to develop a framework to quantify an in idual’s common variant enrichment in clinically actionable systems responsive to existing drugs. This was achieved with a metric designated the pharmagenic enrichment score (PES), which we demonstrate for in idual SNP profiles in a cohort of cases with schizophrenia. A large proportion of these had elevated PES in one or more of eight clinically actionable gene-sets enriched with schizophrenia associated common variation. Notable candidates targeting these pathways included vitamins, insulin modulating agents, and protein kinase inhibitors with putative neuroprotective properties. Interestingly, elevated PES was also observed in in iduals with otherwise low common variant burden. The biological saliency of PES profiles were observed directly through their impact on gene expression in a subset of the cohort with matched transcriptomic data, supporting our assertion that this framework can integrate an in idual’s common variant risk to inform personalised interventions, including drug repositioning, for complex disorders such as schizophrenia.
Publisher: Elsevier BV
Date: 04-2014
Publisher: Springer Science and Business Media LLC
Date: 29-03-2021
DOI: 10.1007/S00109-021-02070-6
Abstract: Circular RNAs (circRNAs) are head-to-tail back-spliced RNA transcripts that have been linked to several biological processes and their perturbation is evident in human disease, including neurological disorders. There is also emerging research suggesting circRNA expression may also be altered in psychiatric and behavioural syndromes. Here, we provide a comprehensive analysis of circRNA expression in peripheral blood mononuclear cells (PBMCs) from 39 patients with schizophrenia and bipolar disorder as well as 20 healthy in iduals using deep RNA-seq. We observed systematic alternative splicing leading to a complex and erse profile of RNA transcripts including 8762 high confidence circRNAs. More specific scrutiny of the circular transcriptome in schizophrenia and bipolar disorder, compared to a non-psychiatric control group, revealed significant dysregulation of 55 circRNAs with a bias towards downregulation. These molecules were predicted to interact with a large number of miRNAs that target genes enriched in psychiatric disorders. Further replication and cross-validation to determine the specificity of these circRNAs across broader diagnostic groups and subgroups in psychiatry will enable their potential utility as biomarkers to be established. KEY MESSAGES: • We identified 8762 high confidence circRNAs with systematic alternative splicing in human PBMCs. • CircRNAs were dysregulated in schizophrenia and bipolar disorder, compared to a non-psychiatric control group. • The DE circRNAs were predicted to interact with miRNAs with target genes enriched in psychiatric disorders. • Some circRNAs have the potential to serve as biomarkers in psychiatry.
Publisher: Springer Science and Business Media LLC
Date: 26-06-2013
DOI: 10.1038/MP.2012.84
Abstract: Progress in determining the aetiology of schizophrenia (Sz) has arguably been limited by a poorly defined phenotype. We sought to delineate empirically derived cognitive subtypes of Sz to investigate the association of a genetic variant identified in a recent genome-wide association study with specific phenotypic characteristics of Sz. We applied Grade of Membership (GoM) analyses to 617 patients meeting ICD-10 criteria for Sz (n=526) or schizoaffective disorder (n=91), using cognitive performance indicators collected within the Australian Schizophrenia Research Bank. Cognitive variables included subscales from the Repeatable Battery for the Assessment of Neuropsychological Status, the Controlled Oral Word Association Test and the Letter Number Sequencing Test, and standardised estimates of premorbid and current intelligence quotient. The most parsimonious GoM solution yielded two subtypes of clinical cases reflecting those with cognitive deficits (CDs N=294), comprising 47.6% of the s le who were impaired across all cognitive measures, and a cognitively spared group (CS N=323) made up of the remaining 52.4% who performed relatively well on all cognitive tests. The CD subgroup were more likely to be unemployed, had an earlier illness onset, and greater severity of functional disability and negative symptoms than the CS group. Risk alleles on the MIR137 single-nucleotide polymorphism (SNP) predicted membership of CD subtype only in combination with higher severity of negative symptoms. These findings provide the first evidence for association of the MIR137 SNP with a specific Sz phenotype characterised by severe CDs and negative symptoms, consistent with the emerging role of microRNAs in the regulation of proteins responsible for neural development and function.
Publisher: Cold Spring Harbor Laboratory
Date: 15-09-2021
DOI: 10.1101/2021.09.12.21263471
Abstract: Almost half of in iduals diagnosed with schizophrenia also present with a substance use disorder, however, little is known about potential molecular mechanisms underlying this comorbidity. We used genetic analyses to enhance our understanding of the molecular overlap between these conditions. Our analyses revealed a positive genetic correlation between schizophrenia and the following dependence phenotypes: alcohol ( r g = 0.3685, SE = 0.0768, P = 1.61 × 10 −06 ), cannabis use disorder ( r g = 0.309, SE = 0.0332, P = 1.19 × 10 −20 ) and nicotine dependence ( r g = 0.1177, SE = 0.0436, P = 7.0 × 10- 03 ), as well as lifetime cannabis use ( r g = 0.234, SE = 0.0298, P = 3.73 × 10 − 15) and drinks per week ( r g = 0.0688, SE = 0.0217, P = 1.5 × 10 −03 ). We further constructed latent causal variable (LCV) models to test for partial genetic causality and found evidence for a potential causal relationship between alcohol dependence and schizophrenia ( GCP = 0.6, SE = 0.22, P = 1.6 × 10 −03 ). This putative causal effect with schizophrenia was not seen using a continuous phenotype of drinks consumed per week, suggesting that distinct molecular mechanisms underlying dependence are involved in the relationship between alcohol and schizophrenia. To localise the specific genetic overlap between schizophrenia and substance use disorders, we conducted a gene-based and gene-set pairwise meta-analysis between schizophrenia and each of the four in idual substance dependence phenotypes in up to 790,806 in iduals. These bivariate meta-analyses identified 44 associations not observed in the in idual GWAS, including five shared genes that play a key role in early central nervous system development. These genes may play an important role in substance dependence in schizophrenia, and, as a result, could represent important targets for future treatment or early intervention, as comorbid substance dependence is associated with poor treatment adherence, greater chronicity and increased mortality.
Publisher: Elsevier BV
Date: 05-2012
DOI: 10.1016/J.NBD.2011.12.029
Abstract: Schizophrenia is a complex neuropsychiatric disorder that involves disturbances in neural circuitry and synaptic function. The exquisite network architecture and capacity for discreet post-synaptic remodeling of neurons requires coordination by an elaborate intracellular network of molecular signal transduction systems. The redundancy of these networks means that many combinations of gene variants have the potential to cause system dysfunction that manifest as related neurobehavioural syndromes. Recent investigation has revealed that posttranscriptional gene regulation and associated small non-coding microRNA (miRNA), are likely to be important factors shaping the topography of these networks. miRNA display complex temporospatial expression patterns in the mammalian brain and have the potential to regulate thousands of target genes by functioning as the specificity factor for intracellular gene-silencing machinery. They are emerging as key regulators of many neurodevelopmental and neurological processes as their dysregulation could lead to pervasive changes in the network structure during development and in the mature brain that are highly significant in the pathophysiology of schizophrenia. This review looks at mounting evidence that mature miRNA levels are altered in both the cerebral cortex and peripheral blood mononuclear cells (PBMCs) in schizophrenia. It also examines compelling evidence that the underlying miRNA biogenesis machinery and miRNA genes themselves are subject to disease-associated genetic mutation and epigenetic influence. Significantly, these changes in miRNA expression and associated machinery may represent new targets for pharmaceutical development, and the identification of miRNA signatures in PBMCs suggest that miRNA biomarkers of schizophrenia may also provide the basis for new clinical diagnostics. These developments have tremendous potential and highlight the significance of this avenue of research.
Publisher: Cold Spring Harbor Laboratory
Date: 11-03-2020
DOI: 10.1101/2020.03.09.984690
Abstract: Data from observational studies have suggested an involvement of abnormal glycaemic regulation in the pathophysiology of psychiatric illness. This may be an attractive target for clinical intervention as glycaemia can be modulated by both lifestyle factors and pharmacological agents. However, observational studies are inherently confounded, and therefore causal relationships cannot be reliably established. We employed genetic variants rigorously associated with three glycaemic traits (fasting glucose, fasting insulin, and glycated haemoglobin) as instrumental variables in a two-s le Mendelian randomisation analysis to investigate the causal effect of these measures on the risk for eight psychiatric disorders. A significant protective effect of a unit increase in fasting insulin levels was observed for anorexia nervosa after the application of multiple testing correction (OR = 0.48 [95% CI: 0.33-0.71] – inverse-variance weighted estimate. The relationship between fasting insulin and anorexia nervosa was supported by a suite of sensitivity analyses, with no statistical evidence of instrument heterogeneity or horizontal pleiotropy. Further investigation is required to explore the relationship between insulin levels and anorexia.
Publisher: Frontiers Media SA
Date: 2013
Publisher: Hindawi Limited
Date: 1993
Abstract: A method is described for the detection of restriction fragment length polymorphisms (RFLPs) in single copy genes in mammalian cells using one 5'-labelled oligonucleotide. This linear lification (LA) method employs a single oligonucleotide as primer, which is extended by Taq DNA polymerase up to a restriction enzyme cleavage site. The products are arithmetically lified by thermal cycling. The size of the products are determined by the sequence of the oligonucleotide and the position of the restriction enzyme cleavage site. Hence, an RFLP can be observed by measuring the size of the products. Polymorphisms which differ in size by a small number of base pairs, as are found in (CA)n repeats, are especially suitable for analysis by the LA procedure since the products are run on DNA sequencing gels. A number of genes were examined by the procedure and all produced a satisfactory signal including GC-rich template. It is proposed that the LA method would be suitable for large-scale genetic linkage analysis. The LA procedure has many advantages including the ability to multiplex signals under the same conditions, and lower cost since only one primer is needed.
Publisher: Cold Spring Harbor Laboratory
Date: 15-09-2021
DOI: 10.1101/2021.09.11.21263146
Abstract: Psychiatric disorders such as schizophrenia are commonly associated with structural brain alterations affecting the cortex, which frequently vary with clinically relevant factors including antipsychotic treatment, duration of illness and age of onset. While the underlying variables mediating these structural changes are poorly understood, recent genetic evidence suggests circulating metabolites and other biochemical traits play a causal role in a number of psychiatric disorders which could be mediated by changes in the cerebral cortex. In the current study, we leveraged publicly available genome-wide association study (GWAS) data to explore shared genetic architecture and evidence for causal relationships between a panel of 50 biochemical traits and measures of cortical thickness and surface area at both the global and regional levels. Linkage disequilibrium score regression identified a total of 20 significant and 156 suggestive genetically correlated biochemical-cortical trait pairings, of which six exhibited strong evidence for causality in a latent causal variable model. Interestingly, a negative causal relationship was identified between a unit increase in serum C-reactive protein levels and thickness of the lingual and lateral occipital regions that was also supported by Mendelian randomisation, while circulating vitamin D (25-hydroxyvitamin D) levels exhibited a positive causal effect on temporal pole thickness. Taken together, our findings suggest a subset of biochemical traits exhibit shared genetic architecture and potentially causal relationships with cortical thickness in functionally distinct regions, which may contribute to alteration of cortical structure in psychiatric disorders.
Publisher: Oxford University Press (OUP)
Date: 17-02-2014
DOI: 10.1093/BIOINFORMATICS/BTU090
Abstract: Summary: SeqGSEA is an open-source Bioconductor package for the functional integration of differential expression and splicing analysis in RNA-Seq data. SeqGSEA implements an analysis pipeline, which first computes differential splicing and differential expression scores, followed by integrating them into a per-gene score that quantifies each gene’s association with a phenotype of interest, and finally executes gene set enrichment analysis in a cutoff-free manner to achieve biological insights. SeqGSEA accounts for biological variability and determines the statistical significance of gene pathways and networks using subject permutation, and thus requires at least five s les per group. Real applications show that SeqGSEA detects more biologically meaningful gene sets without biases toward long or highly expressed genes. SeqGSEA can be set up to run in parallel to reduce the analysis time. Availability and implementation: The SeqGSEA package with a vignette is available at ackages/release/bioc/html/SeqGSEA.html. Contact: Murray.Carins@newcastle.edu.au Supplementary information: Supplementary data are available at Bioinformatics online.
Publisher: Elsevier BV
Date: 08-2009
DOI: 10.1016/J.JINORGBIO.2009.06.001
Abstract: Cisplatin analogues with an attached DNA binding moiety have a higher affinity for DNA, but often suffer from poor aqueous solubility. In this study we examined the DNA sequence specificity of more soluble cisplatin analogues containing the maltolato leaving group in both purified DNA and in intact human cells. In both environments the DNA sequence specificity of these analogues was very similar to cisplatin. However, in purified DNA a higher concentration of the two maltolato-containing analogues was needed to achieve a similar level of DNA damage as cisplatin. This difference in reactivity was not observed in intact cells as the two maltolato-containing complexes were capable of producing a similar level of damage as cisplatin at comparable concentrations. This was consistent with the IC(50) values obtained for both cisplatin and the maltolato compounds which were also similar. This study indicated that maltolato can be utilised as the leaving group to increase the aqueous solubility of cisplatin analogues without reducing their biological activity.
Publisher: Springer Science and Business Media LLC
Date: 22-03-2023
DOI: 10.1038/S41398-023-02390-W
Abstract: In vivo experimental analysis of human brain tissue poses substantial challenges and ethical concerns. To address this problem, we developed a computational method called the Brain Gene Expression and Network-Imputation Engine ( BrainGENIE ) that leverages peripheral-blood transcriptomes to predict brain tissue-specific gene-expression levels. Paired blood–brain transcriptomic data collected by the Genotype-Tissue Expression (GTEx) Project was used to train BrainGENIE models to predict gene-expression levels in ten distinct brain regions using whole-blood gene-expression profiles. The performance of BrainGENIE was compared to PrediXcan , a popular method for imputing gene expression levels from genotypes. BrainGENIE significantly predicted brain tissue-specific expression levels for 2947–11,816 genes (false-discovery rate-adjusted p 0.05), including many transcripts that cannot be predicted significantly by a transcriptome-imputation method such as PrediXcan . BrainGENIE recapitulated measured diagnosis-related gene-expression changes in the brain for autism, bipolar disorder, and schizophrenia better than direct correlations from blood and predictions from PrediXcan . We developed a convenient software toolset for deploying BrainGENIE , and provide recommendations for how best to implement models. BrainGENIE complements and, in some ways, outperforms existing transcriptome-imputation tools, providing biologically meaningful predictions and opening new research avenues.
Publisher: Elsevier BV
Date: 05-2014
DOI: 10.1016/J.JPSYCHIRES.2014.01.011
Abstract: Schizophrenia has a strong genetic basis, and genome-wide association studies (GWAS) have shown that effect sizes for in idual genetic variants which increase disease risk are small, making detection and validation of true disease-associated risk variants extremely challenging. Specifically, we first identify genes with exons showing differential expression between cases and controls, indicating a splicing mechanism that may contribute to variation in disease risk and focus on those showing consistent differential expression between blood and brain tissue. We then perform a genome-wide screen for SNPs associated with both normalised exon intensity of these genes (so called splicing QTLs) as well as association with schizophrenia. We identified a number of significantly associated loci with a biologically plausible role in schizophrenia, including MCPH1, DLG3, ZC3H13, and BICD2, and additional loci that influence splicing of these genes, including YWHAH. Our approach of integrating genome-wide exon intensity with genome-wide polymorphism data has identified a number of plausible SZ associated loci.
Publisher: Elsevier BV
Date: 04-2012
Publisher: Oxford University Press (OUP)
Date: 30-01-2014
Publisher: Springer Science and Business Media LLC
Date: 30-04-2013
DOI: 10.1038/MP.2013.48
Publisher: Royal Society of Chemistry (RSC)
Date: 2015
DOI: 10.1039/C4MB00711E
Abstract: Reference gene-based normalization of expression profiles secures consistent differential expression analysis between s les of different phenotypes or biological conditions, and facilitates comparison between experimental batches.
Publisher: Cold Spring Harbor Laboratory
Date: 22-03-2022
DOI: 10.1101/2022.03.20.22272666
Abstract: Genetically informed drug development and repurposing is an attractive prospect for improving outcomes in patients with psychiatric illness however, the effectiveness of these endeavours can be confounded by heterogeneity. In this study, we propose a novel approach that links interventions implicated by disorder-associated genetic risk, at the population level, to a framework that can target these compounds to in iduals. Specifically, results from genome-wide association studies are integrated with expression data to prioritise in idual 'directional anchor' genes for which the predicted risk-increasing direction of expression could be counteracted by an existing drug. While these compounds represent plausible therapeutic candidates, they are not likely to be equally efficacious for all in iduals. To account for this heterogeneity, we constructed polygenic scores restricted to variants annotated to the network of genes that interact with each directional anchor gene. These metrics, we call pharmagenic enrichment scores (PES), identify in iduals with a higher burden of genetic risk, localised in biological processes related to the candidate drug target, to inform precision drug repurposing. We used this approach to investigate schizophrenia and bipolar disorder and reveal several compounds targeting specific directional anchor genes that could be plausibly repurposed, including antioxidants, vitamins, antiarrhythmics, and lipid modifying agents. These genetic risk scores, mapped to the networks associated with target genes, revealed biological insights that cannot be observed in undifferentiated genome-wide polygenic risk score (PRS). For ex le, an enrichment of these partitioned scores in schizophrenia cases with otherwise low PRS and distinct correlations with measured biochemical traits. In summary, genetic risk could be used more specifically to direct drug repurposing candidates that target particular genes implicated in psychiatric and other complex disorders.
Publisher: Elsevier BV
Date: 2022
Publisher: Frontiers Media SA
Date: 21-08-2017
Publisher: Springer Science and Business Media LLC
Date: 04-2013
Publisher: Oxford University Press (OUP)
Date: 06-2003
DOI: 10.1093/NAR/GKG378
Abstract: The 10-23 RNA cleaving DNAzyme has been shown to cleave any purine-pyrimidine (RY) junction under simulated physiological conditions. In this study, we systematically examine the DNAzymes relative activity against different RY combinations in order to determine the hierarchy of substrate core dinucleotide sequence susceptibility. The reactivity of each substrate dinucleotide compared in the same background sequence with the appropriately matched DNAzyme was found to follow the scheme AU = GU >> or = GC >> AC. The relatively poor activity of the DNAzyme against AC and GC containing substrates was found to be improved substantially by modifications to the binding domain which subtly weaken its interaction with the substrate core. The most effective modification resulting in rate enhancement of up to 200-fold, was achieved by substitution of deoxyguanine with deoxyinosine such that the base pair interaction with the RNA substrates core C is reduced from three hydrogen bonds to two. The increased cleavage activity generated by this modification could be important for application of the 10-23 DNAzyme particularly when the target site core is an AC dinucleotide.
Publisher: Mary Ann Liebert Inc
Date: 10-2000
DOI: 10.1089/OLI.1.2000.10.323
Abstract: A small oligodeoxyribonucleotide derived from in vitro selection has been shown to be capable of efficient sequence-specific cleavage of RNA at purine-pyrimidine junctions. As the reaction readily takes place under simulated physiologic conditions, this molecule described as the 10-23 general purpose RNA-cleaving DNA enzyme, has potential as a therapeutic agent. To further explore the character of this prototype, we examined the influence of base substitution and binding arm length asymmetry on its RNA cleaving activity. Surprisingly, substitution of the proximal nucleotide on the 3'-arm, to allow nonstandard Watson-Crick interactions, was found in some instances to improve the cleavage reaction rate. Although the identity of the unpaired purine in the RNA substrate cleavage site was found to have only a subtle influence on the rate of catalysis, with a slight decrease observed when a G at this position was changed to an A, nucleotide substitution (G to C) in the core motif at position 14 was found to completely abolish catalysis. The effect of arm length reduction varied with RNA substrate sequence and extent of helix asymmetry. Where the cleavage rate of one substrate was impaired by truncation of the deoxyribozymes 5'-arm (6 bp), the same modification in reactions with a different sequence produced a rate enhancement. Truncation of the 3'-arm, however, had no effect on the reaction rate of the one substrate tested yet nearly halved the cleavage rate in another substrate.
Publisher: Springer Science and Business Media LLC
Date: 09-2010
DOI: 10.1038/MP.2009.84
Publisher: Springer Science and Business Media LLC
Date: 07-12-2018
DOI: 10.1038/S41380-018-0305-0
Abstract: Retinoid metabolites of vitamin A are intrinsically linked to neural development, connectivity and plasticity, and have been implicated in the pathophysiology of schizophrenia. We hypothesised that a greater burden of common and rare genomic variation in genes involved with retinoid biogenesis and signalling could be associated with schizophrenia and its cognitive symptoms. Common variants associated with schizophrenia in the largest genome-wide association study were aggregated in retinoid genes and used to formulate a polygenic risk score (PRS Ret ) for each participant in the Australian Schizophrenia Research Bank. In support of our hypothesis, we found PRS Ret to be significantly associated with the disorder. Cases with severe cognitive deficits, while not further differentiated by PRS Ret , were enriched with rare variation in the retinoic acid receptor beta gene RARB , detected through whole-genome sequencing. RARB rare variant burden was also associated with reduced cerebellar volume in the cases with marked cognitive deficit, and with covariation in grey matter throughout the brain. An excess of rare variation was further observed in schizophrenia in retinoic acid response elements proximal to target genes, which we show are differentially expressed in the disorder in two RNA sequencing datasets. Our results suggest that genomic variation may disrupt retinoid signalling in schizophrenia, with particular significance for cases with severe cognitive impairment.
Publisher: Wiley
Date: 30-05-2022
DOI: 10.1111/JHN.13031
Abstract: The interplay between cardiovascular disease (CVD) genetic risk indexed by a polygenic risk score (PRS) and diet quality still requires further investigation amongst older adults or those with established or treated CVD. The present study aimed to evaluate the relative contribution of diet quality, measured using the Australian Recommended Food Score (ARFS) and PRS, with respect to explaining variation in plasma lipids CVD outcomes in the Hunter Cohort. The study comprised a secondary analysis of cross-sectional data from the Hunter Cohort study. Single-nucleotide polymorphisms from previously derived polygenic scores (PGSs) for three lipid classes were obtained: low-density lipoprotein, high-density lipoprotein and triglycerides, as well as PRS for coronary artery disease (CAD) from the PGS catalogue. Regression modelling and odds ratios were used to determine associations between PRS, ARFS and CVD risk. In total, 1703 participants were included: mean ± SD age 66 ± 7.4 years, 51% female, mean ± SD total ARFS 28.1 ± 8 (out of 74). Total diet quality and vegetable subscale were not significantly associated with measured lipids. By contrast, PGS for each lipid demonstrated a markedly strong, statistically significant correlation with its respective measured lipid. There was a significant association between CAD PRS and 5/6 CVD phenotypes (all except atrial fibrillation), with the largest effect size shown with coronary bypass. Adding dietary intake as a covariate did not change this relationship. Lipid PGS explained more variance in measured lipids than diet quality. However, the poor diet quality observed in the current cohort may have limited the ability to observe any beneficial effects. Future research should investigate whether the diet quality of older adults can be improved and also the effect of these improvements on changes in polygenic risk.
Publisher: Public Library of Science (PLoS)
Date: 11-08-2010
Publisher: Cold Spring Harbor Laboratory
Date: 05-08-2019
DOI: 10.1101/725614
Abstract: The complex aetiology of schizophrenia is postulated to share factors with other psychiatric disorders. Recently, this has been supported by genome-wide association studies, with several psychiatric phenotypes displaying high genomic correlation with schizophrenia. We sought to investigate pleiotropy amongst the common variant genomics of schizophrenia and seven other psychiatric disorders using a multimarker test of association. Gene-based analysis of common variation revealed over 50 schizophrenia-associated genes shared with other psychiatric phenotypes including bipolar disorder, major depressive disorder, ADHD, and autism spectrum disorder. In addition, we uncovered 78 genes significantly enriched with common variant associations for schizophrenia that were not linked to any of these seven disorders ( P 0.05). Transcriptomic imputation was then leveraged to investigate the functional significance of variation mapped to these genes, prioritising several interesting functional candidates. Pairwise meta-analysis of schizophrenia and each psychiatric phenotype further revealed 330 significantly associated genes ( P Meta 2.7 × 10 −6 ) that were only nominally associated with each disorder in idually ( P 0.05). Multivariable gene-set association suggested that common variation enrichment within biologically constrained genes observed for schizophrenia also occurs across several psychiatric phenotypes. These analyses consolidate the overlap between the genomic architecture of schizophrenia and other psychiatric disorders and uncovered several pleiotropic genes which warrant further investigation. Schizophrenia and other psychiatric disorders have many similarities, and this includes features of their overall genetic risk. Here, we investigate genes which may play a role in schizophrenia as well one or more of seven other psychiatric phenotypes and demonstrate that a number of them are pleiotropic and influence at least one other disorder. We also identify genes amongst the psychiatric disorders studied here which only show association with schizophrenia. Furthermore, we find a number of genes which were only significant when combining genetic association data from schizophrenia and one of the other seven disorders, suggesting there are shared genetic influences that are revealed through the power of joint analysis. This study identifies interesting novel shared (pleiotropic) genes in psychiatry which warrant future study.
Publisher: Elsevier BV
Date: 04-2014
Publisher: Springer Science and Business Media LLC
Date: 29-06-2022
DOI: 10.1038/S41467-022-31473-3
Abstract: Pneumonia remains one of the leading causes of death worldwide. In this study, we use genome-wide meta-analysis of lifetime pneumonia diagnosis ( N = 391,044) to identify four association signals outside of the previously implicated major histocompatibility complex region. Integrative analyses and finemapping of these signals support clinically tractable targets, including the mucin MUC5AC and tumour necrosis factor receptor superfamily member TNFRSF1A . Moreover, we demonstrate widespread evidence of genetic overlap with pneumonia susceptibility across the human phenome, including particularly significant correlations with psychiatric phenotypes that remain significant after testing differing phenotype definitions for pneumonia or genetically conditioning on smoking behaviour. Finally, we show how polygenic risk could be utilised for precision treatment formulation or drug repurposing through pneumonia risk scores constructed using variants mapped to pathways with known drug targets. In summary, we provide insights into the genetic architecture of pneumonia susceptibility and genetics informed targets for drug development or repositioning.
Publisher: Springer Science and Business Media LLC
Date: 11-02-2016
Publisher: Springer Science and Business Media LLC
Date: 23-01-2020
DOI: 10.1038/S41467-019-14079-0
Abstract: Population health research is increasingly focused on the genetic determinants of healthy ageing, but there is no public resource of whole genome sequences and phenotype data from healthy elderly in iduals. Here we describe the first release of the Medical Genome Reference Bank (MGRB), comprising whole genome sequence and phenotype of 2570 elderly Australians depleted for cancer, cardiovascular disease, and dementia. We analyse the MGRB for single-nucleotide, indel and structural variation in the nuclear and mitochondrial genomes. MGRB in iduals have fewer disease-associated common and rare germline variants, relative to both cancer cases and the gnomAD and UK Biobank cohorts, consistent with risk depletion. Age-related somatic changes are correlated with grip strength in men, suggesting blood-derived whole genomes may also provide a biologic measure of age-related functional deterioration. The MGRB provides a broadly applicable reference cohort for clinical genetics and genomic association studies, and for understanding the genetics of healthy ageing.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 20-01-2023
Abstract: Cancer genetics has to date focused on epithelial malignancies, identifying multiple histotype-specific pathways underlying cancer susceptibility. Sarcomas are rare malignancies predominantly derived from embryonic mesoderm. To identify pathways specific to mesenchymal cancers, we performed whole-genome germline sequencing on 1644 sporadic cases and 3205 matched healthy elderly controls. Using an extreme phenotype design, a combined rare-variant burden and ontologic analysis identified two sarcoma-specific pathways involved in mitotic and telomere functions. Variants in centrosome genes are linked to malignant peripheral nerve sheath and gastrointestinal stromal tumors, whereas heritable defects in the shelterin complex link susceptibility to sarcoma, melanoma, and thyroid cancers. These studies indicate a specific role for heritable defects in mitotic and telomere biology in risk of sarcomas.
Publisher: Springer Science and Business Media LLC
Date: 23-09-2022
DOI: 10.1038/S41398-022-02186-4
Abstract: Almost half of in iduals diagnosed with schizophrenia also present with a substance use disorder, however, little is known about potential molecular mechanisms underlying this comorbidity. We used genetic analyses to enhance our understanding of the molecular overlap between these conditions. Our analyses revealed a positive genetic correlation between schizophrenia and the following dependence phenotypes: alcohol ( r g = 0.368, SE = 0.076, P = 1.61 × 10 −6 ), cannabis use disorder ( r g = 0.309, SE = 0.033, P = 1.97 × 10 −20 ) and nicotine ( r g = 0.117, SE = 0.043, P = 7.0 × 10 −3 ), as well as drinks per week ( r g = 0.087, SE = 0.021, P = 6.36 × 10 −5 ), cigarettes per day ( r g = 0.11, SE = 0.024, P = 4.93 × 10 −6 ) and life-time cannabis use ( r g = 0.234, SE = 0.029, P = 3.74 × 10 −15 ). We further constructed latent causal variable (LCV) models to test for partial genetic causality and found evidence for a potential causal relationship between alcohol dependence and schizophrenia (GCP = 0.6, SE = 0.22, P = 1.6 × 10 −3 ). This putative causal effect with schizophrenia was not seen using a continuous phenotype of drinks consumed per week, suggesting that distinct molecular mechanisms underlying dependence are involved in the relationship between alcohol and schizophrenia. To localise the specific genetic overlap between schizophrenia and substance use disorders (SUDs), we conducted a gene-based and gene-set pairwise meta-analysis between schizophrenia and each of the four in idual substance dependence phenotypes in up to 790,806 in iduals. These bivariate meta-analyses identified 44 associations not observed in the in idual GWAS, including five shared genes that play a key role in early central nervous system development. The results from this study further supports the existence of underlying shared biology that drives the overlap in substance dependence in schizophrenia, including specific biological systems related to metabolism and neuronal function.
Publisher: Elsevier BV
Date: 03-2014
DOI: 10.1016/J.JPSYCHIRES.2013.11.012
Abstract: 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. 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. 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. 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.
Publisher: Elsevier BV
Date: 02-2014
DOI: 10.1016/J.VIROL.2013.12.026
Abstract: Co-infection with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) is common due to shared transmission routes. The genomic basis of HIV/HCV co-infection and its regulation by microRNA (miRNA) is unknown. Therefore, our objective was to investigate genome-wide mRNA expression and its regulation by miRNA in primary PBMCs derived from 27 patients (5 HCV - mono-infected, 5 HIV-mono-infected, 12 HCV/HIV co-infected, and 5 healthy controls). This revealed 27 miRNAs and 476 mRNAs as differentially expressed (DE) in HCV/HIV co-infection when compared to controls (adj p 50, p=4.02E-06), which may have clinical/biological implications.
Publisher: Cold Spring Harbor Laboratory
Date: 06-06-2022
DOI: 10.1101/2022.06.04.22275898
Abstract: Anorexia nervosa is the leading cause of mortality among psychiatric disorders worldwide. Currently no medications are approved for anorexia nervosa treatment, and thus, identification of risk factors for this disorder is pivotal to improve patient outcomes. We used models of genetically imputed expression and splicing from 17 tissues (two blood and fifteen brain regions), leveraging mRNA, protein, and mRNA alternative splicing weights to identify genes, proteins, and transcripts, respectively, associated with anorexia nervosa risk. We uncovered 134 genes for which genetically predicted mRNA expression was associated with anorexia nervosa after multiple-testing correction, as well as four proteins and 16 alternatively spliced transcripts. Conditional analysis of these significantly associated genes on other proximal association signals resulted in 97 genes independently associated with anorexia nervosa. Moreover, probabilistic finemapping further refined these associations and prioritised putative causal genes. The gene WDR6 , for which increased genetically predicted mRNA expression was correlated with anorexia, was strongly supported by both conditional analyses and finemapping. Pathway analysis of genes revealed by finemapping identified regulation of immune system process (overlapping genes = MST1, TREX1, PRKAR2A, PROS1 ) as statistically overrepresented. In summary, we leveraged multiomic datasets to genetically prioritise novel risk genes for anorexia nervosa that warrant further exploration.
Publisher: Elsevier BV
Date: 10-2015
DOI: 10.1016/J.SCHRES.2015.08.010
Abstract: The molecular mechanisms underlying schizophrenia remain largely unknown. Although schizophrenia is a mental disorder, there is increasing evidence to indicate that inflammatory processes driven by erse environmental factors play a significant role in its development. With gene expression studies having been conducted across a variety of s le types, e.g., blood and postmortem brain, it is possible to investigate convergent signatures that may reveal interactions between the immune and nervous systems in schizophrenia pathophysiology. We conducted two meta-analyses of schizophrenia microarray gene expression data (N=474) and non-psychiatric control (N=485) data from postmortem brain and blood. Then, we assessed whether significantly dysregulated genes in schizophrenia could be shared between blood and brain. To validate our findings, we selected a top gene candidate and analyzed its expression by RT-qPCR in a cohort of schizophrenia subjects stabilized by atypical antipsychotic monotherapy (N=29) and matched controls (N=31). Meta-analyses highlighted inflammation as the major biological process associated with schizophrenia and that the chemokine receptor CX3CR1 was significantly down-regulated in schizophrenia. This differential expression was also confirmed in our validation cohort. Given both the recent data demonstrating selective CX3CR1 expression in subsets of neuroimmune cells, as well as behavioral and neuropathological observations of CX3CR1 deficiency in mouse models, our results of reduced CX3CR1 expression adds further support for a role played by monocyte/microglia in the neurodevelopment of schizophrenia.
Publisher: Cold Spring Harbor Laboratory
Date: 27-10-2020
DOI: 10.1101/2020.10.27.356766
Abstract: In vivo experimental analysis of human brain tissue poses substantial challenges and ethical concerns. We developed a novel method called the Brain Gene Expression and Network Imputation Engine ( BrainGENIE ) that uses peripheral-blood transcriptomes to predict brain-tissue-specific gene-expression levels. BrainGENIE reliably predicted brain-tissue-specific expression levels for 1,733 – 11,569 genes (false-discovery rate-adjusted p .05), including many transcripts that cannot be predicted reliably by a transcriptome imputation method such as PrediXcan . We tested the generalizability of BrainGENIE in external within-in idual data from ex vivo peripheral blood and postmortem brain s les from the Religious Orders Study and Memory and Aging Project, wherein we validated 39% of predicted gene expression levels as concordant with observed expression levels in dorsolateral prefrontal cortex and 23% in caudate. BrainGENIE recapitulated diagnosis-related gene expression changes in brain better than direct correlations from blood and predictions from PrediXcan. BrainGENIE complements and, in some ways, outperforms existing transcriptome-imputation tools, providing biologically meaningful predictions and opening new research avenues.
Publisher: Elsevier BV
Date: 04-2013
Publisher: Oxford University Press (OUP)
Date: 22-07-2014
DOI: 10.1093/NAR/GKU594
Publisher: Cambridge University Press (CUP)
Date: 20-02-2023
DOI: 10.1017/S0033291723000235
Abstract: Anorexia nervosa (AN) is a psychiatric disorder associated with marked morbidity. Whilst AN genetic studies could identify novel treatment targets, integration of functional genomics data, including transcriptomics and proteomics, would assist to disentangle correlated signals and reveal causally associated genes. We used models of genetically imputed expression and splicing from 14 tissues, leveraging mRNA, protein, and mRNA alternative splicing weights to identify genes, proteins, and transcripts, respectively, associated with AN risk. This was accomplished through transcriptome, proteome, and spliceosome-wide association studies, followed by conditional analysis and finemapping to prioritise candidate causal genes. We uncovered 134 genes for which genetically predicted mRNA expression was associated with AN after multiple-testing correction, as well as four proteins and 16 alternatively spliced transcripts. Conditional analysis of these significantly associated genes on other proximal association signals resulted in 97 genes independently associated with AN. Moreover, probabilistic finemapping further refined these associations and prioritised putative causal genes. The gene WDR6 , for which increased genetically predicted mRNA expression was correlated with AN, was strongly supported by both conditional analyses and finemapping. Pathway analysis of genes revealed by finemapping identified the pathway regulation of immune system process (overlapping genes = MST1 , TREX1 , PRKAR2A , PROS1 ) as statistically overrepresented. We leveraged multiomic datasets to genetically prioritise novel risk genes for AN. Multiple-lines of evidence support that WDR6 is associated with AN, whilst other prioritised genes were enriched within immune related pathways, further supporting the role of the immune system in AN.
Publisher: Cold Spring Harbor Laboratory
Date: 26-06-2020
DOI: 10.1101/2020.06.25.20139816
Abstract: Impaired lung function is associated with significant morbidity and mortality. Restrictive and obstructive lung disorders are a large contributor to decreased lung function, as well as the acute impact of infection. Measures of pulmonary function are heritable, and thus, we sought to utilise genomics to propose novel drug repurposing candidates which could improve respiratory outcomes. Lung function measures were found to be genetically correlated with metabolic and hormone traits which could be pharmacologically modulated, with a causal effect of increased fasting glucose on diminished lung function supported by latent causal variable models and Mendelian randomisation. We developed polygenic scores for lung function specifically within pathways with known drug targets to prioritise in iduals who may benefit from particular drug repurposing opportunities, accompanied by transcriptome-wide association studies to identify drug-gene interactions with potential lung function increasing modes of action. These drug repurposing candidates were further considered relative to the host-viral interactome of three viruses with associated respiratory pathology (SARS-CoV2, influenza, and human adenovirus). We uncovered an enrichment amongst glycaemic pathways of human proteins which putatively interact with virally expressed SARS-CoV2 proteins, suggesting that antihyperglycaemic agents may have a positive effect both on lung function and SARS-CoV2 progression.
Publisher: MDPI AG
Date: 05-08-2020
DOI: 10.3390/CELLS9081837
Abstract: Schizophrenia is a severe psychiatric disorder with a complex array of signs and symptoms that causes very significant disability in young people. While schizophrenia has a strong genetic component, with heritability around 80%, there is also a very significant range of environmental exposures and stressors that have been implicated in disease development and neuropathology, such as maternal immune infection, obstetric complications, childhood trauma and cannabis exposure. It is postulated that epigenetic factors, as well as regulatory non-coding RNAs, mediate the effects of these environmental stressors. In this review, we explore the most well-known epigenetic marks, including DNA methylation and histone modification, along with emerging RNA mediators of epigenomic state, including miRNAs and lncRNAs, and discuss their collective potential for involvement in the pathophysiology of schizophrenia implicated through the postmortem analysis of brain tissue. Given that peripheral tissues, such as blood, saliva, and olfactory epithelium have the same genetic composition and are exposed to many of the same environmental exposures, we also examine some studies supporting the application of peripheral tissues for epigenomic biomarker discovery in schizophrenia. Finally, we provide some perspective on how these biomarkers may be utilized to capture a signature of past events that informs future treatment.
Publisher: Elsevier BV
Date: 06-1999
DOI: 10.1016/S0167-4781(99)00057-3
Abstract: Nitrogen mustard analogues, bleomycin and dimethyl sulphate (DMS) have been used as probes of protein-DNA interactions in intact human cells. The sites of damage have been determined at base pair resolution in the single copy epsilon-globin gene promoter in erythroid K562 cells, non-erythroid HeLa cells and purified DNA. Exponential lification of gene-specific damage fragments was achieved using the ligation-mediated polymerase chain reaction (LMPCR) technique and analysed on DNA sequencing gels. A comparison of the relative damage band intensities between purified DNA and intact cells revealed several significant differences - both protection (footprint) and enhancement. These differences occurred at putative transcription factor binding sites and hence are thought to be due to protein-DNA interactions. A major feature of the band intensity ratio plots was the footprint observed at the CCAAT box binding motif as revealed by nitrogen mustard analogues. Enhanced band intensity (hypersensitivity) was displayed at the 5'- and 3'-ends of the CCAAT box in K562 cells - this feature was absent in HeLa cells and in vitro reconstitutions. A footprint was found at the GATA-1 motif in K562 cells that was also absent in non-expressing HeLa cells. Footprints were also evident at the TATA box, CACC box and the epsilonF1 DNA binding motif in K562 cells.
Publisher: Springer Science and Business Media LLC
Date: 19-10-2012
Abstract: MicroRNA (miRNA) are small non-coding RNA molecules which function as nucleic acid-based specificity factors in the universal RNA binding complex known as the RNA induced silencing complex (RISC). In the canonical gene-silencing pathway, these activated RISC particles are associated with RNA decay and gene suppression, however, there is evidence to suggest that in some circumstances they may also stabilise their target RNA and even enhance translation. To further explore the role of miRNA in this context, we performed a genome-wide expression analysis to investigate the molecular consequences of bidirectional modulation of the disease-associated miRNAs miR-181b and miR-107 in multiple human cell lines. This data was subjected to pathways analysis and correlated against miRNA targets predicted through seed region homology. This revealed a large number of both conserved and non-conserved miRNA target genes, a selection of which were functionally validated through reporter gene assays. Contrary to expectation we also identified a significant proportion of predicted target genes with both conserved and non-conserved recognition elements that were positively correlated with the modulated miRNA. Finally, a large proportion of miR-181b associated genes devoid of the corresponding miRNA recognition element, were enriched with binding motifs for the E2F1 transcription factor, which is encoded by a miR-181b target gene. These findings suggest that miRNA regulate target genes directly through interactions with both conserved and non-conserved target recognition elements, and can lead to both a decrease and increase in transcript abundance. They also multiply their influence through interaction with transcription factor genes exemplified by the observed miR-181b/E2F1 relationship.
Publisher: Impact Journals, LLC
Date: 15-12-2016
Publisher: Frontiers Media SA
Date: 15-10-2014
Abstract: The SH-SY5Y culture system is a convenient neuronal model with the potential to elaborate human rimate-specific transcription networks and pathways related to human cognitive disorders. While this system allows for the exploration of specialized features in the human genome, there is still significant debate about how this model should be implemented, and its appropriateness for answering complex functional questions related to human neural architecture. In view of these questions we sought to characterize the posttranscriptional regulatory structure of the two-stage ATRA differentiation, BDNF maturation protocol proposed by Encinas et al. ( 2000 ) using integrative whole-genome gene and microRNA (miRNA) expression analysis. We report that ATRA-BDNF induced significant increases in expression of key synaptic genes, brain-specific miRNA and miRNA biogenesis machinery, and in AChE activity, compared with ATRA alone. Functional annotation clustering associated BDNF more significantly with neuronal terms, and with synaptic terms not found in ATRA-only clusters. While our results support use of SH-SY5Y as a neuronal model, we advocate considered selection of the differentiation agent/s relative to the system being modeled.
Publisher: Public Library of Science (PLoS)
Date: 27-04-2012
Publisher: Springer Science and Business Media LLC
Date: 30-10-2019
DOI: 10.1038/S41380-019-0566-2
Abstract: Signalling by retinoid compounds is vital for embryonic development, with particular importance for neurogenesis in the human brain. Retinoids, metabolites of vitamin A, exert influence over the expression of thousands of transcripts genome wide, and thus, act as master regulators of many important biological processes. A significant body of evidence in the literature now supports dysregulation of the retinoid system as being involved in the aetiology of schizophrenia. This includes mechanistic insights from large-scale genomic, transcriptomic and, proteomic studies, which implicate disruption of disparate aspects of retinoid biology such as transport, metabolism, and signalling. As a result, retinoids may present a valuable clinical opportunity in schizophrenia via novel pharmacotherapies and dietary intervention. Further work, however, is required to expand on the largely observational data collected thus far and confirm causality. This review will highlight the fundamentals of retinoid biology and examine the evidence for retinoid dysregulation in schizophrenia.
Publisher: Public Library of Science (PLoS)
Date: 09-03-2009
Publisher: Elsevier
Date: 2014
Publisher: Bentham Science Publishers Ltd.
Date: 06-2002
Abstract: RNA, as an intermediate in the production of every gene encoded protein and the genetic material of many pathogenic viruses, presents an attractive target for both biological and therapeutic manipulation. Despite its extensive involvement in living systems, its chemical ersity based on four units is relatively low compared with protein. This provides the opportunity for a generic approach to targeting with specificity based on primary structure rather than complex higher order structures. This form of recognition occurs naturally in complementary nucleic acids, due to an ability to bind their single stranded target through Watson-Crick interactions. The most established nucleic acid based approach to gene suppression at the RNA level is through antisense oligodeoxynucleotides (ODNs). These compounds form heteroduplex with target RNA which are thought to either block its function or mediate its destruction by activation of RNase H. Alternatively, RNA can be targeted by catalytic RNA such as the hammerhead ribozyme. Ribozymes have the advantage of being equipped with their own RNA cleavage apparatus and are therefore independent of host nuclear protein activity. At present, the utility of ribozyme oligonucleotides is restricted by the relative difficulty synthesising active molecules with sufficient resistance to nuclease degradation. Recently the power of in vitro selection has been used to evolve catalytic DNA sequences with RNA cleavage specificity and activity rivalling the very best ribozymes, while maintaining the more robust chemistry of an ODN. These deoxyribozymes or DNAzymes have tremendous potential as gene suppression agents for both target validation and therapeutic applications. A number of studies evaluating the biological activity of these compounds have shown promising results. However, as with other oligonucleotide based strategies, future exploitation of this approach may depend on accessory technology to assist with the accessibility of a target which is folded by its own secondary structure and hidden within the intracellular compartment.
Publisher: Humana Press
Date: 2004
DOI: 10.1385/1-59259-746-7:267
Abstract: The 10-23 DNAzyme is capable of cleaving RNA with high sequence specificity at sites that contain purine-pyrimidine (R-Y) junctions. Although they are abundant in mRNA, many of these potentially cleavable junctions are protected from DNAzyme activity by secondary structure. To optimise the process of target-site selection in long RNA substrates, a multiplex assay was developed for simultaneous comparative analysis of 50 or more different DNAzymes in one reaction. Using this approach, the efficiency of 80 DNAzyme sites within the E6 component of a full-length HPV16 E6/E7 transcript was examined. The activity of molecules selected in this system was then compared in a conventional assay with DNAzymes of intermediate and low performance. This confirmed the results observed in the multiplex reactions, with 10% of DNAzymes inducing substantial cleavage of the long transcript. These DNAzyme-sensitive regions are potentially accessible to other RNA directed agents such as ribozymes or antisense oligonucleotides. Therefore, in addition to finding the most effective DNAzymes for a particular target mRNA, this method may also be applicable to locating accessible sites for other nucleic acid-based gene suppression strategies.
Publisher: Cold Spring Harbor Laboratory
Date: 08-03-2021
DOI: 10.1101/2021.03.07.434312
Abstract: Psychiatric disorders and other complex traits have a polygenic architecture, often associated with dozens or even hundreds of independent genomic loci. As each of these have a relatively small influence on the trait, the dissection of their biological components is a non-trivial task. For psychiatric disorders in particular, the majority of associated loci lie within non-coding regions of the genome, suggesting that most of the genetic risk for disease originates from the disruption of regulatory sequences. While previously exploration of the heritability of these sequences has focused on variants that modify DNA elements, those that alter cis -acting RNA sequences, such as miRNA binding sites, are also likely to have a significant impact in these disorders. MiRNA have already been shown to be dysregulated in these disorders through both genetic and environmental influence, so it is reasonable to suspect their target genes may also be affected by common variation. In this study, we investigated the distribution of miRNA binding site variants (MBSVs) predicted to alter miRNA binding affinity in psychiatric disorders and observed significant enrichment in schizophrenia, depression, bipolar disorder, and anorexia nervosa. We also observed significant enrichment of MBSVs in genes targeted by several miRNA families, including miR-335-5p, miR-21-5p/590-5p, miR-361-5p, and miR-557 in both schizophrenia and depression, and nominally significant enrichment of MBSV for miR-323b-3p in schizophrenia. We also identified a significant association between MBSVs in gene sets involved in regulation of the synapse and synaptic depression in schizophrenia. While these observations support the role of miRNA in the pathophysiology of psychiatric disorders, we also observed significant association of MBSVs in other complex traits suggesting that MBSVs are an important class of regulatory variants that have functional implications for many disorders.
Publisher: MDPI AG
Date: 25-09-2020
DOI: 10.3390/IJMS21197086
Abstract: Experience-dependent changes to neural circuitry are shaped by spatially-restricted activity-dependent mRNA translation. Although the complexity of mRNA translation in neuronal cells is widely appreciated, translational profiles associated with neuronal excitation remain largely uncharacterized, and the associated regulatory mechanisms are poorly understood. Here, we employed ribosome profiling, mRNA sequencing and small RNA sequencing to profile transcriptome-wide changes in mRNA translation after whole cell depolarization of differentiated neuroblast cultures, and investigate the contribution of sequence-specific regulatory mechanisms. Immediately after depolarization, a functional partition between transcriptional and translational responses was uncovered, in which many mRNAs were subjected to significant changes in abundance or ribosomal occupancy, but not both. After an extended (2 h) post-stimulus rest phase, however, these changes became synchronized, suggesting that there are different layers of post-transcriptional regulation which are temporally separated but become coordinated over time. Globally, changes in mRNA abundance and translation were found to be associated with a number of intrinsic mRNA features, including mRNA length, GC% and secondary structures however, the effect of these factors differed between both post-depolarization time-points. Furthermore, small RNA sequencing revealed that miRNAs and tRNA-derived small RNA fragments were subjected to peak changes in expression immediately after stimulation, during which these molecules were predominantly associated with fluctuations in mRNA abundance, consistent with known regulatory mechanisms. These data suggest that excitation-associated neuronal translation is subjected to extensive temporal coordination, with substantial contributions from a number of sequence-dependent regulatory mechanisms.
Publisher: Impact Journals, LLC
Date: 20-05-2014
Abstract: DNAzymes are a novel class of gene suppressors that selectively bind to an RNA substrate by Watson-Crick base pairing and cleave phosphodiester bonds. To explore the potential for therapeutic use of catalytic DNA molecules, active DNAzymes targeting the bcl-xL gene were generated through a multiplex in vitro selection. The DNAzyme-mediated down-regulation of the bcl-xL expression was demonstrated in various cancer cell lines by Western blots. Treatment of the cells with the active DNAzyme led to increases in percentage of apoptotic cells and cytochrome c release from mitochondria, a hall marker of apoptosis. When combined with chemotherapeutics such as Taxol, the DNAzyme significantly sensitised a panel of cancer cells to apoptosis as measured by cell survival assay. In Taxol-resistant cells, down-regulation of bcl-xL expression by the DNAzyme reversed the chemo-resistant phenotype of the cancer cells. In a xenograft mouse model, the DNAzyme was delivered into the tumors via an ALZET osmotic pump and shown to chemosensitize PC3 tumor when treating with Taxol. The results from the present study demonstrate that bcl-xL DNAzyme treatment facilitates apoptosis in solid tumors and suggest the potential use of bcl-xL DNAzyme in combination with chemotherapeutics for cancer therapy.
Publisher: Elsevier BV
Date: 09-2022
Publisher: MDPI AG
Date: 26-03-2020
Abstract: Breast cancer is the most commonly diagnosed and the second leading cause of cancer-related mortality among women worldwide. miR-518f-5p has been shown to modulate the expression of the metastasis suppressor CD9 in prostate cancer. However, the role of miR-518f-5p and CD9 in breast cancer is unknown. Therefore, this study aimed to elucidate the role of miR-518f-5p and the mechanisms responsible for decreased CD9 expression in breast cancer, as well as the role of CD9 in de novo tumor formation and metastasis. miR-518f-5p function was assessed using migration, adhesion, and proliferation assays. miR-518f-5p was overexpressed in breast cancer cell lines that displayed significantly lower CD9 expression as well as less endogenous CD9 3′UTR activity, as assessed using qPCR and dual luciferase assays. Transfection of miR-518f-5p significantly decreased CD9 protein expression and increased breast cell migration in vitro. Cd9 deletion in the MMTV/PyMT mouse model impaired tumor growth, but had no effect on tumor initiation or metastasis. Therefore, inhibition of miR-518f-5p may restore CD9 expression and aid in the treatment of breast cancer metastasis.
Publisher: Elsevier BV
Date: 12-2009
DOI: 10.1016/J.CELLSIG.2009.07.019
Abstract: Whole-genome microRNA and gene expression analyses were used to monitor changes during retinoic acid induced differentiation of neuroblasts in vitro. Interestingly, the entire miR-17 family was over-represented among the down-regulated miRNA. The implications of these changes are considerable, as target gene prediction suggests that the miR-17 family is involved in the regulation of the mitogen-activated protein kinase (MAPK) signaling pathway, synaptic plasticity and other markers of neuronal differentiation. Significantly, many of the target responses predicted by changes in miRNA expression were supported by the observed changes in gene expression. As expected, markers of neuronal differentiation such as anti-apoptotic protein B-cell lymphoma 2 (BCL2), myocyte enhancer factor-2D (MEF2D) and zipper protein kinase (MAP3K12 aka ZPK/MUK/DLK) were each up-regulated in response to differentiation. The expression of these genes was also reduced in response to miR-17 and miR-20a transfection, and more specifically they were also shown to contain functional miRNA recognition elements for members of the miR-17 family by reporter gene assay. This suggests that the miR-17 family have an integral role in fine-tuning the pathways involved in the regulation of neuronal differentiation.
Publisher: Wiley
Date: 09-1993
Abstract: The basal nucleus of Meynert, incorporating the Ch4 group of cholinergic neurons, was examined in six patients with no signs of neurological abnormalities. The ages of the patients ranged from 20 to 80 years. Despite a number of descriptions of these neurons, few age-related studies have been dedicated to the analysis of the entire anteroposterior extent of the nucleus. Staining with cresyl violet and acetylcholinesterase histochemistry, alone or in combination, was used to identify the cytoarchitectural organization of the Ch4. Computer-assisted morphometry was used for three-dimensional visualization and quantitation. The three-dimensional computer reconstructions revealed a continuous ribbon of neurons with a highly variable density. Four distinct subregions could be clearly identified in all cases by their cytoarchitecture and cellular morphology, although these subgroups were different to those previously described. There were no quantitative differences between the hemispheres in volume, density or cell number of the Ch4, although equivalent levels varied in area and density. The measures were similar in all cases with the exception of the case aged 80 years old. The data demonstrate in idual variability in three dimensions and confirm previous studies that found only a mild decline of the Ch4 in old age.
Publisher: Springer Science and Business Media LLC
Date: 2003
Publisher: Springer Science and Business Media LLC
Date: 28-11-2012
Abstract: HIV-associated dementia (HAD) is the most common dementia type in young adults less than 40 years of age. Although the neurotoxins, oxidative/metabolic stress and impaired activity of neurotrophic factors are believed to be underlying reasons for the development of HAD, the genomic basis, which ultimately defines the virus-host interaction and leads to neurologic manifestation of HIV disease is lacking. Therefore, identifying HIV fingerprints on the host gene machinery and its regulation by microRNA holds a great promise and potential for improving our understanding of HAD pathogenesis, its diagnosis and therapy. A parallel profiling of mRNA and miRNA of the frontal cortex autopsies from HIV positive patients with and without dementia was performed using Illumina Human-6 BeadChip and Affymetrix version 1.0 miRNA array, respectively. The gene ontology and pathway analysis of the two data sets showed high concordance between miRNA and mRNAs, revealing significant interference with the host axon guidance and its downstream signalling pathways in HAD brains. Moreover, the differentially expressed (DE) miRNAs identified in this study, in particular miR-137, 153 and 218, based on which most correlations were built cumulatively targeted neurodegeneration related pathways, implying their future potential in diagnosis, prognosis and possible therapies for HIV-mediated and possibly other neurodegenerative diseases. Furthermore, this relationship between DE miRNAs and DE mRNAs was also reflected in correlation analysis using Bayesian networks by splitting-averaging strategy (SA-BNs), which revealed 195 statistically significant correlated miRNA-mRNA pairs according to Pearson’s correlation test (P .05). Our study provides the first evidence on unambiguous support for intrinsic functional relationship between mRNA and miRNA in the context of HIV-mediated neurodegeneration, which shows that neurologic manifestation in HIV patients possibly occurs through the interference with the host axon guidance and its downstream signalling pathways. These data provide an excellent avenue for the development of new generation of diagnostic rognostic biomarkers and therapeutic intervention strategies for HIV-associated neurodegeneration.
Publisher: Springer Science and Business Media LLC
Date: 31-07-2009
Abstract: Custom solid phase oligonucleotide synthesis is an important foundation supporting nearly every aspect of current genomics. In spite of the demand for oligonucleotide primers, their synthesis remains relatively expensive, time consuming and in many circumstances a wasteful process. In this methodology, described as polymerase mediated oligonucleotide synthesis (PMOS), a DNA polymerase is used to increase the hybridization affinity of one oligonucleotide by using another as a template for DNA synthesis. This self-assembly process provides an opportunity to instantly generate a very large number of useful gene-specific primers from a small library of simple precursors. PMOS can be used to generate primers directly in the end-users laboratory within the context of any DNA polymerase chemistry such as in PCR or sequencing reactions To demonstrate the utility of PMOS, a universal 768-member oligonucleotide library (UniSeq) was designed, fabricated and its performance optimized and evaluated in a range of PCR and DNA sequencing reactions. This methodology used to derive specific 11-mers, performed well in each of these activities and produced the desired lification or sequencing analysis with results comparable to primers made by time consuming and expensive custom synthesis. On the basis of these experiments, we believe this novel system would be broadly applicable and could in many circumstances replace the need for conventional oligonucleotide synthesis.
Publisher: Springer Science and Business Media LLC
Date: 11-05-2019
Publisher: Springer Science and Business Media LLC
Date: 06-07-2022
DOI: 10.1007/S00406-022-01450-4
Abstract: Grey matter volume (GMV) may be associated with polygenic risk for schizophrenia (PRS-SZ) and severe cognitive deficits in people with schizophrenia, schizoaffective disorder (collectively SSD), and bipolar disorder (BD). This study examined the interactive effects of PRS-SZ and cognitive subtypes of SSD and BD in relation to GMV. Two-step cluster analysis was performed on 146 clinical cases (69 SSD and 77 BD) assessed on eight cognitive domains (verbal and visual memory, executive function, processing speed, visual processing, language ability, working memory, and planning). Among them, 55 BD, 51 SSD, and 58 healthy controls (HC), contributed to focal analyses of the relationships between cognitive subtypes, PRS-SZ and their interaction on GMV. Two distinct cognitive subtypes were evident among the combined s le of cases: a ‘cognitive deficit’ group (CD N = 31, 20SSD/11BD) showed severe impairment across all cognitive indices, and a ‘cognitively spared’ (CS N = 75 31SSD/44BD) group showed intermediate cognitive performance that was significantly worse than the HC group but better than the CD subgroup. A cognitive subgroup-by-PRS-SZ interaction was significantly associated with GMV in the left precentral gyrus. Moderation analyses revealed a significant negative relationship between PRS-SZ and GMV in the CD group only. At low and average (but not high) PRS-SZ, larger precentral GMV was evident in the CD group compared to both CS and HC groups, and in the CS group compared to HCs. This study provides evidence for a relationship between regional GMV changes and PRS-SZ in psychosis spectrum cases with cognitive deficits, but not in cases cognitively spared.
Publisher: Wiley
Date: 10-1998
DOI: 10.1080/15216549800203782
Abstract: The DNA sequence specificity of hedamycin damage was compared using two techniques: Ligation-mediated PCR (LMPCR) and Linear Amplification (LA). The electrophoretic mobility of LA products were made comparable with LMPCR products by using a primer with a 27 bp non-binding 5'-extension. By direct comparison of the damage intensity (as represented by each of the methods), considerable bias was found in the LMPCR system with respect to LA--resulting in the under representation of lesions with T as the base 3' to the damage site. In view of this observation some caution should be exercised in the interpretation of data for DNA damage/repair specificity derived by LMPCR. In addition the extended primer LA method used in these experiments, could be applied to generate a dideoxy sequencing ladder for analysis of LMPCR products. This would negate the need to prepare Maxam-Gilbert chemical sequencing fragments for lification through LMPCR.
Publisher: EMBO
Date: 23-01-2019
Publisher: Springer Science and Business Media LLC
Date: 27-01-2016
DOI: 10.1038/NATURE16549
Publisher: Elsevier BV
Date: 11-2018
Publisher: MDPI AG
Date: 20-12-2019
DOI: 10.3390/CELLS9010025
Abstract: Circular RNAs (circRNAs) are a relatively new class of RNA transcript with high abundance in the mammalian brain. Here, we show that circRNAs expression in differentiated neuroblastoma cells were significantly altered after depolarization with 107 upregulated and 47 downregulated circRNAs. This coincided with a global alteration in the expression of microRNA (miRNA) (n = 269) and mRNA (n = 1511) in depolarized cells, suggesting a regulatory axis of circRNA–miRNA–mRNA is involved in the cellular response to neural activity. In support of this, our in silico analysis revealed that the circular transcripts had the capacity to influence mRNA expression through interaction with common miRNAs. Loss-of-function of a highly expressed circRNA, circ-EXOC6B, resulted in altered expression of numerous mRNAs enriched in processes related to the EXOC6B function, suggesting that circRNAs may specifically regulate the genes acting in relation to their host genes. We also found that a subset of circRNAs, particularly in depolarized cells, were associated with ribosomes, suggesting they may be translated into protein. Overall, these data support a role for circRNAs in the modification of gene regulation associated with neuronal activity.
Publisher: Springer Science and Business Media LLC
Date: 13-09-2016
DOI: 10.1038/MP.2016.150
Publisher: Public Library of Science (PLoS)
Date: 25-01-2016
Publisher: Cold Spring Harbor Laboratory
Date: 14-10-2021
DOI: 10.1101/2021.10.13.464216
Abstract: Although genomes from many edible mushrooms are sequenced, studies on fungal miRNAs are scarce. Most of the bioinformatic tools are designed for plants or animals but fungal miRNAs processing and expression share similarities and differences with both kingdoms. Moreover, since mushroom species such as Agaricus bisporus (white button mushroom) are frequently consumed as food, controversial discussions are still evaluating whether their miRNAs might or might not be assimilated, perhaps within extracellular vesicles (i.e exosomes). Therefore, the A. bisporus RNA-seq was studied in order to identify potential de novo miRNA-like small RNAs (milRNAs) that might allow their later detection in the diet. Results pointed to 1 already known and 37 de novo milRNAss. Three milRNAss were selected for RT-qPCR experiments. Precursors and mature milRNAs were found in the edible parts (caps and stipes) validating the predictions carried out in silico . When their potential gene targets were investigated, results pointed that mostly were involved in primary and secondary metabolic regulation. However, when human transcriptome is used as target, the results suggest that they might interfere with important biological processes related with cancer, infectious process and neurodegenerative diseases.
Publisher: Elsevier BV
Date: 03-2012
DOI: 10.1016/J.BBI.2011.12.011
Abstract: Selective serotonin and serotonin norepinephrine reuptake inhibitors (SSRI SNRI) are the first choice pharmacological treatment options for major depression. It has long been assumed that the primary therapeutic mechanism of action of these drugs involves the modulation of monoaminergic systems. However, contemporary investigations have revealed that depression is linked with inflammation, and that SSRI/SNRIs possess significant anti-inflammatory actions. While these anti-inflammatory properties initially only related to work undertaken on cells of the peripheral immune system, it has recently become apparent that these drugs also exert anti-inflammatory effects on microglia, the principal cells within the CNS that regulate and respond to inflammatory factors. The aim of the current study was to compare SSRI/SNRIs in terms of their anti-inflammatory potency, and to determine the specific mechanisms through which these effects are mediated. Accordingly, the current study evaluated the ability of five different SSRIs (fluoxetine, sertraline, paroxetine, fluvoxamine and citalopram) and one SNRI (venlafaxine) to suppress microglial responses to an inflammatory stimulus. Specifically, we examined their ability to alter tumour necrosis factor-α (TNF-α) and nitric oxide (NO) production after 4 and 24 h stimulation with lipopolysaccharide. Our results indicated that the SSRIs potently inhibited microglial TNF-α and NO production. We then investigated whether these effects might involve either β-adrenoceptor or cAMP signalling. Using the protein kinase A inhibitor Rp-CAMPs, we found evidence to suggest that cAMP signalling is involved in regulating the anti-inflammatory response. These findings suggest that antidepressants may owe at least some of their therapeutic effectiveness to their anti-inflammatory properties.
Publisher: Cold Spring Harbor Laboratory
Date: 14-05-2021
DOI: 10.1101/2021.05.11.21257061
Abstract: There is a long-standing interest in exploring the relationship between blood-based biomarkers of biological exposures and psychiatric disorders, despite their causal role being difficult to resolve in observational studies. In this study, we leverage genome-wide association study data for a large panel of heritable biochemical traits measured from serum to refine our understanding of causal effect in biochemical-psychiatric trait parings. In accordance with expectation we observed widespread evidence of positive and negative genetic correlation between psychiatric disorders and biochemical traits. We then implemented causal inference to distinguish causation from correlation and found strong evidence that C-reactive protein (CRP) exerts a causal effect on psychiatric disorders, along with other putatively causal relationships involving urate and glucose. Strikingly, these analyses suggested CRP has a protective effect on three disorders including anorexia nervosa, obsessive-compulsive disorder, and schizophrenia, whilst being a risk factor for major depressive disorder. Multivariable models that conditioned CRP effects on interleukin-6 signalling and body mass index suggested that CRP-schizophrenia relationship was not likely mediated by those factors. Collectively, these data suggest that there are shared pathways that influence both biochemical traits and psychiatric illness, including factors such as CRP that are likely to constitute a causal effect and could be targets for therapeutic intervention and precision medicine.
Publisher: Springer Science and Business Media LLC
Date: 08-09-2022
DOI: 10.1038/S41398-022-02141-3
Abstract: Psychiatric disorders such as schizophrenia are commonly associated with structural brain alterations affecting the cortex. Recent genetic evidence suggests circulating metabolites and other biochemical traits play a causal role in many psychiatric disorders which could be mediated by changes in the cerebral cortex. Here, we leveraged publicly available genome-wide association study data to explore shared genetic architecture and evidence for causal relationships between a panel of 50 biochemical traits and measures of cortical thickness and surface area. Linkage disequilibrium score regression identified 191 genetically correlated biochemical-cortical trait pairings, with consistent representation of blood cell counts and other biomarkers such as C-reactive protein (CRP), haemoglobin and calcium. Spatially organised patterns of genetic correlation were additionally uncovered upon clustering of region-specific correlation profiles. Interestingly, by employing latent causal variable models, we found strong evidence suggesting CRP and vitamin D exert causal effects on region-specific cortical thickness, with univariable and multivariable Mendelian randomization further supporting a negative causal relationship between serum CRP levels and thickness of the lingual region. Our findings suggest a subset of biochemical traits exhibit shared genetic architecture and potentially causal relationships with cortical structure in functionally distinct regions, which may contribute to alteration of cortical structure in psychiatric disorders.
Publisher: Wiley
Date: 14-03-2007
Publisher: Elsevier BV
Date: 03-2016
DOI: 10.1016/J.BBI.2015.12.010
Abstract: 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.
Publisher: American Association for Cancer Research (AACR)
Date: 04-2013
DOI: 10.1158/1538-7445.AM2013-5283
Abstract: Rationale: Tetraspanins are involved in modulating various cellular functions related to cancer progression, such as cell-cell adhesion, migration and signalling. The tetraspanin CD151 (pro-metastatic) is typically over-expressed in cancers, whereas CD9 (metastasis suppressor) is generally under-expressed in cancers. Increased CD151 protein expression in breast and prostate cancers significantly correlates with poor patient outcomes, whereas high CD9 protein expression in these cancers is associated with good patient prognosis. However, progress in developing CD151 and CD9 as prognostic biomarkers and therapeutic targets is h ered by a lack of understanding of the mechanisms controlling altered CD151 and CD9 protein expression in cancers. Objective: miRNAs, which are small non-coding RNAs involved in post-transcriptional control, are known to be dysregulated in breast and prostate cancers. Bioinformatics analysis has identified around 250 miRNA, which are predicted to bind CD151 or CD9, thus we aim to investigate if miRNAs are able to regulate the expression of CD151 and CD9 in vitro using a range of breast and prostate cancer cell lines. Methods and Results: Using a dual luciferase reporter assay the level of protein expression regulation via CD151 or CD9 3’UTR, where miRNA generally bind their targets, was determined in 13 breast and prostate cell lines. This analysis showed that the amount of targeting of CD151 and CD9 varied across these cell lines indicating a role for miRNA. Analysis of miRNA expression in normal and cancerous cell lines using miRNA expression arrays and qPCR has confirmed that some miRNAs which are predicted to target CD9 such as miR-25 are up-regulated in many prostate and breast cancer cell lines compared to non-tumourigenic cells. Conversely, miRNA were identified with different expression levels that are predicted to target CD151. To determine whether these miRNAs directly regulate CD151 or CD9, a dual luciferase 3’UTR reporter assay encompassing specific miRNA mimics is being used. Conclusion: Altered miRNA expression is one way in which prostate and breast cancer cells might alter tetraspanin protein expression to allow cancer progression and metastasis. Citation Format: Danielle R. Bond, Murray Cairns, Leonie K. Ashman, Judith Weidenhofer. Regulation of tetraspanins CD151 and CD9 by micro-RNA in breast and prostate cancers. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research 2013 Apr 6-10 Washington, DC. Philadelphia (PA): AACR Cancer Res 2013 (8 Suppl):Abstract nr 5283. doi:10.1158/1538-7445.AM2013-5283 Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
Publisher: Elsevier BV
Date: 04-2014
Publisher: Cold Spring Harbor Laboratory
Date: 17-04-2023
DOI: 10.1101/2023.04.17.537256
Abstract: Diffuse midline glioma (DMG), including tumors diagnosed in the brainstem (diffuse intrinsic pontine glioma – DIPG), are uniformly fatal brain tumors that lack effective pharmacological treatment. Analysis of pooled CRISPR-Cas9 loss-of-function gene deletion screen datasets, identified PIK3CA and MTOR as targetable molecular dependencies across DIPG patient derived models, highlighting the therapeutic potential of the blood-brain barrier penetrant PI3K/Akt/mTOR inhibitor paxalisib. At the human equivalent maximum tolerated dose, mice treated with paxalisib experienced systemic feedback resulting in increased blood glucose and insulin levels, commensurate with DIPG patients in Phase 1b clinical trials who experienced hyperglycemia/hyperinsulinemia. To exploit genetic dependences, but maintain compliance and benefit, we optimized a paxalisib treatment regimen that employed reduced dosing more frequently, in combination with the anti-hyperglycemic drug, metformin. Combining optimized dosing with metformin restored glucose homeostasis and decreased phosphorylation of the insulin receptor in vivo , a common mechanism of PI3K-inhibitor resistance, extending the survival of DIPG xenograft models. RNA sequencing and phosphoproteomic profiling of DIPG models treated with paxalisib identified increased calcium-activated PKC signaling. Using the brain penetrant PKC inhibitor, enzastaurin in combination with paxalisib, we synergistically extended the survival of orthotopic xenograft models, benefits further promoted by metformin thus, identifying a clinically relevant DIPG combinatorial approach. Diffuse intrinsic pontine glioma is a lethal childhood brain tumor. Here we identify PIK3CA as a genetic dependency targeted by the brain penetrant pan-PI3K-inhibitor paxalisib.
Publisher: Oxford University Press (OUP)
Date: 15-08-1997
Abstract: Four nitrogen mustards have been used in this study to examine protein-DNA interactions in intact human cells, specifically at the locus control region hypersensitive site-2 (LCR HS-2) of the human beta-globin locus. Three of these nitrogen mustards are DNA-targeted by attachment of an acridine or amsacrine intercalating chromophore, while the fourth (chlorambucil) is a non-targeted mustard. The ligation-mediated PCR technique was used to determine the sites of damage at base pair resolution on DNA sequencing gels. A densitometric comparison was made between DNA damaged in intact erythroid K562 cells and in purified DNA. The intensity of DNA damage sites in the LCR HS-2 were found to differ significantly between intact K562 cells and purified DNA. At the NF-E2/AP-1 motif, pronounced damage protection was observed in DNA derived from drug treated cells. The nuclear factor- erythroid 2 (NF-E2) protein factor is thought to bind at this NF-E2/AP-1 motif in K562 cells. Other sites of protection and enhancement that corresponded to known transcription factor binding sites were also detected. These nitrogen mustards are therefore very effective compounds for detection of transcription factor binding to DNA in intact cells and are superior to other commonly used agents. The sequence selectivity of the compounds was determined using plasmid DNA and compared to that found in intact cells. The acridine-based nitrogen mustard had a preference for forming adducts at guanine bases, while the two amsacrine-based nitrogen mustards and chlorambucil formed adducts at both guanine and adenine bases.
Publisher: Wiley
Date: 03-04-2009
DOI: 10.1002/IJC.24298
Abstract: Genome-wide microRNA (miRNA) expression profiling of salivary gland pleomorphic adenomas revealed a distinct expression signature consisting largely of upregulated miRNAs compared with matched normal tissue. Microarray data were confirmed by quantitative real time RT-PCR (q-RTPCR). Five miRNA genes upregulated in the tumours were found in close proximity to fragile sites and/or cancer associated genomic regions. Interestingly, q-RTPCR revealed an increase in the expression of components of the miRNA processing machinery (Dicer, Drosha, DGCR8 and p68) in tumours suggesting that the deregulation of miRNA expression may result from increased miRNA biogenesis. Target gene prediction analysis of the altered miRNAs indicated that genes in a number of signalling pathways important in tumourigenesis including WNT, MAPK and JAK-STAT were overrepresented. Significantly, the oncogene PLAG1 was overexpressed in our cohort and may be potentially regulated by these miRNAs. This is the first study to examine changes in the miRNA milieu in pleomorphic adenoma, the most common salivary gland tumour. This study has demonstrated an upregulation of both miRNAs genes and an upregulation of the miRNA processing machinery. These changes may be potential underlying mechanisms for the development of these benign tumours.
Publisher: MDPI AG
Date: 18-04-2020
DOI: 10.3390/CELLS9041014
Abstract: MicroRNA (miRNA) coordinate complex gene expression networks in cells that are vital to support highly specialised morphology and cytoarchitecture. Neurons express a rich array of miRNA, including many that are specific or enriched, which have important functions in this context and implications for neurological conditions. While the neurological function of a number of brain-derived miRNAs have been examined thoroughly, the mechanistic basis of many remain obscure. In this case, we investigated the transcriptome-wide impact of schizophrenia-associated miR-1271-5p in response to bidirectional modulation. Alteration of miR-1271-5p induced considerable changes to mRNA abundance and translation, which spanned a erse range of cellular functions, including directly targeted genes strongly associated with cytoskeletal dynamics and cellular junctions. Mechanistic analyses additionally revealed that upregulation of miR-1271-5p predominantly repressed mRNAs through destabilisation, wherein 3′UTR and coding sequence binding sites exhibited similar efficacy. Knockdown, however, produced no discernible trend in target gene expression and strikingly resulted in increased expression of the highly conserved miR-96-5p, which shares an identical seed region with miR-1271-5p, suggesting the presence of feedback mechanisms that sense disruptions to miRNA levels. These findings indicate that, while bidirectional regulation of miR-1271-5p results in substantial remodeling of the neuronal transcriptome, these effects are not inverse in nature. In addition, we provide further support for the idea that destabilisation of mRNA is the predominant mechanism by which miRNAs regulate complementary mRNAs.
Publisher: Springer Science and Business Media LLC
Date: 14-12-2011
Publisher: Bentham Science Publishers Ltd.
Date: 2010
DOI: 10.2174/157489110790112590
Abstract: The advent of gene silencing siRNA technology has created opportunities to develop therapeutics based on targeting the genomics of the disease state. Amongst the first applications of siRNA technology, antiviral applications have been quickly and extensively exploited allowing emergence of a range of antiviral therapeutic strategies. Patent activity has encompassed a range of the components required to utilize this technology ranging from the identification of susceptible genomic targets through to the development of vector systems to express the siRNA endogenously or the synthesis of stable RNA oligonucleotides for in vivo therapeutics. Indeed the primary focus of research effort in this area has been to overcome the challenge common to all of gene therapeutics - delivery of the oligonucleotide - to the diseased tissues and organs, sites of infection and/or sites of drug action. Here we survey the development of siRNA therapeutics both in terms of the range of virus species targeted and the strategic approaches employed. Our study illustrates features commonly observed in the field of nucleic acid drug development. While in vitro studies provide a broad range of molecules and molecular targets for potential therapeutics, the field is however severely limited in terms of safe, effective means to deliver the potential siRNA therapeutics in vivo, to the intracellular site of action.
Publisher: Springer Science and Business Media LLC
Date: 28-08-2003
Publisher: Springer New York
Date: 2016
Publisher: Frontiers Media SA
Date: 25-10-2016
Publisher: Elsevier BV
Date: 04-2010
Publisher: Elsevier BV
Date: 2011
DOI: 10.1016/J.BIOPSYCH.2010.09.030
Abstract: MicroRNA (miRNA) are capable of regulating multitudes of target genes and are essential factors in mediating healthy neurodevelopment. We hypothesize that abnormal miRNA levels contribute to the complex global changes in gene expression that underlie the pathophysiology of schizophrenia. With a commercial bead array platform, we investigated miRNA expression in 74 s les of postmortem dorsolateral prefrontal cortex (Brodmann Area 46) (n = 37 matched pairs schizophrenia/schizoaffective disorder and control subjects). A subset of differentially expressed miRNA and genes in the miRNA biogenesis pathway was also analyzed with quantitative reverse transcription-polymerase chain reaction. Gene targets of miRNAs demonstrating significantly altered expression were predicted, and pathways analysis was performed. After correction for multiple testing, microarray analysis identified differential expression of 28 miRNA in the schizophrenia group. Significantly, 89% of these molecules were elevated in accordance with earlier work in other brain regions that showed a broad increase in miRNA expression in schizophrenia. These observations were supported by quantitative reverse transcription-polymerase chain reaction, for miR-328, miR-17-5p, miR-134, miR-652, miR-382, and miR-107 and were consistent with a schizophrenia-associated increase in miRNA processing through elevated Dicer expression. Target and pathways analysis provided insight into the potential cellular effects, with particular enrichment of miRNA targets in axon guidance and long-term potentiation. These results suggest that schizophrenia is associated with altered miRNA biogenesis and expression, which might have important implications in the complex pathophysiology of the disorder.
Publisher: Oxford University Press (OUP)
Date: 10-09-2020
Abstract: Genome-wide association studies (GWAS) of schizophrenia have strongly implicated a risk locus in close proximity to the gene for miR-137. While there are candidate single-nucleotide polymorphisms (SNPs) with functional implications for the microRNA’s expression encompassed by the common haplotype tagged by rs1625579, there are likely to be others, such as the variable number tandem repeat (VNTR) variant rs58335419, that have no proxy on the SNP genotyping platforms used in GWAS to date. Using whole-genome sequencing data from schizophrenia patients (n = 299) and healthy controls (n = 131), we observed that the MIR137 4-repeats VNTR (VNTR4) variant was enriched in a cognitive deficit subtype of schizophrenia and associated with altered brain morphology, including thicker left inferior temporal gyrus and deeper right postcentral sulcus. These findings suggest that the MIR137 VNTR4 may impact neuroanatomical development that may, in turn, influence the expression of more severe cognitive symptoms in patients with schizophrenia.
Publisher: Elsevier BV
Date: 04-2012
Publisher: Elsevier BV
Date: 04-2019
Publisher: Springer Science and Business Media LLC
Date: 12-05-2020
DOI: 10.1038/S41398-020-0817-7
Abstract: The complex aetiology of schizophrenia is postulated to share components with other psychiatric disorders. We investigated pleiotropy amongst the common variant genomics of schizophrenia and seven other psychiatric disorders using a multimarker association test. Transcriptomic imputation was then leveraged to investigate the functional significance of variation mapped to these genes, prioritising several interesting functional candidates. Gene-based analysis of common variation revealed 67 schizophrenia-associated genes shared with other psychiatric phenotypes, including bipolar disorder, major depressive disorder, ADHD and autism-spectrum disorder. In addition, we uncovered 78 genes significantly enriched with common variant associations for schizophrenia that were not linked to any of these seven disorders ( P 0.05). Multivariable gene-set association suggested that common variation enrichment within biologically constrained genes observed for schizophrenia also occurs across several psychiatric phenotypes. Pairwise meta-analysis of schizophrenia and each psychiatric phenotype was implemented and identified 330 significantly associated genes ( P Meta 2.7 × 10 −6 ) that were only nominally associated with each disorder in idually ( P 0.05). These analyses consolidate the overlap between the genomic architecture of schizophrenia and other psychiatric disorders, uncovering several candidate pleiotropic genes which warrant further investigation.
Publisher: Humana Press
Date: 2004
DOI: 10.1385/1-59259-746-7:291
Abstract: The sequence specificity of the "10-23" RNA-cleaving DNA enzyme can be utilized to discriminate between subtle differences in nucleic acid sequence. We examined this potential by comparing the cleavage activity of DNAzymes that target sequences derived from a relatively conserved segment of the L1 gene from different human papillomavirus (HPV) genotypes. DNAzyme activity was found to be highly sensitive to mismatches between its binding domain and substrate sequences containing polymorphisms. Type-specific DNAzyme-cleavable substrates can also be generated by genomic PCR using a chimeric primer containing three bases of RNA. The RNA component enables each licon to be cleavable in the presence of its matching DNAzyme. In this format, the specificity of DNAzyme cleavage is defined by Watson-Crick interactions between one substrate-binding domain (arm I) and the polymorphic sequence that is lified during polymerase chain reaction (PCR). DNAzyme-mediated cleavage of licons generated by this method was used to examine the HPV status of genomic DNA derived from Caski cells, which are known to be positive for HPV16. This method is applicable to many types of nucleic acid sequence variation, including single-nucleotide polymorphisms (SNPs).
Publisher: Elsevier BV
Date: 11-2015
DOI: 10.1016/J.PSCYCHRESNS.2015.09.004
Abstract: Previous research has demonstrated that in iduals with schizophrenia who are homozygous at the c.267C>A single nucleotide polymorphism (rs2067477) within the cholinergic muscarinic M1 receptor (CHRM1) perform less well on the Wisconsin Card Sorting Test (WCST) than those who are heterozygous. This study sought to determine whether variation in the rs2067477 genotype was associated with differential changes in brain structure. Data from 227 patients with established schizophrenia or schizoaffective disorder were obtained from the Australian Schizophrenia Research Bank. Whole-brain voxel-based morphometry was performed to compare regional grey matter volume (GMV) between the 267C/C (N=191) and 267C/A (N=36) groups. Secondary analyses tested for an effect of genotype on cognition (the WCST was not available). In iduals who were homozygous (267C/C) demonstrated significantly reduced GMV in the right precentral gyrus compared to those who were heterozygous (267C/A). These preliminary results suggest that the rs2067477 genotype is associated with brain structure in the right precentral gyrus in in iduals with schizophrenia/schizoaffective disorder. Future studies are required to replicate these results and directly link the volumetric reductions with specific cognitive processes.
Publisher: Elsevier BV
Date: 04-2014
Publisher: Oxford University Press (OUP)
Date: 09-06-2023
DOI: 10.1093/NAR/GKAD499
Abstract: Differentiation of neural progenitor cells into mature neuronal phenotypes relies on extensive temporospatial coordination of mRNA expression to support the development of functional brain circuitry. Cleavage and polyadenylation of mRNA has tremendous regulatory capacity through the alteration of mRNA stability and modulation of microRNA (miRNA) function, however the extent of utilization in neuronal development is currently unclear. Here, we employed poly(A) tail sequencing, mRNA sequencing, ribosome profiling and small RNA sequencing to explore the functional relationship between mRNA abundance, translation, poly(A) tail length, alternative polyadenylation (APA) and miRNA expression in an in vitro model of neuronal differentiation. Differential analysis revealed a strong bias towards poly(A) tail and 3′UTR lengthening during differentiation, both of which were positively correlated with changes in mRNA abundance, but not translation. Globally, changes in miRNA expression were predominantly associated with mRNA abundance and translation, however several miRNA–mRNA pairings with potential to regulate poly(A) tail length were identified. Furthermore, 3′UTR lengthening was observed to significantly increase the inclusion of non-conserved miRNA binding sites, potentially enhancing the regulatory capacity of these molecules in mature neuronal cells. Together, our findings suggest poly(A) tail length and APA function as part of a rich post-transcriptional regulatory matrix during neuronal differentiation.
Publisher: Oxford University Press (OUP)
Date: 06-01-2013
Publisher: Elsevier BV
Date: 04-2012
Publisher: Elsevier BV
Date: 10-2019
DOI: 10.1016/J.BBI.2019.06.009
Abstract: A hallmark feature of schizophrenia is altered high frequency neural oscillations, including reduced auditory-evoked gamma oscillatory power, which is underpinned by parvalbumin (PV) interneuron dysfunction. Maternal immune activation (MIA) in rodents models an environmental risk factor for schizophrenia and recapitulates these PV interneuron changes. This study sought to link reduced PV expression in the MIA model with alterations to auditory-evoked gamma oscillations and transcript expression. We further aligned transcriptional findings from the animal model with human genome sequencing data. We show that MIA, induced by the viral mimetic, poly-I:C in C57Bl/6 mice, caused in adult offspring reduced auditory-evoked gamma and theta oscillatory power paralleled by reduced PV protein levels. We then showed the Arx gene, critical to healthy neurodevelopment of PV interneurons, is reduced in the forebrain of MIA exposed mice. Finally, in a whole-genome sequenced patient cohort, we identified a novel missense mutation of ARX in a patient with schizophrenia and in the Psychiatric Genomics Consortium 2 cohort, a nominal association of proximal ARX SNPs with the disorder. This suggests MIA, as a risk factor for schizophrenia, may be influencing Arx expression to induce the GABAergic dysfunction seen in schizophrenia and that the ARX gene may play a role in the prenatal origins of schizophrenia pathophysiology.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 22-06-2018
Abstract: Consistent classification of neuropsychiatric diseases is problematic because it can lead to misunderstanding of etiology. The Brainstorm Consortium examined multiple genome-wide association studies drawn from more than 200,000 patients for 25 brain-associated disorders and 17 phenotypes. Broadly, it appears that psychiatric and neurologic disorders share relatively little common genetic risk. However, different and independent pathways can result in similar clinical manifestations (e.g., psychosis, which occurs in both schizophrenia and Alzheimer's disease). Schizophrenia correlated with many psychiatric disorders, whereas the immunopathological affliction Crohn's disease did not, and posttraumatic stress syndrome was also largely independent of underlying traits. Essentially, the earlier the onset of a disorder, the more inheritable it appeared to be. Science , this issue p. eaap8757
Publisher: Elsevier BV
Date: 05-2019
DOI: 10.1016/J.JPSYCHIRES.2019.02.023
Abstract: The aetiology of schizophrenia is complex, heterogeneous, and involves interplay of many genetic and environmental influences. While significant progress has been made in the understanding the common heritable component, we are still grappling with the genomic encoding of environmental risk. One class of molecule that has tremendous potential is miRNA. These molecules are regulated by genetic and environmental factors associated with schizophrenia and have a very significant impact on temporospatial patterns of gene expression. To better understand the relationship between miRNA and gene expression in the disorder we analysed these molecules in RNA isolated from peripheral blood mononuclear cells (PBMCs) obtained from an Australian cohort of 36 in iduals with schizophrenia and 15 healthy controls using next-generation RNA sequencing. Significant changes in both mRNA and miRNA expression profiles were observed implicating important interaction networks involved in immune activity and development. We also observed sexual dimorphism, particularly in relation to variation in mRNA, with males showing significantly more differentially expressed genes. Interestingly, while we explored expression in lymphocytes, the systems biology of miRNA-mRNA interactions was suggestive of significant pleiotropy with enrichment of networks related to neuronal activity.
Publisher: Research Square Platform LLC
Date: 16-02-2021
DOI: 10.21203/RS.3.RS-231116/V1
Abstract: Circular RNA (circRNA) are head-to-tail back-spliced RNA transcripts that have been linked to several biological processes and their perturbation is evident in human diseases, including neurological disorders. There is also emerging research suggesting circRNA expression may also be altered in psychiatric and behavioural syndromes. Here, we provide a comprehensive analysis of circRNA expression in peripheral blood mononuclear cells (PBMCs) from 39 patients with schizophrenia and bipolar disorder as well as 20 healthy in iduals using deep RNA-seq. We observed systematic alternative splicing leading to a complex and erse profile of RNA transcripts including 8,762 high confidence circRNAs. More specific scrutiny of the circular transcriptome in schizophrenia and bipolar disorder, compared to a non-psychiatric control group, revealed significant dysregulation of 55 circRNAs with a bias towards downregulation. These molecules were predicted to interact with a large number of miRNAs that target genes enriched in psychiatric disorders. Further replication and cross validation to determine the specificity of these circRNAs across broader diagnostic groups and subgroups in psychiatry will enable their potential utility as biomarkers to be established.
Publisher: Springer Science and Business Media LLC
Date: 04-2014
Publisher: InTech
Date: 21-06-2017
DOI: 10.5772/67603
Publisher: Elsevier BV
Date: 08-2016
DOI: 10.1016/J.PNEUROBIO.2016.06.005
Abstract: The developmental processes that establish the synaptic architecture of the brain while retaining capacity for activity-dependent remodeling, are complex and involve a combination of genetic and epigenetic influences. Dysregulation of these processes can lead to problems with neural circuitry which manifest in humans as a range of neurodevelopmental syndromes, such as schizophrenia, bipolar disorder and fragile X mental retardation. Recent studies suggest that prenatal, postnatal and intergenerational environmental factors play an important role in the aetiology of stress-related psychopathology. A number of these disorders have been shown to display epigenetic changes in the postmortem brain that reflect early life experience. These changes affect the regulation of gene expression though chromatin remodeling (transcriptional) and post-transcriptional influences, especially small noncoding microRNA (miRNA). These dynamic and influential molecules appear to play an important function in both brain development and its adaption to stress. In this review, we examine the role of miRNA in mediating the brain's response to both prenatal and postnatal environmental perturbations and explore how stress- induced alterations in miRNA expression can regulate the stress response via modulation of the immune system. Given the close relationship between environmental stress, miRNA, and brain development/function, we assert that miRNA hold a significant position at the molecular crossroads between neural development and adaptations to environmental stress. A greater understanding of the dynamics that mediate an in idual's predisposition to stress-induced neuropathology has major human health benefits and is an important area of research.
Publisher: Springer Science and Business Media LLC
Date: 09-09-2014
Publisher: Elsevier BV
Date: 06-1999
Publisher: Springer Science and Business Media LLC
Date: 05-1999
DOI: 10.1038/8658
Abstract: A small catalytic DNA, known as the 10-23 DNA enzyme or deoxyribozyme, has been shown to efficiently hydrolyze RNA at purine-pyrimidine (R-Y) junctions in vitro. Although these potentially cleavable junctions are ubiquitous, they are often protected from deoxyribozyme activity by RNA secondary structure. We have developed a multiplex cleavage assay for screening the entire length of a target RNA molecule for deoxyribozyme cleavage sites that are efficient, both in terms of kinetics and accessibility. This strategy allowed us to simultaneously compare the RNA cleaving activity of 80 deoxyribozymes for a model target gene (HPV16 E6), and an additional 60 deoxyribozymes against the rat c-myc target. The human papilloma virus (HPV) target was used primarily to characterize the multiplex system and determine its validity. The c-myc target, coupled with a smooth muscle cell proliferation assay, allowed us to assess the relationship between in vitro cleavage efficiency and c-myc gene suppression in cell culture. The multiplex reaction approach streamlines the process of revealing effective deoxyribozymes in a functional assay and provides accessibility data that may also be applicable to site selection for other hybridization-based agents.
Publisher: Mary Ann Liebert Inc
Date: 04-1998
Abstract: The DNA sequence specificity of hedamycin (HDM) damage was investigated in the single-copy human beta-globin gene cluster in an erythroid cell line, a nonerythroid cell line, and purified genomic DNA. The target DNA sequences for this study were the beta-globin gene locus control region (LCR) hypersensitive site 2 (HS-2) and the beta-globin gene promoter. The DNA fragments produced by HDM damage in these target sequences were selectively lified by the ligation-mediated polymerase chain reaction (LMPCR) and analyzed at nucleotide resolution by DNA-sequencing gel electrophoresis. The DNA sequences damaged by HDM in the cellular environment were found to be similar to that observed in the purified genomic DNA. However, substantial differences did occur between the intensity of cellular and purified genomic DNA reaction products at discrete regions corresponding to transcription factor-binding motifs. This was most apparent in the LCR HS-2 at the tandem NF-E2/AP-1 motif, where the DNA damage activity of HDM was severely impaired. This motif has been shown to bind to the erythroid-specific nuclear factor-erythroid 2 (NF-E2) and the widely distributed activator protein-1 (AP-1). The HDM damage protection patterns or "genomic footprints" observed at this motif were probably caused by protein-DNA interactions with one or both of these transcription factors. This result indicates that the DNA damaging activity of HDM in cells is sensitive to bound nuclear factors. Because HDM can enter intact cells, where its DNA damaging activity is modulated by protein-DNA interactions, it may have application in genomic footprinting experiments.
Location: No location found
Location: Australia
Start Date: 05-2017
End Date: 06-2018
Amount: $900,000.00
Summary: Access to the National Computing Infrastructure peak supercomputing facility. This project aims to continue the access of Intersect’s computational researchers to the National Computational Infrastructure (NCI) peak supercomputing facility. The peak supercomputing facility at NCI is critical collaborative infrastructure on a globally competitive scale. Transformative advances in science and technology increasingly rely on high performance computing capabilities across a wide range of research di .... Access to the National Computing Infrastructure peak supercomputing facility. This project aims to continue the access of Intersect’s computational researchers to the National Computational Infrastructure (NCI) peak supercomputing facility. The peak supercomputing facility at NCI is critical collaborative infrastructure on a globally competitive scale. Transformative advances in science and technology increasingly rely on high performance computing capabilities across a wide range of research disciplines. Ongoing access to this facility will allow researchers to tackle major problems in national priority areas including energy, health, and environmental change. Read more Read less
Funder: Australian Research Council
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