scholarly journals Gene Expression Elucidates Functional Impact of Polygenic Risk for Schizophrenia

2016 ◽  
Author(s):  
Menachem Fromer ◽  
Panos Roussos ◽  
Solveig K Sieberts ◽  
Jessica S Johnson ◽  
David H Kavanagh ◽  
...  
Keyword(s):  
Gene Expression ◽  
Differential Expression ◽  
Neural Progenitor Cells ◽  
Single Gene ◽  
Genetic Regulation ◽  
Brain Diseases ◽  
Common Variants ◽  
Genetic Associations ◽  
Significant Differential Expression ◽  
Altered Expression

ABSTRACTOver 100 genetic loci harbor schizophrenia associated variants, yet how these common variants confer risk is uncertain. The CommonMind Consortium has sequenced dorsolateral prefrontal cortex RNA from schizophrenia cases (n=258) and control subjects (n=279), creating the largest publicly available resource to date of gene expression and its genetic regulation; ∼5 times larger than the latest release of GTEx. Using this resource, we find that ∼20% of the schizophrenia risk loci have common variants that could explain regulation of brain gene expression. In five loci, these variants modulate expression of a single gene: FURIN, TSNARE1, CNTN4, CLCN3 or SNAP91. Experimentally altered expression of three of them, FURIN, TSNARE1, and CNTN4, perturbs the proliferation and apoptotic index of neural progenitors and leads to neuroanatomical deficits in zebrafish. Furthermore, shRNA mediated knock-down of FURIN1 in neural progenitor cells derived from human induced pluripotent stem cells produces abnormal neural migration. Although 4.2% of genes (N = 693) display significant differential expression between cases and controls, 44% show some evidence for differential expression. All fold changes are ≤ 1.33, and an independent cohort yields similar differential expression for these 693 genes (r = 0.58). These findings are consistent with schizophrenia being highly polygenic, as has been reported in investigations of common and rare genetic variation. Co-expression analyses identify a gene module that shows enrichment for genetic associations and is thus relevant for schizophrenia. Taken together, these results pave the way for mechanistic interpretations of genetic liability for schizophrenia and other brain diseases.

scholarly journals Identification of unique venous thromboembolism-susceptibility variants in African-Americans

2017 ◽  
Vol 117 (04) ◽  
pp. 758-768 ◽  
Author(s):  
Sebastian Armasu ◽  
Bryan McCauley ◽  
Iftikhar Kullo ◽  
Hugues Sicotte ◽  
Jyotishman Pathak ◽  
...  
Keyword(s):  
Gene Expression ◽  
Venous Thromboembolism ◽  
African Americans ◽  
Differential Expression ◽  
White Women ◽  
Genome Wide Association Study ◽  
Expression Data ◽  
Significant Differential Expression ◽  
Genome Wide ◽  
A Genome

SummaryTo identify novel single nucleotide polymorphisms (SNPs) associated with venous thromboembolism (VTE) in African-Americans (AAs), we performed a genome-wide association study (GWAS) of VTE in AAs using the Electronic Medical Records and Genomics (eMERGE) Network, comprised of seven sites each with DNA biobanks (total ~39,200 unique DNA samples) with genome-wide SNP data (imputed to 1000 Genomes Project cosmopolitan reference panel) and linked to electronic health records (EHRs). Using a validated EHR-driven phenotype extraction algorithm, we identified VTE cases and controls and tested for an association between each SNP and VTE using unconditional logistic regression, adjusted for age, sex, stroke, site-platform combination and sickle cell risk genotype. Among 393 AA VTE cases and 4,941 AA controls, three intragenic SNPs reached genome-wide significance: LEMD3 rs138916004 (OR=3.2; p=1.3E-08), LY86 rs3804476 (OR=1.8; p=2E-08) and LOC100130298 rs142143628 (OR=4.5; p=4.4E-08); all three SNPs validated using internal cross-validation, parametric bootstrap and meta-analysis methods. LEMD3 rs138916004 and LOC100130298 rs142143628 are only present in Africans (1000G data). LEMD3 showed a significant differential expression in both NCBI Gene Expression Omnibus (GEO) and the Mayo Clinic gene expression data, LOC100130298 showed a significant differential expression only in the GEO expression data, and LY86 showed a significant differential expression only in the Mayo expression data. LEMD3 encodes for an antagonist of TGF-β-induced cell proliferation arrest. LY86 encodes for MD-1 which down-regulates the pro-inflammatory response to lipopolysaccharide; LY86 variation was previously associated with VTE in white women; LOC100130298 is a non-coding RNA gene with unknown regulatory activity in gene expression and epigenetics.Supplementary Material to this article is available online at www.thrombosis-online.com.

Identification of candidate tumor related genes using comprehensive gene expression analysis of neuroblastic tumors

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 9051-9051
Author(s):  
J. Mora ◽  
C. Lavarino ◽  
G. Domenech ◽  
J. Rios ◽  
W. Gerald ◽  
...  
Keyword(s):  
Gene Expression ◽  
Differential Expression ◽  
Expression Analysis ◽  
Gene Expression Analysis ◽  
Protein Biosynthesis ◽  
Neuroblastoma Cell ◽  
Genetic Alterations ◽  
Altered Expression ◽  
Stage 4 ◽  
Neuroblastic Tumors

9051 Background: Neuroblastic tumors (NBTs) represent a heterogeneous and relatively well defined spectrum of neoplastic diseases. We performed gene expression analysis to molecularly characterize the distinct clinicobiological subtypes of NBTs. Methods: Gene expression analysis of 106 NBTs (10 ganglioneuromas, 10 stage 4s, 29 loco-regional (stages 1, 2, 3), and 57 stage 4) and 12 neuroblastoma cell lines was performed using Affymetrix Genechip Human Genome U95 Set Arrays. Differential expression between predefined groups of biological and clinical relevance was determined by differences >3 standard deviations between the means for groups, step-down permutation and false discovery rate methods. Results: Gene expression analysis of clinically defined groups including stage 4 infants versus children, metastatic versus non metastatic, and stroma poor loco-regional versus stage 4, revealed that many differentially expressed genes mapped to chromosomal regions with well described recurrent abnormalities in NBTs (chromosomes 1, 11, 17, 19 and X). Pairwise comparison analysis of biologically defined groups, including triploid versus diploid/tetraploid NBTs, identified significantly discriminating genes that map to the same chromosomal regions. Gene expression analysis of MYCN-amplified versus MYCN non amplified NBTs, confirmed a functional overrepresentation for genes involved in protein biosynthesis. Conclusions: Gene expression profile analysis of clinically and biologically relevant subgroups of NBTs revealed differential expression of genes at specific chromosomal regions known to have strong association between genetic alterations and NBT clinical features. The identification of altered expression helps to define critical chromosomal regions and identify tumor related candidate genes within each region. No significant financial relationships to disclose.

scholarly journals hnRNP U is differentially expressed in whole blood from patients with sepsis.

2020 ◽  
Author(s):  
Shahan Mamoor
Keyword(s):  
Gene Expression ◽  
Differential Expression ◽  
Whole Blood ◽  
Differentially Expressed ◽  
Significant Differential Expression ◽  
Hnrnp U ◽  
Significant Gene ◽  
Nuclear Ribonucleoprotein ◽  
Microarray Datasets

We probed published and public microarray datasets (1, 2) to discover the most significant gene expression changes in the blood of patients with sepsis. We identified significant differential expression of the heterogenous nuclear ribonucleoprotein hnRNP U in whole blood from patients with sepsis.

Curcumin Reverts the Protein Differential Expression in the Liver of the Diabetic Obese db/db mice

2021 ◽  
Vol 18 ◽  
Author(s):  
Oscar Gerardo Silva-Gaona ◽  
Juan Manuel Guzmán-Flores ◽  
Magdalena Hernández-Ortiz ◽  
Katya Vargas-Ortiz ◽  
Joel Ramírez-Emiliano ◽  
...  
Keyword(s):  
Gene Expression ◽  
Protein Expression ◽  
Differential Expression ◽  
Protein Profile ◽  
Enrichment Analysis ◽  
2D Electrophoresis ◽  
Standard Diet ◽  
Liver Protein ◽  
Diabetic Mice ◽  
Altered Expression

Background: In type 2 diabetic mouse liver, hyperglycemia, and insulin modify gene expression. Curcumin is a powerful antioxidant and antidiabetic agent that regulates the gene expression of different signaling pathways through various transcription factors. Therefore, we hypothesized that curcumin modifies the protein expression profile in the liver of diabetic db/db mice. Objective: To determine the effects of curcumin on the liver protein profile of diabetic db/db mice. Methods: db/db and wild type (WT) male mice were allocated in four groups, and they were fed for eight weeks. Three WT and three diabetic db/db mice received a standard diet (SD; WT and db/db groups, respectively); three WT and three diabetic db/db mice received a SD supplemented with 0.75 % (w/w) curcumin (WT+C and db/db+C groups, respectively). Liver proteins were separated by 2D electrophoresis. Differential protein expression analysis was performed on ImageMaster 2D Platinum software, and selected proteins were identified by MALDI-TOF-MS and subjected to enrichment analysis using STRING and DAVID databases. Results: Thirty-six proteins with differential expression due to the diabetic background and curcumin treatment were found; these proteins participate in the metabolism of amino acids, carbohydrates, and lipids. Interestingly, the altered expression of seven proteins was prevented in the liver of the diabetic mice that received curcumin. Conclusions: Among all differentially expressed proteins, curcumin reverted the altered expression of seven proteins. Thus, although it was observed that curcumin did not affect the biochemical parameters, it does modify the expression of some liver proteins in diabetic mice.

scholarly journals Accurate and simultaneous identification of differential expression and splicing using hierarchical Bayesian analysis

2019 ◽  
Author(s):  
Guy Karlebach ◽  
Peter Hansen ◽  
Diogo F.T. Veiga ◽  
Robin Steinhaus ◽  
Daniel Danis ◽  
...  
Keyword(s):  
Gene Expression ◽  
Alternative Splicing ◽  
Bayesian Analysis ◽  
Differential Expression ◽  
Protein Complexes ◽  
Tissue Expression ◽  
Hierarchical Bayesian ◽  
Mrna Isoforms ◽  
Significant Differential Expression ◽  
Hierarchical Bayesian Analysis

AbstractThe regulation of mRNA controls both overall gene expression as well as the distribution of mRNA isoforms encoded by the gene. Current algorithmic approaches focus on characterization of significant differential expression or alternative splicing events or isoform distribution without integrating both events. Here, we present Hierarchical Bayesian Analysis of Differential Expression and ALternative SPlicing (HBA-DEALS), which simultaneously characterizes differential expression and splicing in cohorts. HBA-DEALS attains state of the art or better performance for both expression and splicing, and allows genes to be characterized as having differential gene expression (DGE), differential alternative splicing (DAST), both, or neither. Based on an analysis of Genotype-Tissue Expression (GTEx) data we demonstrate the existence of sets of genes that show predominant DGE or DAST across a comparison of 20 tissue types, and show that these sets have pervasive differences with respect to gene structure, function, membership in protein complexes, and promoter architecture.

scholarly journals Genetic dysregulation of gene expression and splicing during a ten-year period of human aging

2019 ◽  
Author(s):  
Brunilda Balliu ◽  
Matthew Durrant ◽  
Olivia de Goede ◽  
Nathan Abell ◽  
Xin Li ◽  
...  
Keyword(s):  
Gene Expression ◽  
Alternative Splicing ◽  
Expression Profiles ◽  
Genetic Regulation ◽  
Older Age ◽  
Small Subset ◽  
Genetic Associations ◽  
Cross Sectional ◽  
Age Related ◽  
Alternatively Spliced

SummaryMolecular and cellular changes are intrinsic to aging and age-related diseases. Prior cross-sectional studies have investigated the combined effects of age and genetics on gene expression and alternative splicing; however, there has been no long-term, longitudinal characterization of these molecular changes, especially in older age. We performed RNA sequencing in whole-blood from the same individuals from the PIVUS study at ages 70 and 80 to quantify how gene expression, alternative splicing, and their genetic regulation are altered during this 10-year period of advanced aging. We observe that individuals are more similar to their own expression profiles later in life than profiles of other individuals their own age; 93% of samples cluster with their own measurement at another age, and there is a strong correlation of genetic effects on expression between the two ages (median ρG = 0.96). Despite this, we identify 1,291 and 294 genes differentially expressed and alternatively spliced with age, as well as 529 genes with outlying individual trajectories of aging. Further, 7.8% and 9.6% of tested genes show a reduction in genetic associations with expression and alternative splicing in older age, with impacted genes enriched in DNA repair pathways. Together these findings indicate that, although gene expression and alternative splicing and their genetic regulation are mostly stable late in life, a small subset of genes is dynamic and is characterized by changes in expression and splicing and a reduction in genetic regulation.

scholarly journals Parallel Genome-Wide Expression Profiling of Host and Pathogen During Soybean Cyst Nematode Infection of Soybean

2007 ◽  
Vol 20 (3) ◽  
pp. 293-305 ◽  
Author(s):  
Nagabhushana Ithal ◽  
Justin Recknor ◽  
Dan Nettleton ◽  
Leonard Hearne ◽  
Tom Maier ◽  
...  
Keyword(s):  
Gene Expression ◽  
Differential Expression ◽  
Soybean Cyst Nematode ◽  
Defense Responses ◽  
Cyst Nematode ◽  
Nematode Infection ◽  
Primary Metabolism ◽  
Compatible Interaction ◽  
Significant Differential Expression ◽  
Genome Wide

Global analysis of gene expression changes in soybean (Glycine max) and Heterodera glycines (soybean cyst nematode [SCN]) during the course of infection in a compatible interaction was performed using the Affymetrix GeneChip soybean genome array. Among 35,611 soybean transcripts monitored, we identified 429 genes that showed statistically significant differential expression between uninfected and nematode-infected root tissues. These included genes encoding enzymes involved in primary metabolism; biosynthesis of phenolic compounds, lignin, and flavonoids; genes related to stress and defense responses; cell wall modification; cellular signaling; and transcriptional regulation. Among 7,431 SCN transcripts monitored, 1,850 genes showed statistically significant differential expression across different stages of nematode parasitism and development. Differentially expressed SCN genes were grouped into nine different clusters based on their expression profiles during parasitism of soybean roots. The patterns of gene expression we observed in SCN suggest coordinated regulation of genes involved in parasitism. Quantitative real-time reverse-transcription polymerase chain reaction confirmed the results of our microarray analysis. The simultaneous genome-wide analysis of gene expression changes in the host and pathogen during a compatible interaction provides new insights into soybean responses to nematode infection and the first profile of transcript abundance changes occurring in the nematode as it infects and establishes a permanent feeding site within a host plant root.

Differential regulation of gene expression by ovariectomy in mouse aorta

2003 ◽  
Vol 12 (3) ◽  
pp. 175-185 ◽  
Author(s):  
Amparo C. Villablanca ◽  
Kristine A. Lewis ◽  
Doris Tham ◽  
John C. Rutledge
Keyword(s):  
Gene Expression ◽  
Real Time ◽  
Differential Expression ◽  
Hormonal Regulation ◽  
Regulation Of Gene Expression ◽  
Elongation Factor ◽  
Nadh:Ubiquinone Oxidoreductase ◽  
Rt Pcr ◽  
Mitochondrial Energy Metabolism ◽  
Altered Expression

The purpose of this study was to investigate the effects of ovarian hormones on gene expression in the vascular wall. Our approach employed an RT-PCR-based cloning strategy of DNA differential display analysis and verification/confirmation of differential expression by semi-quantitative PCR and real-time PCR. mRNA analysis of normal aortas from intact and ovariectomized female C57BL/6J mice, showed altered expression of 20 genes with significant (>70%) sequence homology to known genes. Eight were selected for further study based on the genes’ known function and potential relevance to vascular physiology. Differential expression of mRNA for three genes was confirmed by both semi-quantitative and real-time RT-PCR using gene-specific primers. Ovariectomy downregulated expression of elongation factor-1α (3.5-fold), ganglioside-induced differentiation associated protein (8.2-fold), and NADH:ubiquinone oxidoreductase (3.8-fold). Thus, in normal mouse aortas, ovariectomy resulted in significant differential downregulation of a number of vascular genes important to vascular cell growth and angiogenesis, cellular differentiation, and mitochondrial energy metabolism, respectively. These studies have implications for our understanding of hormonal regulation of vascular gene expression and the therapeutic targeting of specific vascular genetic sequences by female sex steroid hormones.

scholarly journals Trypanosoma cruzi Modulates PIWI-Interacting RNA Expression in Primary Human Cardiac Myocytes during the Early Phase of Infection

2020 ◽  
Vol 21 (24) ◽  
pp. 9439
Author(s):  
Kayla J. Rayford ◽  
Ayorinde Cooley ◽  
Ashutosh Arun ◽  
Girish Rachakonda ◽  
Yulia Kleschenko ◽  
...  
Keyword(s):  
Gene Expression ◽  
Trypanosoma Cruzi ◽  
Differential Expression ◽  
Early Phase ◽  
Regulation Of Gene Expression ◽  
Disease Model ◽  
In Silico Analysis ◽  
Differentially Expressed ◽  
Significant Differential Expression ◽  
Human Cardiomyocytes

Trypanosoma cruzi dysregulates the gene expression profile of primary human cardiomyocytes (PHCM) during the early phase of infection through a mechanism which remains to be elucidated. The role that small non-coding RNAs (sncRNA) including PIWI-interacting RNA (piRNA) play in regulating gene expression during the early phase of infection is unknown. To understand how T. cruzi dysregulate gene expression in the heart, we challenged PHCM with T. cruzi trypomastigotes and analyzed sncRNA, especially piRNA, by RNA-sequencing. The parasite induced significant differential expression of host piRNAs, which can target and regulate the genes which are important during the early infection phase. An average of 21,595,866 (88.40%) of clean reads mapped to the human reference genome. The parasite induced 217 unique piRNAs that were significantly differentially expressed (q ≥ 0.8). Of these differentially expressed piRNAs, 6 were known and 211 were novel piRNAs. In silico analysis showed that some of the dysregulated known and novel piRNAs could target and potentially regulate the expression of genes including NFATC2, FOS and TGF-β1, reported to play important roles during T. cruzi infection. Further evaluation of the specific functions of the piRNAs in the regulation of gene expression during the early phase of infection will enhance our understanding of the molecular mechanism of T. cruzi pathogenesis. Our novel findings constitute the first report that T. cruzi can induce differential expression of piRNAs in PHCM, advancing our knowledge about the involvement of piRNAs in an infectious disease model, which can be exploited for biomarker and therapeutic development.

Identification of CSF Biomarkers for the Diagnosis of CNS Lymphoma.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2036-2036
Author(s):  
James L. Rubenstein ◽  
Cigall Kadoch ◽  
Jon Karch ◽  
Andrew Josephson ◽  
Samar Issa ◽  
...  
Keyword(s):  
Gene Expression ◽  
Differential Expression ◽  
Biomarker Discovery ◽  
Residual Disease ◽  
Characteristic Curve ◽  
Primary Cns Lymphoma ◽  
Cns Lymphoma ◽  
Csf Biomarkers ◽  
Prognostic Information ◽  
Significant Differential Expression

Abstract CNS lymphoma is an aggressive form of non-Hodgkin’s lymphoma. The current means for establishing its diagnosis are: brain biopsy, associated with risk of brain hemorrhage; cytological analysis of the cerebrospinal fluid (CSF), which is insensitive in over 50% of cases. The identification of novel, sensitive and specific biomarkers are required to facilitate early, non-invasive diagnosis of lymphomatous involvement of the CNS. Moreover, elevation of CSF protein is an established adverse prognostic variable in patients with primary CNS lymphoma; however specific peptide markers which relate to prognosis have not previously been identified within the CSF. We are testing the hypothesis that peptide biomarkers for CNS lymphoma are present in the CSF and that these may facilitate noninvasive, early diagnosis, provide prognostic information and enhance clinical monitoring in the setting of minimal residual disease. We describe a two-dimensional liquid chromatographymass spectrometry-based sensitive method for differential quantification and identification of several hundred CSF proteins. Proprietary spectral interpretation and intensity-normalization software was used to quantify differential expression of proteins between controls and lymphoma patients in CSF. An application of this approach to biomarker discovery in CSF is presented. We performed two sets of analyses using independent CSF specimens. In the experimental set we compared the pattern of expression in 9 control vs 9 cases of CNS lymphoma. 130 peptides were differentially expressed between the two groups (p<0.001). In a second, validation set of cases consisting of 7 controls and 7 cases of CNS lymphoma, we observed 131 peptides which exhibited significant differential expression between the two groups (p<0.001). At least 28 candidate biomarker proteins were found to exhibit differential expression in both experimental and validation sets of cases. Unsupervised clustering of the relative expression of these candidate biomarkers identifies peptides which correlate with adverse prognosis (p<0.003). In addition, we have validated the differential expression of four candidate biomarkers by immunoblot analysis of CSF. Quantitative measurement of two such novel CNS lymphoma peptide biomarkers has also been determined by ELISA methods. One of these biomarkers, a serine protease inhibitor, termed L1, was shown to be expressed within CNS lymphoma tumors by microarray as well as by quantitative RT-PCR. Immunohistochemistry localizes L1 expression to tumor cells and tumor vasculature. In addition, both gene expression analyses and ELISA reveal that high L1 concentrations in CSF correlate with significantly worse prognosis. Receiver operator characteristic curve analysis of L1 suggests that this marker may distinguish CNS lymphoma from a variety of non-malignant neurologic conditions with promising sensitivity and specificity. A second novel biomarker which we have identified and validated by immunoblot and by ELISA is a lymphoid chemokine, also found to be expressed in CNS lymphomas by gene expression analysis. Elevated concentrations of this chemokine in the CSF were also shown to be associated with adverse outcome in CNS lymphoma patients.

Sign in / Sign up

Export Citation Format

Share Document