Post-mortem molecular profiling of three psychiatric disorders
Abstract Background Psychiatric disorders are multigenic diseases with complex etiology that contribute significantly to human morbidity and mortality. Although clinically distinct, several disorders share many symptoms, suggesting common underlying molecular changes exist that may implicate importa...
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doaj-29db10a441b94b67924cb7c4510ec9e22020-11-25T00:27:51ZengBMCGenome Medicine1756-994X2017-07-019111210.1186/s13073-017-0458-5Post-mortem molecular profiling of three psychiatric disordersRyne C. Ramaker0Kevin M. Bowling1Brittany N. Lasseigne2Megan H. Hagenauer3Andrew A. Hardigan4Nicholas S. Davis5Jason Gertz6Preston M. Cartagena7David M. Walsh8Marquis P. Vawter9Edward G. JonesAlan F. Schatzberg10Jack D. Barchas11Stanley J. Watson12Blynn G. Bunney13Huda Akil14William E. Bunney15Jun Z. Li16Sara J. Cooper17Richard M. Myers18HudsonAlpha Institute for BiotechnologyHudsonAlpha Institute for BiotechnologyHudsonAlpha Institute for BiotechnologyMental Health Research Institute, University of MichiganHudsonAlpha Institute for BiotechnologyHudsonAlpha Institute for BiotechnologyHudsonAlpha Institute for BiotechnologyDepartment of Psychiatry and Human Behavior, College of Medicine, University of CaliforniaDepartment of Psychiatry and Human Behavior, College of Medicine, University of CaliforniaDepartment of Psychiatry and Human Behavior, College of Medicine, University of CaliforniaDepartment of Psychiatry, Stanford University School of MedicinePsychiatry, Weill Cornell Medical CollegeMental Health Research Institute, University of MichiganDepartment of Psychiatry and Human Behavior, College of Medicine, University of CaliforniaMental Health Research Institute, University of MichiganDepartment of Psychiatry and Human Behavior, College of Medicine, University of CaliforniaDepartment of Human Genetics, University of MichiganHudsonAlpha Institute for BiotechnologyHudsonAlpha Institute for BiotechnologyAbstract Background Psychiatric disorders are multigenic diseases with complex etiology that contribute significantly to human morbidity and mortality. Although clinically distinct, several disorders share many symptoms, suggesting common underlying molecular changes exist that may implicate important regulators of pathogenesis and provide new therapeutic targets. Methods We performed RNA sequencing on tissue from the anterior cingulate cortex, dorsolateral prefrontal cortex, and nucleus accumbens from three groups of 24 patients each diagnosed with schizophrenia, bipolar disorder, or major depressive disorder, and from 24 control subjects. We identified differentially expressed genes and validated the results in an independent cohort. Anterior cingulate cortex samples were also subjected to metabolomic analysis. ChIP-seq data were used to characterize binding of the transcription factor EGR1. Results We compared molecular signatures across the three brain regions and disorders in the transcriptomes of post-mortem human brain samples. The most significant disease-related differences were in the anterior cingulate cortex of schizophrenia samples compared to controls. Transcriptional changes were assessed in an independent cohort, revealing the transcription factor EGR1 as significantly down-regulated in both cohorts and as a potential regulator of broader transcription changes observed in schizophrenia patients. Additionally, broad down-regulation of genes specific to neurons and concordant up-regulation of genes specific to astrocytes was observed in schizophrenia and bipolar disorder patients relative to controls. Metabolomic profiling identified disruption of GABA levels in schizophrenia patients. Conclusions We provide a comprehensive post-mortem transcriptome profile of three psychiatric disorders across three brain regions. We highlight a high-confidence set of independently validated genes differentially expressed between schizophrenia and control patients in the anterior cingulate cortex and integrate transcriptional changes with untargeted metabolite profiling.http://link.springer.com/article/10.1186/s13073-017-0458-5SchizophreniaBipolar disorderMajor depressive disorderRNA sequencingMetabolomicsEGR1 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Ryne C. Ramaker Kevin M. Bowling Brittany N. Lasseigne Megan H. Hagenauer Andrew A. Hardigan Nicholas S. Davis Jason Gertz Preston M. Cartagena David M. Walsh Marquis P. Vawter Edward G. Jones Alan F. Schatzberg Jack D. Barchas Stanley J. Watson Blynn G. Bunney Huda Akil William E. Bunney Jun Z. Li Sara J. Cooper Richard M. Myers |
spellingShingle |
Ryne C. Ramaker Kevin M. Bowling Brittany N. Lasseigne Megan H. Hagenauer Andrew A. Hardigan Nicholas S. Davis Jason Gertz Preston M. Cartagena David M. Walsh Marquis P. Vawter Edward G. Jones Alan F. Schatzberg Jack D. Barchas Stanley J. Watson Blynn G. Bunney Huda Akil William E. Bunney Jun Z. Li Sara J. Cooper Richard M. Myers Post-mortem molecular profiling of three psychiatric disorders Genome Medicine Schizophrenia Bipolar disorder Major depressive disorder RNA sequencing Metabolomics EGR1 |
author_facet |
Ryne C. Ramaker Kevin M. Bowling Brittany N. Lasseigne Megan H. Hagenauer Andrew A. Hardigan Nicholas S. Davis Jason Gertz Preston M. Cartagena David M. Walsh Marquis P. Vawter Edward G. Jones Alan F. Schatzberg Jack D. Barchas Stanley J. Watson Blynn G. Bunney Huda Akil William E. Bunney Jun Z. Li Sara J. Cooper Richard M. Myers |
author_sort |
Ryne C. Ramaker |
title |
Post-mortem molecular profiling of three psychiatric disorders |
title_short |
Post-mortem molecular profiling of three psychiatric disorders |
title_full |
Post-mortem molecular profiling of three psychiatric disorders |
title_fullStr |
Post-mortem molecular profiling of three psychiatric disorders |
title_full_unstemmed |
Post-mortem molecular profiling of three psychiatric disorders |
title_sort |
post-mortem molecular profiling of three psychiatric disorders |
publisher |
BMC |
series |
Genome Medicine |
issn |
1756-994X |
publishDate |
2017-07-01 |
description |
Abstract Background Psychiatric disorders are multigenic diseases with complex etiology that contribute significantly to human morbidity and mortality. Although clinically distinct, several disorders share many symptoms, suggesting common underlying molecular changes exist that may implicate important regulators of pathogenesis and provide new therapeutic targets. Methods We performed RNA sequencing on tissue from the anterior cingulate cortex, dorsolateral prefrontal cortex, and nucleus accumbens from three groups of 24 patients each diagnosed with schizophrenia, bipolar disorder, or major depressive disorder, and from 24 control subjects. We identified differentially expressed genes and validated the results in an independent cohort. Anterior cingulate cortex samples were also subjected to metabolomic analysis. ChIP-seq data were used to characterize binding of the transcription factor EGR1. Results We compared molecular signatures across the three brain regions and disorders in the transcriptomes of post-mortem human brain samples. The most significant disease-related differences were in the anterior cingulate cortex of schizophrenia samples compared to controls. Transcriptional changes were assessed in an independent cohort, revealing the transcription factor EGR1 as significantly down-regulated in both cohorts and as a potential regulator of broader transcription changes observed in schizophrenia patients. Additionally, broad down-regulation of genes specific to neurons and concordant up-regulation of genes specific to astrocytes was observed in schizophrenia and bipolar disorder patients relative to controls. Metabolomic profiling identified disruption of GABA levels in schizophrenia patients. Conclusions We provide a comprehensive post-mortem transcriptome profile of three psychiatric disorders across three brain regions. We highlight a high-confidence set of independently validated genes differentially expressed between schizophrenia and control patients in the anterior cingulate cortex and integrate transcriptional changes with untargeted metabolite profiling. |
topic |
Schizophrenia Bipolar disorder Major depressive disorder RNA sequencing Metabolomics EGR1 |
url |
http://link.springer.com/article/10.1186/s13073-017-0458-5 |
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