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Genome Med. 2017 Jul 28;9(1):72. doi: 10.1186/s13073-017-0458-5.

Post-mortem molecular profiling of three psychiatric disorders.

Author information

1
HudsonAlpha Institute for Biotechnology, 601 Genome Way, Huntsville, AL, 35806, USA.
2
Department of Genetics, The University of Alabama at Birmingham, Birmingham, AL, USA.
3
Mental Health Research Institute, University of Michigan, Ann Arbor, MI, USA.
4
Present address: Duke University, Durham, NC, USA.
5
Present address: University of Utah School of Medicine, Salt Lake City, UT, USA.
6
Department of Psychiatry and Human Behavior, College of Medicine, University of California, Irvine, CA, USA.
7
Department of Psychiatry, Stanford University School of Medicine, Stanford, CA, USA.
8
Psychiatry, Weill Cornell Medical College, New York, NY, USA.
9
Department of Human Genetics, University of Michigan, Ann Arbor, MI, USA.
10
HudsonAlpha Institute for Biotechnology, 601 Genome Way, Huntsville, AL, 35806, USA. rmyers@hudsonalpha.org.

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.

KEYWORDS:

Bipolar disorder; EGR1; Major depressive disorder; Metabolomics; RNA sequencing; Schizophrenia

PMID:
28754123
PMCID:
PMC5534072
DOI:
10.1186/s13073-017-0458-5
[Indexed for MEDLINE]
Free PMC Article

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