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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 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.

SUBMITTER: Ramaker RC

PROVIDER: S-EPMC5534072 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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Post-mortem molecular profiling of three psychiatric disorders.

Ramaker Ryne C RC Bowling Kevin M KM Lasseigne Brittany N BN Hagenauer Megan H MH Hardigan Andrew A AA Davis Nicholas S NS Gertz Jason J Cartagena Preston M PM Walsh David M DM Vawter Marquis P MP Jones Edward G EG Schatzberg Alan F AF Barchas Jack D JD Watson Stanley J SJ Bunney Blynn G BG Akil Huda H Bunney William E WE Li Jun Z JZ Cooper Sara J SJ Myers Richard M RM

Genome medicine 20170728 1

<h4>Background</h4>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.<h4>Methods</h4>We performed RNA sequencing on tissue from the anterior cingulate cortex, dorsolateral prefrontal cortex, and nucleus a ...[more]

PMID: 28754123

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Project description:BackgroundSkin-restricted lupus is a chronic inflammatory disease associated with high rates of depression and anxiety disorders. Patients without psychiatric disorders can experience anxiety and depressive symptoms at a subclinical level, which could be risk factors for progression towards psychiatric disorders. It was decided, therefore, to investigate the presence of specific symptoms in skin-restricted lupus patients without axis I psychiatric disorders and their impact on the occurrence of axis I psychiatric disorders during the study follow-up.MethodsLongitudinal data of 38 patients and 76 matched controls without active axis I psychiatric disorders from the LuPsy cohort were used. Depressive, neurovegetative, psychic and somatic anxiety symptom scores were established from the Montgomery-Asberg Depression Rating Scale (MADRS) and the Hamilton Anxiety Rating scale (HAMA).ResultsNone of the participants had any current active axis I psychiatric disorders but the patients had personality disorders more frequently and had received more past psychotropic treatments than the controls. They also had higher MADRS and HAMA scores than the controls, in particular neurovegetative, psychic anxiety and somatic symptoms scores. No dermatological factor tested was associated with these scores, whereas being a lupus patient was associated with higher neurovegetative and somatic symptoms scores, having a current personality disorder with higher depressive and neurovegetative scores and receiving more past psychotropic treatments with psychic anxiety and somatic symptoms scores. The occurrence of psychiatric disorders during the study follow-up was associated with an elevated psychic anxiety score at baseline and past psychotropic treatment but not with history of psychiatric disorder.LimitationsThe LuPsy cohort included a large number of patients with axis I psychiatric disorders, the sample without axis I psychiatric disorders is therefore limited.ConclusionsWe observed numerous psychiatric symptoms among the skin-restricted lupus patients. They should therefore receive special attention in the management of their subclinical symptoms before they progress towards full psychiatric disorders.

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Post-mortem molecular profiling of three psychiatric disorders.

Publications

Post-mortem molecular profiling of three psychiatric disorders.

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