Included in schizophrenia theme

Post-mortem molecular profiling of three psychiatric disorders reveals widespread dysregulation of cell-type associated transcripts and refined disease-related transcription changes

Created on 29th June 2016

Kevin Bowling; Ryne C. Ramaker; Brittany N. Lasseigne; Megan Hagenauer; Andrew Hardigan; Nick Davis; Jason Gertz; Preston Cartagena; David Walsh; Marquis Vawter; Alan Schatzberg; Jack Barchas; Stan Watson; Blynn Bunney; Huda Akil; William Bunney; Jun Li; Sara Cooper; Richard M. Myers;

Background: Psychiatric disorders are multigenic diseases with complex etiology contributing 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 new therapeutic targets. Results: We compared molecular signatures across brain regions and disorders in the transcriptomes of postmortem human brain samples. RNA sequencing was performed 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 and result were validated in the independent cohort. The most significant disease differences were observed in the anterior cingulate cortex of schizophrenia samples compared to controls and biochemical consequences of gene expression changes were assessed with untargeted metabolomic profiling. We detected significant transcriptional heterogeneity within schizophrenia and bipolar disorder samples and find no evidence this heterogeneity is linked to any known clinical phenotypes or technical variables, however it does appear to be highly correlated with transcripts previously identified as specific to brain cell types. We also present evidence that altered expression of the transcription factor NPAS4 in schizophrenia patients is robust to the effects of cell-type heterogeneity and that NPAS4 regulates the expression of several genes implicated by previous schizophrenia GWAS analyses. Conclusions: We provide a set of high confidence, independently validated genes differentially expressed between schizophrenia and control patients and propose a refined list of putative cell-type independent transcription changes, including NPAS4, which may particularly warrant further investigation.

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