RT Journal Article
SR Electronic
T1 Post-mortem molecular profiling of three psychiatric disorders
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 061416
DO 10.1101/061416
A1 Ryne C. Ramaker
A1 Kevin M. Bowling
A1 Brittany N. Lasseigne
A1 Megan H. Hagenauer
A1 Andrew A. Hardigan
A1 Nick S. Davis
A1 Jason Gertz
A1 Preston M. Cartagena
A1 David M. Walsh
A1 Marquis P. Vawter
A1 Edward G. Jones
A1 Alan F. Schatzberg
A1 Jack D. Barchas
A1 Stan J. Watson
A1 Blynn G. Bunney
A1 Huda Akil
A1 William E. Bunney
A1 Jun Z. Li
A1 Sara J. Cooper
A1 Richard M. Myers
YR 2017
UL http://biorxiv.org/content/early/2017/06/02/061416.abstract
AB 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. 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, and validated the results in an independent cohort. The most significant disease 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 SZ and BPD patients relative to controls. We also assessed the biochemical consequences of gene expression changes with untargeted metabolomic profiling and 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.RNA-seqRNA sequencingGABAgamma-Aminobutyric acidGWASgenome-wide association studySZschizophreniaBPDbipolar disorderMDDmajor depression disorderCTLcontrolAnCganterior cingulate gyrusDLPFCdorsolateral prefrontal cortexnAccnucleus accumbensGOgene ontologyChIP-seqchromatin immunoprecipitation with DNA sequencingPCAprincipal component analysis