title: Transcriptome sequencing revealed significant alteration of cortical promoter usage and splicing in schizophrenia.
abstract: BACKGROUND
  While hybridization based analysis of the cortical transcriptome has provided important insight into the neuropathology of schizophrenia, it represents a restricted view of disease-associated gene activity based on predetermined probes. By contrast, sequencing technology can provide un-biased analysis of transcription at nucleotide resolution. Here we use this approach to investigate schizophrenia-associated cortical gene expression.
  
  
  RESULTS
  The data was generated from 76 bp reads of RNA-Seq, aligned to the reference genome and assembled into transcripts for quantification of exons, splice variants and alternative promoters in postmortem superior temporal gyrus (STG/BA22) from 9 male subjects with schizophrenia and 9 matched non-psychiatric controls. Differentially expressed genes were then subjected to further sequence and functional group analysis. The output, amounting to more than 38 Gb of sequence, revealed significant alteration of gene expression including many previously shown to be associated with schizophrenia. Gene ontology enrichment analysis followed by functional map construction identified three functional clusters highly relevant to schizophrenia including neurotransmission related functions, synaptic vesicle trafficking, and neural development. Significantly, more than 2000 genes displayed schizophrenia-associated alternative promoter usage and more than 1000 genes showed differential splicing (FDR<0.05). Both types of transcriptional isoforms were exemplified by reads aligned to the neurodevelopmentally significant doublecortin-like kinase 1 (DCLK1) gene.
  
  
  CONCLUSIONS
  This study provided the first deep and un-biased analysis of schizophrenia-associated transcriptional diversity within the STG, and revealed variants with important implications for the complex pathophysiology of schizophrenia.
authors.affiliation: Schizophrenia Research Institute, Sydney, Australia.
authors.forename: Jing Qin
authors.initials: JQ
authors.lastname: Wu
authors.forename: Xi
authors.initials: X
authors.lastname: Wang
authors.forename: Natalie J
authors.initials: NJ
authors.lastname: Beveridge
authors.forename: Paul A
authors.initials: PA
authors.lastname: Tooney
authors.forename: Rodney J
authors.initials: RJ
authors.lastname: Scott
authors.forename: Vaughan J
authors.initials: VJ
authors.lastname: Carr
authors.forename: Murray J
authors.initials: MJ
authors.lastname: Cairns
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D017398:Alternative Splicing / Q000235:genetics*; D001483:Base Sequence; D016022:Case-Control Studies; D002540:Cerebral Cortex / Q000378:metabolism* / Q000473:pathology; D000089742:Doublecortin-Like Kinases; D020869:Gene Expression Profiling; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D008297:Male; D008875:Middle Aged; D011401:Promoter Regions, Genetic / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D059368:RNA Isoforms / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D015203:Reproducibility of Results; D012559:Schizophrenia / Q000235:genetics*; D017423:Sequence Analysis, RNA; D013569:Synapses / Q000235:genetics; D055815:Young Adult
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D059368:RNA Isoforms; D012333:RNA, Messenger; C117347:DCLK1 protein, human; D000089742:Doublecortin-Like Kinases; D017346:Protein Serine-Threonine Kinases