Transcriptomic analysis of postmortem brain identifies dysregulated splicing events in novel candidate genes for schizophrenia.
The diverse spatial and temporal expression of alternatively spliced transcript isoforms shapes neurodevelopment and plays a major role in neuronal adaptability. Although alternative splicing is extremely common in the brain, its role in mental illnesses such as schizophrenia has received little attention. To examine this relationship, postmortem brain tissue was obtained from 20 individuals with schizophrenia (SZ) and 20 neuropsychiatrically normal comparison subjects. Gray matter samples were extracted from two brain regions implicated in the disorder: Brodmann Area 10 and caudate. Affymetrix Human Gene 1.0 ST arrays were used on four subjects per group to attain an initial profile of differential expression of transcribed elements within and across brain regions in SZ. Numerous genes of interest with altered mRNA transcripts were identified by microarray through the differential expression of particular exons and 3' untranslated regions (UTRs) between diagnostic groups. Select microarray results--including dysregulation of ENAH exon 11a and CPNE3 3'UTR--were verified by qRTPCR and replicated in the remaining independent sample of 16 SZ patients and 16 normal comparison subjects. These results, if further replicated, clearly illustrate the importance of Identifying transcriptomic variants in expression studies, and implicate novel candidate genes in the disorder.
Psychiatric Genetic Epidemiology & Neurobiology Laboratory (PsychGENe Lab), USA.
Ori S
OS
Cohen
Sarah Y
SY
Mccoy
Frank A
FA
Middleton
Sean
S
Bialosuknia
Yanli
Y
Zhang-James
Lu
L
Liu
Ming T
MT
Tsuang
Stephen V
SV
Faraone
Stephen J
SJ
Glatt
D000368:Aged; D000369:Aged, 80 and over; D017398:Alternative Splicing / Q000235:genetics*; D029681:Arabidopsis Proteins / Q000378:metabolism; D001921:Brain / Q000378:metabolism*; D019295:Computational Biology; D005091:Exons / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D019751:Intramolecular Transferases / Q000378:metabolism; D008297:Male; D008840:Microfilament Proteins / Q000235:genetics*; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D010750:Phosphoproteins / Q000235:genetics*; D011180:Postmortem Changes; D012559:Schizophrenia / Q000235:genetics* / Q000473:pathology*; D059467:Transcriptome
D029681:Arabidopsis Proteins; C511939:Enah protein, human; D008840:Microfilament Proteins; D010750:Phosphoproteins; C415882:copine III; D019751:Intramolecular Transferases; C568454:marneral synthase, Arabidopsis