Genomic convergence analysis of schizophrenia: mRNA sequencing reveals altered synaptic vesicular transport in post-mortem cerebellum.
Schizophrenia (SCZ) is a common, disabling mental illness with high heritability but complex, poorly understood genetic etiology. As the first phase of a genomic convergence analysis of SCZ, we generated 16.7 billion nucleotides of short read, shotgun sequences of cDNA from post-mortem cerebellar cortices of 14 patients and six, matched controls. A rigorous analysis pipeline was developed for analysis of digital gene expression studies. Sequences aligned to approximately 33,200 transcripts in each sample, with average coverage of 450 reads per gene. Following adjustments for confounding clinical, sample and experimental sources of variation, 215 genes differed significantly in expression between cases and controls. Golgi apparatus, vesicular transport, membrane association, Zinc binding and regulation of transcription were over-represented among differentially expressed genes. Twenty three genes with altered expression and involvement in presynaptic vesicular transport, Golgi function and GABAergic neurotransmission define a unifying molecular hypothesis for dysfunction in cerebellar cortex in SCZ.
Mudge
Joann
J
National Center for Genome Resources, Santa Fe, NM, USA.
Miller
Neil A
NA
Khrebtukova
Irina
I
Lindquist
Ingrid E
IE
May
Gregory D
GD
Huntley
Jim J
JJ
Luo
Shujun
S
Zhang
Lu
L
van Velkinburgh
Jennifer C
JC
Farmer
Andrew D
AD
Lewis
Sharon
S
Beavis
William D
WD
Schilkey
Faye D
FD
Virk
Selene M
SM
Black
C Forrest
CF
Myers
M Kathy
MK
Mader
Lar C
LC
Langley
Ray J
RJ
Utsey
John P
JP
Kim
Ryan W
RW
Roberts
Rosalinda C
RC
Khalsa
Sat Kirpal
SK
Garcia
Meredith
M
Ambriz-Griffith
Victoria
V
Harlan
Richard
R
Czika
Wendy
W
Martin
Stanton
S
Wolfinger
Russell D
RD
Perrone-Bizzozero
Nora I
NI
Schroth
Gary P
GP
Kingsmore
Stephen F
SF
D000328:Adult; D000368:Aged; D001344:Autopsy; D016022:Case-Control Studies; D002531:Cerebellum / Q000378:metabolism / Q000473:pathology*; D020869:Gene Expression Profiling; D015894:Genome, Human; D006801:Humans; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D012559:Schizophrenia / Q000235:genetics* / Q000473:pathology; D017422:Sequence Analysis, DNA / Q000379:methods*; D013572:Synaptic Vesicles / Q000235:genetics* / Q000378:metabolism
D012333:RNA, Messenger