Pamela Sklar, Whitehead Institute

To identify genes involved in

psychiatric disorders, we performed microarray expression profiling using

Affymetrix gene-chips (~12,000 genes) on post-mortem prefrontal cortex (area 46)

and cerebellum samples from 15 each of control, schizophrenia, bipolar disorder,

and depression patients.  We initially investigated all samples from

prefrontal cortex and cerebellum, and were able to distinguish these

morphologically and functionally different regions by their distinct gene

expression profiles.  In particular, we detected high prefrontal cortex

expression of neurogranin and human brain factor-1, and high cerebellum

expression of Zic and NeuroD, consistent with the known regional

expression patterns of these genes, thereby indicating that our methods are

robust.  A minority of samples did not demonstrate region-specific

expression profiles, suggestive of sample or experimental error, thus these

samples were discarded from further analyses.  Investigation of

schizophrenia patient expression profiles identified twelve genes with

significantly decreased expression in prefrontal cortex compared to controls

(95% significance level under random permutation testing).  The most

significantly decreased gene, Feb65/APBBI, is known to interact with the

beta-amyloid precursor protein, and is implicated in transcription and cell

mortility. No genes had significantly increased expression in

schizophrenia prefrontal cortex compared to controls, nor were there any genes

differentially expressed between schizophrenia and control cerebellum.

Investigation of bipolar disorder patient expression profiles identified two

genes with significantly increased expression (99% significance level) in

bipolar prefrontal cortex: human kinesin-like motor protein, involved in vesicle

transport, and ryudocan (syndecan-4), an endothelial heparan sulfate

proteoglycan.  In addition, 15 genes had increased prefrontal cortex

expression at the 95% significance level. No genes had significantly decreased

expression in bipolar prefrontal cortex compared to controls, and no genes were

differentially expressed between bipolar disorder and control cerebellum. 

Analysis of microarray gene expression data of the depression patient samples is

currently in progress.  TaqMan quantitative RT-PCR is being used to confirm

the microarray expression results of selected genes.  Genes with confirmed

differential expression in patient brain samples will be prioritized for

association studies in patient populations, and for functional assays to

identify their roles in brain development and/or function.