MICROARRAY ANALYSIS OF THE STANLEY
BRAIN COLLECTION
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.