Microarray techniques hold great promise for identifying risk factors for schizophrenia (SZ) but have not yet generated widely reproducible results due to methodological differences between studies and the high risk of type I inferential errors. Here we established a protocol for conservative analysis and interpretation of gene expression data from the dorsolateral prefrontal cortex of SZ patients using statistical and bioinformatic methods that limit false positives. We also compared brain gene expression profiles with those from peripheral blood cells of a separate sample of SZ patients to identify disease-associated genes that generalize across tissues and populations and further substantiate the use of gene expression profiling of blood for detecting valid SZ biomarkers. Implementing this systematic approach, we: (i) discovered 177 putative SZ risk genes in brain, 28 of which map to linked chromosomal loci; (ii) delineated six biological processes and 12 molecular functions that may be particularly disrupted in the illness; (iii) identified 123 putative SZ biomarkers in blood, 6 of which (BTG1, GSK3A, HLA-DRB1, HNRPA3, SELENBP1, and SFRS1) had corresponding differential expression in brain; (iv) verified the differential expression of the strongest candidate SZ biomarker (SELENBP1) in blood; and (v) demonstrated neuronal and glial expression of SELENBP1 protein in brain. The continued application of this approach in other brain regions and populations should facilitate the discovery of highly reliable and reproducible candidate risk genes and biomarkers for SZ. The identification of valid peripheral biomarkers for SZ may ultimately facilitate early identification, intervention, and prevention efforts as well.
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"Mouse Genome Oligo Microarray G4122A chips (Agilent Technologies, Palo Alto, CA, USA). The gene expression data were analyzed by the statistical tool corgon as previously described (Glatt et al., 2005; Sasik et al., 2002). "
"However, a viable alternative is the study of mRNA levels in lymphocytes from living individuals , which are free of the variability observed in post-mortem studies (Czermak et al., 2004). It has been reported that the expression level of genes encoding neurotransmitter receptors and other proteins is similar in peripheral blood lymphocytes and in the central nervous system (Glatt et al., 2005). "
"Demethylating agents that can reverse the reduced hSP56 expression, consequently recovering the normal balance of HIF-1α and hSP56, may become interesting candidates for future chemopreventive drug development. Understanding the mechanisms by which hSP56 expression is regulated may become useful to understand the functions of hSP56 in other diseases, since SELENBP1 gene expression has been shown to be upregulated in major psychotic disorders such as schizophrenia (26, 27). "
[Show abstract][Hide abstract] ABSTRACT: In the present study, we demonstrate that ectopic expression of 56-kDa human selenium binding protein-1 (hSP56) in PC-3 cells that do not normally express hSP56 results in a marked inhibition of cell growth in vitro and in vivo. Down-regulation of hSP56 in LNCaP cells that normally express hSP56 results in enhanced anchorage-independent growth. PC-3 cells expressing hSP56 exhibit a significant reduction of hypoxia inducible protein (HIF)-1α protein levels under hypoxic conditions without altering HIF-1α mRNA (HIF1A) levels. Taken together, our findings strongly suggest that hSP56 plays a critical role in prostate cells by mechanisms including negative regulation of HIF-1α, thus identifying hSP56 as a candidate anti-oncogene product.