Comparative gene expression analysis of blood and brain provides concurrent validation of SELENBP1 up-regulation in schizophrenia

Laval University, Quebec City, Quebec, Canada
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 11/2005; 102(43):15533-8. DOI: 10.1073/pnas.0507666102
Source: PubMed


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.

Download full-text


Available from: Jacques Corbeil, Oct 05, 2015
25 Reads
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Despite the widespread use of antipsychotics, little is known of the molecular bases behind the action of antipsychotic drugs. A genome-wide study is needed to characterize the genes that affect the clinical response and the adverse effects. Here we show the analysis of the blood transcriptome of 22 schizophrenia patients before and after medication with atypical antipsychotics by next generation sequencing. We found that 17 genes, among the 21495 genes analyzed, have significantly altered expression after medication (P value adjusted <0.05). Six genes (ADAMTS2, CD177, CNTNAP3, ENTPD2, RFX2 and UNC45B) out of the 17 are among the 200 genes that we characterized with differential expression in a previous study between antipsychotic naïve schizophrenia patients and controls(Sainz et al., 2013). This number of schizophrenia altered expression genes is significantly higher than expected by chance (Chi-test, Padj. 1.19E-50), suggesting that at least part of the antipsychotic beneficial effects is exerted modulating the expression of these genes. Interestingly, all these six genes are over expressed in patients and are reverted to control levels of expression after treatment. We also find a significant enrichment of genes related to obesity and diabetes, known adverse affects of antipsychotics. These results may facilitate to understand unknown molecular mechanisms behind schizophrenia symptoms and the molecular mechanisms of antipsychotic drugs. © The Author 2014. Published by Oxford University Press on behalf of CINP.
    The International Journal of Neuropsychopharmacology 10/2014; 18(4). DOI:10.1093/ijnp/pyu066 · 4.01 Impact Factor
  • Source
    • "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.
    BMB reports 05/2014; 47(7). DOI:10.5483/BMBRep.2014.47.7.104 · 2.60 Impact Factor
  • Source
    • "us, we sought to correlate blood-based gene expression of the Wnt/í µí»½í µí»½-catenin signaling pathway with negative and positive symptom severity indices of patients with a history of psychosis (i.e., schizophrenia or bipolar disorder). We were guided by previous research that has examined the relationship between psychosis symptom severity and other gene expression pathways in peripheral blood [3] [4] and has demonstrated the utility of blood as a source of biomarkers for brain disorders [5] "
    [Show abstract] [Hide abstract]
    ABSTRACT: Genes in the Wnt (wingless)/ β -catenin signaling pathway have been implicated in schizophrenia pathogenesis. No study has examined this pathway in the broader context of psychosis symptom severity. We investigated the association between symptom severity scores and expression of 25 Wnt pathway genes in blood from 19 psychotic patients. Significant correlations between negative symptom scores and deshivelled 2 (DVL2) (r adj = -0.70; P = 0.0008) and glycogen synthase kinase 3 beta (GSK3B) (r adj = 0.48; P = 0.039) were observed. No gene expression levels were associated with positive symptoms. Our findings suggest that the Wnt signaling pathway may harbor biomarkers for severity of negative but not positive symptoms.
    11/2013; 2013(3):852930. DOI:10.1155/2013/852930
Show more