Suicide candidate genes associated with bipolar disorder and schizophrenia: An exploratory gene expression profiling analysis of post-mortem prefrontal cortex

Department of Psychiatry, Univ, of Texas Southwestern Medical Center, Dallas, Texas 75390-9070, USA. .
BMC Genomics (Impact Factor: 4.04). 02/2007; 8:413. DOI: 10.1186/1471-2164-8-413
Source: PubMed

ABSTRACT Suicide is an important and potentially preventable consequence of serious mental disorders of unknown etiology. Gene expression profiling technology provides an unbiased approach to identifying candidate genes for mental disorders. Microarray studies with post-mortem prefrontal cortex (Brodmann's Area 46/10) tissue require larger sample sizes. This study poses the question: to what extent are differentially expressed genes for suicide a diagnostic specific set of genes (bipolar disorder vs. schizophrenia) vs. a shared common pathway?
In a reanalysis of a large set of Affymetrix Human Genome U133A microarray data, gene expression levels were compared between suicide completers vs. non-suicide groups within a diagnostic group, namely Bipolar disorder (N = 45; 22 suicide completers; 23 non-suicide) or Schizophrenia (N = 45; 10 suicide completers ; 35 non-suicide). Among bipolar samples, 13 genes were found and among schizophrenia samples, 70 genes were found as differentially expressed. Two genes, PLSCR4 (phospholipid scramblase 4) and EMX2 (empty spiracles homolog 2 (Drosophila)) were differentially expressed in suicide groups of both diagnostic groups by microarray analysis. By qRT-PCR, PLSCR4 and EMX2 were significantly down-regulated in the schizophrenia suicide completers, but could not be confirmed in bipolar disorder.
This molecular level analysis suggests that diagnostic specific genes predominate to shared genes in common among suicide vs. non-suicide groups. These differentially expressed, candidate genes are neural correlates of suicide, not necessarily causal. While suicide is a complex endpoint with many pathways, these candidate genes provide entry points for future studies of molecular mechanisms and genetic association studies to test causality.

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    • "among attempters compared to non attempters. This is in line with work which suggest that Wnt/b-catenine signaling pathway may be involved in suicidal behavior, based on reports of alteration in glutamine synthetase activity in suicide brains (Kim et al., 2007; Sequeira et al., 2009; Klempan et al., 2009; Karege et al., 2007). "
    European Neuropsychopharmacology 10/2013; 23:S370-S371. DOI:10.1016/S0924-977X(13)70585-6 · 5.40 Impact Factor
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    • "among attempters compared to non attempters. This is in line with work which suggest that Wnt/b-catenine signaling pathway may be involved in suicidal behavior, based on reports of alteration in glutamine synthetase activity in suicide brains (Kim et al., 2007; Sequeira et al., 2009; Klempan et al., 2009; Karege et al., 2007). "
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    ABSTRACT: Bipolar patients (BP) are at high risk of suicide. Causal factors underlying suicidal behavior are still unclear. However, it has been shown that lithium has antisuicidal properties. Genes involved in its putative mechanism of action such as the phosphoinositol and the Wnt/β-catenine pathways could be considered candidates for suicidal behavior (SB). Our aim was to investigate the association of the IMPA1 and 2, INPP1, GSK3α and β genes with suicidal behavior in BP. 199 BP were recruited. Polymorphisms at the IMPA1 (rs915, rs1058401 and rs2268432) and IMPA2 (rs66938, rs1020294, rs1250171 and rs630110), INPP1 (rs3791809, rs4853694 and 909270), GSK3α (rs3745233) and GSK3β (rs334558, rs1732170 and rs11921360) genes were genotyped. All patients were grouped and compared according to the presence or not of history of SB (defined as the presence of at least one previous suicidal attempt). Single SNP analyses showed that suicide attempters had higher frequencies of AA genotype of the rs669838-IMPA2 and GG genotype of the rs4853694-INPP1gene compared to non-attempters. Results also revealed that T-allele carriers of the rs1732170-GSK3β gene and A-allele carriers of the rs11921360-GSK3β gene had a higher risk for attempting suicide. Haplotype analysis showed that attempters had lower frequencies of A:A haplotype (rs4853694:rs909270) at the INPP1 gene. Higher frequencies of the C:A haplotype and lower frequencies of the A:C haplotype at the GSK-3β gene (rs1732170:rs11921360) were also found to be associated to SB in BP. Therefore, our results suggest that genetic variability at IMPA2, INPP1 and GSK3β genes is associated with the emergence of SB in BP.
    European neuropsychopharmacology: the journal of the European College of Neuropsychopharmacology 02/2013; 23(11). DOI:10.1016/j.euroneuro.2013.01.007 · 5.40 Impact Factor
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    • "The schizophrenia subjects selected for RT-qPCR contained a large proportion that committed suicide (16/20) whereas the healthy controls expired due to natural or accidental causes. Since suicide as a cause of death appears to modulate gene expression (Kim et al., 2007; Sequeira et al., 2012), RT-qPCR analysis was carried out in a further control group, which consisted of nonschizophrenic subjects containing a similar proportion of suicide completers (Supplementary Table 5). The downregulation of EGR1 and SST in the schizophrenia group can be clearly attributed to schizophrenia since these genes were inversely upregulated in the non-schizophrenia suicide-completer group (Fig. 2A). "
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    ABSTRACT: Small cohort sizes and modest levels of gene expression changes in brain tissue have plagued the statistical approaches employed in microarray studies investigating the mechanism of schizophrenia. To combat these problems a combined analysis of six prior microarray studies was performed to facilitate the robust statistical analysis of gene expression data from the dorsolateral prefrontal cortex of 107 patients with schizophrenia and 118 healthy subjects. Multivariate permutation tests identified 144 genes that were differentially expressed between schizophrenia and control groups. Seventy of these genes were identified as differentially expressed in at least one component microarray study but none of these individual studies had the power to identify the remaining 74 genes, demonstrating the utility of a combined approach. Gene ontology terms and biological pathways that were significantly enriched for differentially expressed genes were related to neuronal cell-cell signaling, mesenchymal induction, and mitogen-activated protein kinase signaling, which have all previously been associated with the etiopathogenesis of schizophrenia. The differential expression of BAG3, C4B, EGR1, MT1X, NEUROD6, SST and S100A8 was confirmed by real-time quantitative PCR in an independent cohort using postmortem human prefrontal cortex samples. Comparison of gene expression between schizophrenic subjects with and without detectable levels of antipsychotics in their blood suggests that the modulation of MT1X and S100A8 may be the result of drug exposure. In conclusion, this combined analysis has resulted in a statistically robust identification of genes whose dysregulation may contribute to the mechanism of schizophrenia.
    Journal of Psychiatric Research 09/2012; 46(11):1464-74. DOI:10.1016/j.jpsychires.2012.08.005 · 4.09 Impact Factor
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