| 1 | Neurosci. Lett. 2004 Oct 369: 126-31 |
|---|---|
| PMID | 15450681 |
| Title | Tumor suppressor gene TP53 is genetically associated with schizophrenia in the Chinese population. |
| Abstract | schizophrenia is a debilitating mental disorder. The TP53 tumor suppressor gene, encoding a phosphoprotein, is a key element in maintaining genomic stability and cell apoptosis. Recently, reduced risk of cancer in patients of schizophrenia has been reported. Some evidence also suggests the possible implication of TP53 in neurodevelopment. In order to examine the role of the TP53 gene in the pathogenesis of schizophrenic disorders, we investigated the genetic association between a functional polymorphism rs1042522 and schizophrenia by sequencing the fragment covering 72Pro> Arg in 701 cases and 695 controls in this work. In addition, we studied two other SNPs rs2078486 and rs8064946 by allele-specific PCR in the same samples. Though rs1042522 and rs8064946 did not show positive association with schizophrenia, we did observe statistically significant differences on SNP rs2078486 (P-value = 0.029; OR = 1.21; 95% CI 1.02-1.42) and on haplotype CAC (P-value = 0.0068; OR = 1.36; 95% CI 1.09-1.70). These results demonstrated that TP53 might play a role in susceptibility to schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 2 | Neurosci. Lett. 2004 Oct 369: 126-31 |
| PMID | 15450681 |
| Title | Tumor suppressor gene TP53 is genetically associated with schizophrenia in the Chinese population. |
| Abstract | schizophrenia is a debilitating mental disorder. The TP53 tumor suppressor gene, encoding a phosphoprotein, is a key element in maintaining genomic stability and cell apoptosis. Recently, reduced risk of cancer in patients of schizophrenia has been reported. Some evidence also suggests the possible implication of TP53 in neurodevelopment. In order to examine the role of the TP53 gene in the pathogenesis of schizophrenic disorders, we investigated the genetic association between a functional polymorphism rs1042522 and schizophrenia by sequencing the fragment covering 72Pro> Arg in 701 cases and 695 controls in this work. In addition, we studied two other SNPs rs2078486 and rs8064946 by allele-specific PCR in the same samples. Though rs1042522 and rs8064946 did not show positive association with schizophrenia, we did observe statistically significant differences on SNP rs2078486 (P-value = 0.029; OR = 1.21; 95% CI 1.02-1.42) and on haplotype CAC (P-value = 0.0068; OR = 1.36; 95% CI 1.09-1.70). These results demonstrated that TP53 might play a role in susceptibility to schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 3 | Neurosci. Lett. 2004 Jun 363: 78-80 |
| PMID | 15158001 |
| Title | Analysis of polymorphisms at the tumor suppressor gene p53 (TP53) in contributing to the risk for schizophrenia and its associated neurocognitive deficits. |
| Abstract | Owing to the role of the nuclear phosphoprotein p53 in the regulation of neurodegeneration and neurodevelopmental processes, some authors have suggested TP53 as a candidate gene for schizophrenia and/or the neurocognitive deficits commonly observed in these patients. In the present study we have analyzed two polymorphisms (Pro72Arg and 16 bp insertion) located on the TP53 gene in order to investigate their role in the risk of developing schizophrenia and their effect on the neurocognitive profile of these patients in the context of an association study. The distribution of genotypes, alleles and haplotypes did not differ between cases and controls. Additionally, we did not detect any influence of this genetic variability in the neurocognitive functions of schizophrenic patients. Our findings suggest that the analyzed variability of the TP53 gene does not influence (i) the risk of suffering from schizophrenia and (ii) the deficits in the neurocognitive profile of these patients. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 4 | Neurosci. Lett. 2004 Jun 363: 78-80 |
| PMID | 15158001 |
| Title | Analysis of polymorphisms at the tumor suppressor gene p53 (TP53) in contributing to the risk for schizophrenia and its associated neurocognitive deficits. |
| Abstract | Owing to the role of the nuclear phosphoprotein p53 in the regulation of neurodegeneration and neurodevelopmental processes, some authors have suggested TP53 as a candidate gene for schizophrenia and/or the neurocognitive deficits commonly observed in these patients. In the present study we have analyzed two polymorphisms (Pro72Arg and 16 bp insertion) located on the TP53 gene in order to investigate their role in the risk of developing schizophrenia and their effect on the neurocognitive profile of these patients in the context of an association study. The distribution of genotypes, alleles and haplotypes did not differ between cases and controls. Additionally, we did not detect any influence of this genetic variability in the neurocognitive functions of schizophrenic patients. Our findings suggest that the analyzed variability of the TP53 gene does not influence (i) the risk of suffering from schizophrenia and (ii) the deficits in the neurocognitive profile of these patients. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 5 | Neurosci. Lett. 2005 Nov 388: 173-8 |
| PMID | 16039051 |
| Title | Human p53 tumor suppressor gene (TP53) and schizophrenia: case-control and family studies. |
| Abstract | The human p53 tumor suppressor gene (TP53) is considered as a candidate susceptibility gene for schizophrenia because of its functions in neurodevelopment. To test for an association between TP53 and schizophrenia, both the case-control study and the transmission disequilibrium test (TDT) were performed on genotype data from eight polymorphisms in TP53. Our samples included 286 Toronto schizophrenia cases and 264 controls, and 163 Portuguese nuclear families. In the Toronto case-control study significant differences of allele frequencies of the CAA Ins/Del (p=0.027) and the 16bp Ins/Del (p=0.022) were detected. In TDT analysis we found significant differences for transmission of the CAA Ins/Del (p=0.017) in Portuguese schizophrenia families. Haplotype analysis also showed a significant association between TP53 and schizophrenia. These results provide further evidence that TP53 may play a role in the pathogenesis of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 6 | Nat. Genet. 2008 Jul 40: 827-34 |
| PMID | 18583979 |
| Title | Systematic meta-analyses and field synopsis of genetic association studies in schizophrenia: the SzGene database. |
| Abstract | In an effort to pinpoint potential genetic risk factors for schizophrenia, research groups worldwide have published over 1,000 genetic association studies with largely inconsistent results. To facilitate the interpretation of these findings, we have created a regularly updated online database of all published genetic association studies for schizophrenia ('SzGene'). For all polymorphisms having genotype data available in at least four independent case-control samples, we systematically carried out random-effects meta-analyses using allelic contrasts. Across 118 meta-analyses, a total of 24 genetic variants in 16 different genes (APOE, COMT, DAO, DRD1, DRD2, DRD4, DTNBP1, GABRB2, GRIN2B, HP, IL1B, MTHFR, PLXNA2, SLC6A4, TP53 and TPH1) showed nominally significant effects with average summary odds ratios of approximately 1.23. Seven of these variants had not been previously meta-analyzed. According to recently proposed criteria for the assessment of cumulative evidence in genetic association studies, four of the significant results can be characterized as showing 'strong' epidemiological credibility. Our project represents the first comprehensive online resource for systematically synthesized and graded evidence of genetic association studies in schizophrenia. As such, it could serve as a model for field synopses of genetic associations in other common and genetically complex disorders. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 7 | Schizophr. Res. 2008 Sep 104: 96-107 |
| PMID | 18715757 |
| Title | Genetic associations with schizophrenia: meta-analyses of 12 candidate genes. |
| Abstract | Genetic association studies on schizophrenia (SZ) have been repeatedly performed over the last two decades, resulting in a consensus that results are generally inconsistent. This consensus has begun to change as a result of meta-analyses (e.g., [Glatt, S.J. and Jonsson, E.G., 2006. The Cys allele of the DRD2 Ser311Cys polymorphism has a dominant effect on risk for schizophrenia: evidence from fixed- and random-effects meta-analyses. Am. J. Med. Genet. B. Neuropsychiatr. Genet. 141, 149-154.]). The schizophreniaGene database (http://www.schizophreniaforum.org/res/sczgene/default.asp) has been a leader in meta-analyses of SZ association data, by dynamically and comprehensively cataloging all public genetic association studies, and preparing meta-analyses of case-control data. There are 19 "top" candidate genes from these analyses (access on December 20, 2007), showing the highest effect sizes and nominally significant associations of at least one variant in the meta-analyses of all ethnic samples or of samples of Caucasian ancestry. We selected 40 polymorphisms in 12 selected "top" genes for additional meta-analyses, which had at least one familial association data. We found gene-wide (correction for the number of meta-analyses for each gene) significant allelic association evidence for seven genes in the combined samples. The odds ratios (ORs) of the associated minor risk alleles range from 1.072 to 1.121, for DRD4, MTHFR, PPP3CC and TP53. For protective allele associations, the ORs are between 0.842 and 0.886, for DAO, IL1B, and SLC6A4. In population-based sub-analyses, we found significant results in four genes in Asians (ORs between 1.084 and 1.309 for DRD4, GABRB2, PPP3CC, and TP53), and one gene in European (OR of 0.888 for SLC6A4). The association of rs1816072 of GABRB2 with SZ in Asians was significant (adjusted P=0.048 after correction for 80 tests). No significant heterogeneity between case-control and family-based study designs was detected in 35 out of 40 polymorphisms. Our results further support eight potential SZ candidate genes and suggest that family data can reasonably be included in the meta-analysis of genetic associations. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 8 | Psychiatr. Genet. 2008 Dec 18: 313-7 |
| PMID | 19018238 |
| Title | Evidence for association between structural variants in lissencephaly-related genes and executive deficits in schizophrenia or bipolar patients from a Spanish isolate population. |
| Abstract | There is evidence for an association between structural variants in genes for lissencephaly, which are involved in neuronal migration, and prefrontal cognitive deficits in schizophrenia and bipolar patients. On the basis of these intriguing findings, we analyzed 16 markers located in the lissencephaly critical region (LCR in chromosome 17p13.3) in 124 schizophrenic, 56 bipolar, and 141 healthy individuals. All recruits were from a Spanish population isolate of Basque origin that is characterized by low genetic heterogeneity. In addition, we examined whether structural genomic variations in the LCR were associated with executive cognition. Twenty-three patients (12.8%), but none of the controls, showed structural variants (deletions and insertions) in either of two markers related with lissencephaly (D17S1566 on tumor suppressor gene TP53: tumor protein p53 and D17S22 on SMG6 gene: Smg-6 homolog, nonsense mediated mRNA decay factor- Caenorhabditis elegans). These patients performed significantly worse in the Wisconsin Card Sorting Test-Categories in comparison with patients without such variations in lissencephaly-related genes. The presence of structural variants was related to completed categories, and accounted for 10.7% of the variance (P=0.001). Finally, logistic regression showed that poor Wisconsin Card Sorting Test-Categories performance was the only predictor of belonging to the positive LCR variations group. These new findings provide further evidence for the association between some lissencephaly-related genes and both schizophrenia and bipolar disorder, and influence on frontal executive functioning. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 9 | Psychiatr. Genet. 2008 Dec 18: 313-7 |
| PMID | 19018238 |
| Title | Evidence for association between structural variants in lissencephaly-related genes and executive deficits in schizophrenia or bipolar patients from a Spanish isolate population. |
| Abstract | There is evidence for an association between structural variants in genes for lissencephaly, which are involved in neuronal migration, and prefrontal cognitive deficits in schizophrenia and bipolar patients. On the basis of these intriguing findings, we analyzed 16 markers located in the lissencephaly critical region (LCR in chromosome 17p13.3) in 124 schizophrenic, 56 bipolar, and 141 healthy individuals. All recruits were from a Spanish population isolate of Basque origin that is characterized by low genetic heterogeneity. In addition, we examined whether structural genomic variations in the LCR were associated with executive cognition. Twenty-three patients (12.8%), but none of the controls, showed structural variants (deletions and insertions) in either of two markers related with lissencephaly (D17S1566 on tumor suppressor gene TP53: tumor protein p53 and D17S22 on SMG6 gene: Smg-6 homolog, nonsense mediated mRNA decay factor- Caenorhabditis elegans). These patients performed significantly worse in the Wisconsin Card Sorting Test-Categories in comparison with patients without such variations in lissencephaly-related genes. The presence of structural variants was related to completed categories, and accounted for 10.7% of the variance (P=0.001). Finally, logistic regression showed that poor Wisconsin Card Sorting Test-Categories performance was the only predictor of belonging to the positive LCR variations group. These new findings provide further evidence for the association between some lissencephaly-related genes and both schizophrenia and bipolar disorder, and influence on frontal executive functioning. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 10 | Schizophr Bull 2009 Nov 35: 1163-82 |
| PMID | 18552348 |
| Title | Schizophrenia susceptibility genes directly implicated in the life cycles of pathogens: cytomegalovirus, influenza, herpes simplex, rubella, and Toxoplasma gondii. |
| Abstract | Many genes implicated in schizophrenia can be related to glutamatergic transmission and neuroplasticity, oligodendrocyte function, and other families clearly related to neurobiology and schizophrenia phenotypes. Others appear rather to be involved in the life cycles of the pathogens implicated in the disease. For example, aspartylglucosaminidase (AGA), PLA2, SIAT8B, GALNT7, or B3GAT1 metabolize chemical ligands to which the influenza virus, herpes simplex, cytomegalovirus (CMV), rubella, or Toxoplasma gondii bind. The epidermal growth factor receptor (EGR/EGFR) is used by the CMV to gain entry to cells, and a CMV gene codes for an interleukin (IL-10) mimic that binds the host cognate receptor, IL10R. The fibroblast growth factor receptor (FGFR1) is used by herpes simplex. KPNA3 and RANBP5 control the nuclear import of the influenza virus. Disrupted in schizophrenia 1 (DISC1) controls the microtubule network that is used by viruses as a route to the nucleus, while DTNBP1, MUTED, and BLOC1S3 regulate endosomal to lysosomal routing that is also important in viral traffic. Neuregulin 1 activates ERBB receptors releasing a factor, EBP1, known to inhibit the influenza virus transcriptase. Other viral or bacterial components bind to genes or proteins encoded by CALR, FEZ1, FYN, HSPA1B, IL2, HTR2A, KPNA3, MED12, MED15, MICB, NQO2, PAX6, PIK3C3, RANBP5, or TP53, while the cerebral infectivity of the herpes simplex virus is modified by Apolipoprotein E (APOE). Genes encoding for proteins related to the innate immune response, including cytokine related (CCR5, CSF2RA, CSF2RB, IL1B, IL1RN, IL2, IL3, IL3RA, IL4, IL10, IL10RA, IL18RAP, lymphotoxin-alpha, tumor necrosis factor alpha [TNF]), human leukocyte antigen (HLA) antigens (HLA-A10, HLA-B, HLA-DRB1), and genes involved in antigen processing (angiotensin-converting enzyme and tripeptidyl peptidase 2) are all concerned with defense against invading pathogens. Human microRNAs (Hsa-mir-198 and Hsa-mir-206) are predicted to bind to influenza, rubella, or poliovirus genes. Certain genes associated with schizophrenia, including those also concerned with neurophysiology, are intimately related to the life cycles of the pathogens implicated in the disease. Several genes may affect pathogen virulence, while the pathogens in turn may affect genes and processes relevant to the neurophysiology of schizophrenia. For such genes, the strength of association in genetic studies is likely to be conditioned by the presence of the pathogen, which varies in different populations at different times, a factor that may explain the heterogeneity that plagues such studies. This scenario also suggests that drugs or vaccines designed to eliminate the pathogens that so clearly interact with schizophrenia susceptibility genes could have a dramatic effect on the incidence of the disease. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 11 | BMC Med. Genet. 2009 -1 10: 147 |
| PMID | 20040103 |
| Title | Association of DRD4 uVNTR and TP53 codon 72 polymorphisms with schizophrenia: a case-control study. |
| Abstract | The tumour supressor gene TP53 is thought to be involved in neural apoptosis. The polymorphism at codon 72 in TP53 and the long form variants of the upstream variable number of tandem repeats (uVNTR) polymorphism in the dopamine D4 receptor (DRD4) gene are reported to confer susceptibility to schizophrenia. We recruited 934 patients with schizophrenia and 433 healthy individuals, and genotyped the locus of the TP53 codon 72 and DRD4 uVNTR polymorphisms by combining the polymerase chain reaction-restriction fragment length polymorphism method (PCR-RFLP) with direct sequencing. No significant differences were found in the frequency of the genotype of the TP53 codon72 polymorphism between patients with schizophrenia and their controls. However, the long form alleles (> or = 5 repeats) of the DRD4 uVNTR polymorphism were more frequent in patients with schizophrenia than in controls (p = 0.001). Hence, this class of alleles might be a risk factor for enhanced vulnerability to schizophrenia (odds ratio = 3.189, 95% confidence interval = 1.535-6.622). In the logistic regression analysis, the long form variants of the DRD4 polymorphism did predict schizophrenia after the contributions of the age and gender of the subjects were included (p = 0.036, OR = 2.319), but the CC and GG genotypes of the codon 72 polymorphism of TP53 did not. The long form variants of the uVNTR polymorphism in DRD4 were associated with schizophrenia, in a manner that was independent of the TP53 codon 72 polymorphism. In addition, given that the genetic effect of the TP53 codon 72 polymorphism on the risk of developing schizophrenia was very small, this polymorphism is unlikely to be associated with schizophrenia. The roles that other single nucleotide polymorphisms (SNPs) in the TP53 gene or in other apoptosis-related genes play in the synaptic dysfunction involved in the pathogenesis of schizophrenia should be investigated. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 12 | Neuroimage 2011 May 56: 45-51 |
| PMID | 21296169 |
| Title | Convergent evidence of the contribution of TP53 genetic variation (Pro72Arg) to metabolic activity and white matter volume in the frontal lobe in schizophrenia patients. |
| Abstract | Abnormalities in white matter (WM) volumes and integrity in schizophrenia, together with post-mortem studies showing reduced expression of oligodendrocyte/myelination genes and apoptotic processes taking place in oligodendrocytes, suggest the interest of major regulators of apoptosis as candidate genes for some features related to myelin integrity in schizophrenia. Protein p53, encoded by TP53 gene, has a central role in the control of apoptosis and is involved in oligodendrocyte development. TP53 gene polymorphisms may account for variability in WM features, metabolic activity and biochemical markers of neuronal integrity and membrane turnover. Pro72Arg and Ins16bp polymorphisms at TP53 gene were analyzed in 20 DSM-IV schizophrenia patients. T1/T2-weighted sequences of these patients were acquired using a 1.5T Philips Gyroscan system. Scans were transformed into Talairach space and segmented into gray matter (GM), WM and cerebrospinal fluid (CSF) using Statistical Parametric Mapping under a ROI approach. Likewise dorsolateral prefrontal cortex (DLPFC) metabolic activity was measured using a procedure based on MRI/PET image fusion. In 13 of these patients proton magnetic resonance spectroscopy was used to examine N-acetylaspartate (NAA), creatine (Cr) and choline (Cho) levels in dorsolateral-medial prefrontal cortex (DLMPFC). MRI data were adjusted for age and brain volume using regression parameters from a healthy control group (n=45). Patients Pro/Arg heterozygous (Pro72Arg polymorphism) showed a generalized deficit in whole-brain WM that was especially prominent in frontal lobe and a lower metabolic activity in the DLPFC as compared to Pro/Pro homozygous. Pro/Arg subjects also showed decreased NAA/Cho and increased Cho/Cr ratios in right DLMPFC. TP53 genetic variability influences WM volumes in frontal lobes and it seems to modulate the metabolic activity in this region. Our results suggest that TP53 might influence aspects of myelin and white matter integrity which may account for some of the frontal dysfunction features commonly described in these patients. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 13 | Arch. Med. Res. 2013 Feb 44: 121-6 |
| PMID | 23360829 |
| Title | Association between polymorphisms in the genes for tumor suppressor protein p53 and its regulator NAD(P)H: quinone oxidoreductase 1 (NQO1) and schizophrenia in a Syrian study cohort. |
| Abstract | The contribution of genetic factors to the susceptibility for developing schizophrenia is well established. Several hypotheses have been developed in an attempt to identify the pathophysiological mechanisms in schizophrenia, with several findings implicating an important role for apoptosis. A limited number of studies investigated the effects of polymorphisms in apoptotic genes on the susceptibility to schizophrenia in different ethnic groups, with none involving an Arab population. The aim of the present study was to investigate the association between multiple polymorphisms in genes for the central apoptotic protein p53 and its regulator NQO1 and the susceptibility for developing schizophrenia in an Arab population from Syria. The studied polymorphisms included exon 4 G>C Arg72Pro (rs1042522), IVS3 16 bp Del/Ins (rs17878362), and MspI IVS6+62A>G (rs1625895) of the TP53 gene, and C609T of the NQO1 gene. The study cohort consisted of 90 patients and 144 healthy controls. Association with each of the four polymorphisms was tested under numerous genetic models. The four polymorphisms were genotyped simultaneously using a quadruplex Tetra-Primer ARMS-PCR method described earlier. The combined effects of polymorphisms in NQO1 and TP53 genes were examined. No statistically significant association was found for any of the four polymorphisms. Our results do not support an association between the studied polymorphisms and schizophrenia in the Syrian population. |
| SCZ Keywords | schizophrenia, schizophrenic |