Enzyme activity of the PIP4K2A gene product polymorphism that is implicated in schizophrenia.
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ABSTRACT:
SUBMITTER: Clarke JH
PROVIDER: S-EPMC3825611 | biostudies-literature | 2013 Nov
REPOSITORIES: biostudies-literature
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Enzyme activity of the PIP4K2A gene product polymorphism that is implicated in schizophrenia.
Clarke Jonathan H JH Irvine Robin F RF
Psychopharmacology 20131001 2
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Project description:ContextKynurenic acid, a metabolite of the kynurenine pathway of tryptophan degradation, is an antagonist at N-methyl-d-aspartate and α7 nicotinic acetylcholine receptors and modulates glutamate, dopamine, and acetylcholine signaling. Cortical kynurenic acid concentrations are elevated in the brain and cerebrospinal fluid of schizophrenia patients. The proximal cause may be an impairment of kynurenine 3-monooxygenase (KMO), a rate-limiting enzyme at the branching point of the kynurenine pathway.ObjectivesTo examine KMO messenger RNA expression and KMO enzyme activity in postmortem tissue from the frontal eye field (FEF; Brodmann area 6) obtained from schizophrenia individuals compared with healthy control individuals and to explore the relationship between KMO single-nucleotide polymorphisms and schizophrenia oculomotor endophenotypes.DesignCase-control postmortem and clinical study.SettingMaryland Brain Collection, outpatient clinics.ParticipantsPostmortem specimens from schizophrenia patients (n = 32) and control donors (n = 32) and a clinical sample of schizophrenia patients (n = 248) and healthy controls (n = 228).Main outcome measuresComparison of quantitative KMO messenger RNA expression and KMO enzyme activity in postmortem FEF tissue between schizophrenia patients and controls and association of KMO single-nucleotide polymorphisms with messenger RNA expression in postmortem FEF and schizophrenia and oculomotor endophenotypes (ie, smooth pursuit eye movements and oculomotor delayed response).ResultsIn postmortem tissue, we found a significant and correlated reduction in KMO gene expression and KMO enzyme activity in the FEF in schizophrenia patients. In the clinical sample, KMO rs2275163 was not associated with a diagnosis of schizophrenia but showed modest effects on predictive pursuit and visuospatial working memory endophenotypes.ConclusionOur results provide converging lines of evidence implicating reduced KMO activity in the etiopathophysiology of schizophrenia and related neurocognitive deficits.
| S-EPMC3855543 | biostudies-literature
Project description:Previous studies with biological and genetic evidence indicate that the myo-inositol monophosphatase 2 (IMPA2) gene may influence schizophrenia. We performed a genetic association study in Han Chinese cohorts. Five single nucleotide polymorphisms within IMPA2 promoter region (rs971363, rs971362, rs2075824, rs111410794 and rs111610121), as well as one (rs45442994, in intron 1) that was positively associated in another study, were selected for genotyping in 1397 patients with schizophrenia and 1285 mentally healthy controls. Genotype and allele frequencies were assessed by gender stratification. Interestingly, rs2075824 showed a strong association with schizophrenia (P = 4.1 × 10-4 ), and the T allele was more frequent in cases than controls [P = 5.6 × 10-5 , OR (95% CI) = 1.26 (1.13-1.41)]. In vitro promoter assay showed that the transcription activity of the T allele promoter was higher than that of the C allele promoter and the T allele of rs2075824 contributed to risk for schizophrenia. By stratifying males and females, we found a gender-specific association for IMPA2 and schizophrenia: the T allele of rs2075824 was more frequent in male cases compared with male controls [P = 1.4 × 10-4 , OR (95% CI) = 1.33 (1.15-1.55)]. Our data suggest that a promoter polymorphism of IMPA2 possibly contributed to risk for schizophrenia by elevating transcription activity in Han Chinese individuals.
| S-EPMC5345638 | biostudies-literature
Project description:Molecular studies support pharmacological evidence that phosphoinositide signaling is perturbed in schizophrenia and bipolar disorder. The phosphatidylinositol-4-phosphate-5-kinase type-II alpha (PIP4K2A) gene is located on chromosome 10p12. This region has been implicated in both diseases by linkage, and PIP4K2A directly by association. Given linkage evidence in the Irish Study of High Density Schizophrenia Families (ISHDSF) to a region including 10p12, we performed an association study between genetic variants at PIP4K2A and disease. No association was detected through single-marker or haplotype analysis of the whole sample. However, stratification into families positive and negative for the ISHDSF schizophrenia high-risk haplotype (HRH) in the DTNBP1 gene and re-analysis for linkage showed reduced amplitude of the 10p12 linkage peak in the DTNBP1 HRH positive families. Association analysis of the stratified sample showed a trend toward association of PIP4K2A SNPs rs1417374 and rs1409395 with schizophrenia in the DTNBP1 HRH positive families. Despite this apparent paradox, our data may therefore suggest involvement of PIP4K2A in schizophrenia in those families for whom genetic variation in DTNBP1 appears also to be a risk factor. This trend appears to arise from under-transmission of common alleles to female cases. Follow-up association analysis in a large Irish schizophrenia case-control sample (ICCSS) showed significant association with disease of a haplotype comprising these same SNPs rs1417374-rs1409395, again more so in affected females, and in cases with negative family history of the disease. This study supports a minor role for PIP4K2A in schizophrenia etiology in the Irish population.
| S-EPMC4011176 | biostudies-literature
Project description:We evaluated the hypothesis that dopaminergic polymorphisms are risk factors for schizophrenia (SZ). In stage I, we screened 18 dopamine-related genes in two independent US Caucasian samples: 150 trios and 328 cases/501 controls. The most promising associations were detected with SLC6A3 (alias DAT), DRD3, COMT and SLC18A2 (alias VMAT2). In stage II, we comprehensively evaluated these four genes by genotyping 68 SNPs in all 478 cases and 501 controls from stage I. Fifteen (23.1%) significant associations were found (p < or = 0.05). We sought epistasis between pairs of SNPs providing evidence of a main effect and observed 17 significant interactions (169 tests); 41.2% of significant interactions involved rs3756450 (5' near promoter) or rs464049 (intron 4) at SLC6A3. In stage III, we confirmed our findings by genotyping 65 SNPs among 659 Bulgarian trios. Both SLC6A3 variants implicated in the US interactions were overtransmitted in this cohort (rs3756450, p = 0.035; rs464049, p = 0.011). Joint analyses from stages II and III identified associations at all four genes (p(joint) < 0.05). We tested 29 putative interactions from stage II and detected replication between seven locus pairs (p < or = 0.05). Simulations suggested our stage II and stage III interaction results were unlikely to have occurred by chance (p = 0.008 and 0.001, respectively). In stage IV we evaluated rs464049 and rs3756450 for functional effects and found significant allele-specific differences at rs3756450 using electrophoretic mobility shift assays and dual-luciferase promoter assays. Our data suggest that a network of dopaminergic polymorphisms increase risk for SZ.
| S-EPMC3777405 | biostudies-literature
Project description: Not available
| S-EPMC5078619 | biostudies-literature
Project description:Noncoding variants in the human MIR137 gene locus increase schizophrenia risk with genome-wide significance. However, the functional consequence of these risk alleles is unknown. Here we examined induced human neurons harboring the minor alleles of four disease-associated single nucleotide polymorphisms in MIR137. We observed increased MIR137 levels compared to those in major allele-carrying cells. microRNA-137 gain of function caused downregulation of the presynaptic target genes complexin-1 (Cplx1), Nsf and synaptotagmin-1 (Syt1), leading to impaired vesicle release. In vivo, miR-137 gain of function resulted in changes in synaptic vesicle pool distribution, impaired induction of mossy fiber long-term potentiation and deficits in hippocampus-dependent learning and memory. By sequestering endogenous miR-137, we were able to ameliorate the synaptic phenotypes. Moreover, reinstatement of Syt1 expression partially restored synaptic plasticity, demonstrating the importance of Syt1 as a miR-137 target. Our data provide new insight into the mechanism by which miR-137 dysregulation can impair synaptic plasticity in the hippocampus.
| S-EPMC4506960 | biostudies-literature
Project description:BackgroundInsulin-degrading enzyme (IDE) is an important gene in studies of the pathophysiology of type 2 diabetes mellitus (T2DM). Recent studies have suggested a possible link between type 2 diabetes mellitus (T2DM) and the pathophysiology of schizophrenia (SZ). At the same time, significant changes in insulin-degrading enzyme (IDE) gene expression have been found in the brains of people with schizophrenia. These findings highlight the need to further investigate the role of IDE in schizophrenia pathogenesis.MethodsWe enrolled 733 participants from the Czech Republic, including 383 patients with schizophrenia and 350 healthy controls. Our study focused on the single nucleotide polymorphism (SNP) rs2421943 in the IDE gene, which has previously been associated with the pathogenesis of Alzheimer's disease. The SNP was analyzed using the PCR-RFLP method.ResultsThe G allele of the rs2421943 polymorphism was found to significantly increase the risk of developing SZ (p < 0.01) when a gender-based analysis showed that both AG and GG genotypes were associated with a more than 1.55 times increased risk of SZ in females (p < 0.03) but not in males. Besides, we identified a potential binding site at the G allele locus for has-miR-7110-5p, providing a potential mechanism for the observed association.ConclusionOur results confirm the role of the IDE gene in schizophrenia pathogenesis and suggest that future research should investigate the relationship between miRNA and estrogen influence on IDE expression in schizophrenia pathogenesis.
| S-EPMC10492455 | biostudies-literature
Project description:BackgroundThe activity of angiotension converting enzyme (ACE; OMIM: 106180) in different brain regions of patients with schizophrenia changed, suggesting a possible involvement of ACE in psychiatric disorders. Genetic polymorphism of insertion/deletion (I/D; dbSNP rs4646994) in the gene encoding ACE has been well defined.MethodsThe present case-control study was performed on 363 (268 males, 95 females) in-patients with schizophrenia diagnosis, and 363 (268 males, 95 females) healthy blood donor controls. The genotypes of I/D ACE polymorphism were determined using PCR method. PCR products were separated and sized by electrophoresis on a 2% agarose gel. The insertion allele (I) was detected as a 478 bp band, and the deletion allele (D) was visualized as a 191 bp band. The association between genotypes of the I/D polymorphism and the schizophrenia risk was examined by use of odds ratios (OR) and 95% of confidence intervals (CIs).ResultsAmong females, the II genotype significantly decreased the risk of schizophrenia compared with the DD genotype (OR=0.18, 95%CI: 0.04-0.72, P=0.015). There was significant linear trend for the number of the I allele and schizophrenia risk among females (Chi(2)=5.19, P=0.023). There was no significant association between I/D polymorphism and susceptibility to schizophrenia among male subjects. There was significant interaction between gender and the II genotype (P=0.031).ConclusionThe II genotype of the I/D polymorphism has a protective effect for schizophrenia among females.
| S-EPMC4402415 | biostudies-literature
Project description:Literature suggests that disease severity and neurotransmitter signaling pathway genes can accurately identify antipsychotic response in schizophrenia patients. However, putative role of signaling molecules has not been tested in schizophrenia patients based on severity of illness, despite its biological plausibility. In the present study we investigated the possible association of polymorphisms from five candidate genes RGS4, SLC6A3, PIP4K2A, BDNF, PI4KA with response to antipsychotic in variably ill schizophrenia patients. Thus in present study, a total 53 SNPs on the basis of previous reports and functional grounds were examined for their association with antipsychotic response in 423 schizophrenia patients segregated into low and high severity groups. Additionally, haplotype, diplotype, multivariate logistic regression and multifactor-dimensionality reduction (MDR) analyses were performed. Furthermore, observed associations were investigated in atypical monotherapy (n = 355) and risperidone (n = 260) treated subgroups. All associations were estimated as odds ratio (OR) and 95% confidence interval (CI) and test for multiple corrections was applied. Single locus analysis showed significant association of nine variants from SLC6A3, PIP4K2A and BDNF genes with incomplete antipsychotic response in schizophrenia patients with high severity. We identified significant association of six marker diplotype ATTGCT/ATTGCT (rs746203-rs10828317-rs7094131-rs2296624-rs11013052-rs1409396) of PIP4K2A gene in incomplete responders (corrected p-value = 0.001; adjusted-OR = 3.19, 95%-CI = 1.46-6.98) with high severity. These associations were further observed in atypical monotherapy and risperidone sub-groups. MDR approach identified gene-gene interaction among BDNF_rs7103411-BDNF_rs1491851-SLC6A3_rs40184 in severely ill incomplete responders (OR = 7.91, 95%-CI = 4.08-15.36). While RGS4_rs2842026-SLC6A3_rs2975226 interacted synergistically in incomplete responders with low severity (OR = 4.09, 95%-CI = 2.09-8.02). Our findings provide strong evidence that diplotype ATTGCT/ATTGCT of PIP4K2A gene conferred approximately three-times higher incomplete responsiveness towards antipsychotics in severely ill patients. These results are consistent with the known role of phosphatidyl-inositol-signaling elements in antipsychotic action and outcome. Findings have implication for future molecular genetic studies as well as personalized medicine. However more work is warranted to elucidate underlying causal biological pathway.
| S-EPMC4099378 | biostudies-literature
Project description:BackgroundProtein encoding genes have long been the major targets for research in schizophrenia genetics. However, with the identification of regulatory microRNAs (miRNAs) as important in brain development and function, miRNAs genes have emerged as candidates for schizophrenia-associated genetic factors. Indeed, the growing understanding of the regulatory properties and pleiotropic effects that miRNA have on molecular and cellular mechanisms, suggests that alterations in the interactions between miRNAs and their mRNA targets may contribute to phenotypic variation.Methodology/principal findingsWe have studied the association between schizophrenia and genetic variants of miRNA genes associated with brain-expression using a case-control study design on three Scandinavian samples. Eighteen known SNPs within or near brain-expressed miRNAs in three samples (Danish, Swedish and Norwegian: 420/163/257 schizophrenia patients and 1006/177/293 control subjects), were analyzed. Subsequently, joint analysis of the three samples was performed on SNPs showing marginal association. Two SNPs rs17578796 and rs1700 in hsa-mir-206 (mir-206) and hsa-mit-198 (mir-198) showed nominal significant allelic association to schizophrenia in the Danish and Norwegian sample respectively (P = 0.0021 & p = 0.038), of which only rs17578796 was significant in the joint sample. In-silico analysis revealed that 8 of the 15 genes predicted to be regulated by both mir-206 and mir-198, are transcriptional targets or interaction partners of the JUN, ATF2 and TAF1 connected in a tight network. JUN and two of the miRNA targets (CCND2 and PTPN1) in the network have previously been associated with schizophrenia.Conclusions/significanceWe found nominal association between brain-expressed miRNAs and schizophrenia for rs17578796 and rs1700 located in mir-206 and mir-198 respectively. These two miRNAs have a surprising large number (15) of targets in common, eight of which are also connected by the same transcription factors.
| S-EPMC1964806 | biostudies-literature