Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036341 (schizophrenia)
 60,220 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The purpose of this study was to determine whether genetic linkage or association could be observed between schizophrenia (SZ) and the CAG repeat polymorphisms within the genes KCNN3 (known previously as hSKCa3) and PPP2R2B (linked to Spino-Cerebellar Atrophy 12) in the Xhosa population in South Africa. Neither locus has been studied previously in African populations. The polymorphisms were genotyped in 589 individuals to form samples for Transmission Disequilibrium Test (TDT) analysis (176 unrelated probands, 145 with both parents and 30 with one parent genotyped), linkage analysis (49 families with 54 independent affected sib pairs [ASPs]), and case-control analyses (67 familial cases with a first-degree SZ relative, 101 sporadic cases with no affected first- or second-degree relative, and 90 control cases). No significant differences were found among familial cases, sporadic cases and controls in allele sizes (Kruskal-Wallis tests) or the numbers of alleles with sizes above and below the mean size for each polymorphism. Allele size was not correlated with age of onset (Spearman correlation). No significant evidence for association was observed using TDT analyses for all triads and separately for the familial triads. No significant evidence for linkage was observed for either locus with affected sib pair analysis using the possible triangle method or with Non-Parametric Linkage (NPL) analysis of the multiplex families. In conclusion, no significant evidence for linkage or association with SZ was observed for either polymorphism in this population.
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PMID:CAG repeat polymorphisms in KCNN3 (HSKCa3) and PPP2R2B show no association or linkage to schizophrenia. 1249 13

Schizophrenia has a complex and non-Mendelian mode of inheritance. Recently, trinucleotide repeat (TNR)-containing genes have been considered as the candidate genes predisposing to schizophrenia. The purpose of this study was to determine whether a genetic association could be observed between schizophrenia and the TNR polymorphisms within the KLHL1AS/SCA8, PPP2R2B/SCA12, and TBP/SCA17 genes. We studied 100 unrelated schizophrenia patients and 124 controls without evident neurodegenerative or psychiatric disorders. The overall allele frequency distributions of the KLHL1AS/SCA8 and PPP2R2B/SCA12 genes were not significantly different between the schizophrenic patients and the control subjects (P>0.05). The allele frequency distribution in the schizophrenic patients was significantly different from that in the controls at the TBP/SCA17 gene (P=0.0149), with an increased frequency of 36 repeats in the patients and two patients carrying 45 TNR expansions were identified. TBP/SCA17 is the TATA box binding protein gene mapped to chromosome 6q27. The study suggests that TNR expansions of the TBP/SCA17 gene may contribute to the genetic risk of schizophrenia in rare cases.
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PMID:Expanded trinucleotide repeats in the TBP/SCA17 gene mapped to chromosome 6q27 are associated with schizophrenia. 1605 4

PPP2R2B, a protein widely expressed in neurons throughout the brain, regulates the protein phosphatase 2A (PP2A) activity for the microtubule-associated protein tau and other substrates. Altered PP2A activity has been implicated in spinocerebellar ataxia 12, Alzheimer's disease (AD), and other tauopathies. Through a case-control study and a reporter assay, we investigated the association of PPP2R2B CAG repeat polymorphism with Taiwanese AD, essential tremor (ET), Parkinson's disease (PD), and schizophrenia and clarified the functional implication of this polymorphism. The distribution of the alleles was not significantly different between patients and controls, with 68.6-76.1% alleles at lengths of 10, 13, and 16 triplets. No expanded alleles were detected in either group. However, the frequency of the individuals carrying the short 5-, 6-, and 7-triplet alleles was notably higher in patients with AD (5/180 [2.8%], Fisher's exact test, P = 0.003; including 2 homozygotes) and ET (4/132 [3.0%], Fisher's exact test, P < 0.001) than in the controls (1/625 [0.2%]). The PPP2R2B transcriptional activity was significantly lower in the luciferase reporter constructs containing the (CAG)(5-7) allele than in those containing the common 10-, 13-, and 16-triplet alleles in both neuroblastoma and embryonic kidney cells. Therefore, our preliminary results suggest that the PPP2R2B gene CAG repeat polymorphism may be functional and may, in part, play a role in conferring susceptibility to AD and ET in Taiwan.
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PMID:PPP2R2B CAG repeat length in the Han Chinese in Taiwan: Association analyses in neurological and psychiatric disorders and potential functional implications. 1848 86

Variation in prefrontal dopaminergic signaling mediated by D2 receptor has been implicated in cognitive phenotypes of schizophrenia, including working memory. Molecular cascades downstream of D2 receptor include a cAMP-dependent- and a cAMP-independent-pathway. Protein-Phosphatase-2A (PP2A) is a key partner of D2 receptor in cAMP-independent signaling. This enzyme comprises a regulatory subunit that is coded by PPP2R2B gene. Given the molecular relationship between PP2A and D2 signaling, we hypothesized genetic variation in PPP2R2B affecting mRNA expression of this gene in prefrontal cortex to be associated with prefrontal processing during working memory. In order to probe such a hypothesis we investigated SNPs associated with PPP2R2B expression in two independent samples of human postmortem prefrontal cortex. Then, we tested SNPs for which association was replicated as predictors of prefrontal activity during WM as probed by functional magnetic resonance (fMRI) in a sample of healthy humans. We found that a SNP associated with PPP2R2B expression (rs959627) predicted prefrontal activity during the N-Back working memory task. In particular, individuals carrying rs959627T allele, a condition associated with lower PPP2R2B expression in postmortem prefrontal cortex, showed greater activity in right inferior frontal gyrus (IFG) during N-Back compared to CC subjects. Furthermore, such an activity was negatively correlated with behavioral performance at the task. Consistently with previous studies, these findings suggest reduced right IFG efficiency during working memory processing in rs959627 T-carriers, as indexed by their greater need to activate this brain region in order to achieve similar levels of behavioral proficiency as compared to CC individuals.
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PMID:Association of functional genetic variation in PP2A with prefrontal working memory processing. 2759 Nov 84

Antipsychotic drugs targeting dopamine neurotransmission are still the principal mean of therapeutic intervention for schizophrenia. However, about one third of people do not respond to dopaminergic antipsychotics. Genome wide association studies (GWAS), have shown that multiple genetic factors play a role in schizophrenia pathophysiology. Most of these schizophrenia risk variants are not related to dopamine or antipsychotic drugs mechanism of action. Genetic factors have also been implicated in defining response to antipsychotic medication. In contrast to disease risk, variation of genes coding for molecular targets of antipsychotics have been associated with treatment response. Among genes implicated, those involved in dopamine signaling mediated by D2-class dopamine receptor, including DRD2 itself and its molecular effectors, have been implicated as key genetic predictors of response to treatments. Studies have also reported that genetic variation in genes coding for proteins that cross-talk with DRD2 at the molecular level, such as AKT1, GSK3B, Beta-catenin, and PPP2R2B are associated with response to antipsychotics. In this review we discuss the relative contribution to antipsychotic drug responsiveness of candidate genes and GWAS identified genes encoding proteins involved in dopamine responses. We also suggest that in addition of these older players, a deeper investigation of new GWAS identified schizophrenia risk genes such as FXR1 can provide new prospects that are not clearly engaged in dopamine function while being targeted by dopamine-associated signaling molecules. Overall, further examination of genes proximally or distally related to signaling mechanisms engaged by medications and associated with disease risk and/or treatment responsiveness may uncover an interface between genes involved in disease causation with those affecting disease remediation. Such a nexus would provide realistic targets for therapy and further the development of genetically personalized approaches for schizophrenia.
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PMID:Antipsychotic Drug Responsiveness and Dopamine Receptor Signaling; Old Players and New Prospects. 3068 36