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)

Synergistic interaction between genes on chromosome 22q11 recently has been proposed as a possible mechanism which could confer increased risk for schizophrenia. Based on this hypothesis, our study aimed to explore main, cis- and trans-interacting effects of three candidate genes on 22q11, ProDH, COMT and ZDHHC8. We selected four putative risk variants, residing within these genes, ProDH 1945, ProDH 2026, COMT ValMet and ZDHHC8 rs175174, and studied these in a large family-based schizophrenia association sample of European origin (488 Bulgarian parent-offspring trios). The presence of interaction between the variants was tested by conditional logistic regression analysis based on a case-pseudocontrol design. Our study did not find statistical evidence for allelic (investigation of ProDH markers only), genotypic, haplotypic, or interactive effects between ProDH, COMT and ZDHHC8. Our data do not support the hypothesis that an interaction between these genes influences susceptibility to schizophrenia.
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PMID:Analysis of ProDH, COMT and ZDHHC8 risk variants does not support individual or interactive effects on schizophrenia susceptibility. 1686 May 41

Linkage, association and postmortem studies have implicated regulator of G-protein signaling 4 (RGS4), which negatively modulates signal transduction at G-protein-coupled receptors, as a candidate schizophrenia susceptibility gene. We compared RGS4 mRNA expression in the dorsolateral prefrontal cortex (DLPFC), between normal controls and patients with schizophrenia in two independent cohorts (>100 subjects each) (the CBDB/NIMH Collection and the Stanley Array Collection), and in the hippocampus in the CBDB/NIMH Collection. We also examined the effects of the four previously identified putative RGS4 risk SNPs (rs10917670, rs951436, rs951439, rs2661319) on RGS4 expression levels in these cohorts. As dopamine signaling is linked to RGS4 expression and there is evidence for statistical epistasis between COMT Val158Met polymorphism and RGS4 alleles, we also examined relationships between the COMT Val158Met genotype and RGS4 expression in the DLPFC. We did not detect a difference in RGS4 expression levels between schizophrenic patients (or bipolar disorder patients in the Stanley Collection) and controls and found no significant association between any of the RGS4 risk SNPs and RGS4 expression. However, COMT Val158Met genotype was associated with prefrontal and hippocampal RGS4 mRNA expression in an allele dose-dependent manner, with carriers of the COMT Val allele showing significantly lower expression than heterozygous individuals or subjects homozygous for the Met allele. Consistent with these genotype effects, RGS4 mRNA was inversely correlated with the COMT enzyme activity in the DLPFC. These data suggest that RGS4 mRNA expression is associated with cortical dopamine signaling and illustrate the importance of genetic and/or environmental background in gene expression studies in schizophrenia.
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PMID:RGS4 mRNA expression in postmortem human cortex is associated with COMT Val158Met genotype and COMT enzyme activity. 1690 60

The variability in phenotypic presentations and the lack of consistency of genetic associations in mental illnesses remain a major challenge in molecular psychiatry. Recently, it has become increasingly clear that altered promoter DNA methylation could play a critical role in mediating differential regulation of genes and in facilitating short-term adaptation in response to the environment. Here, we report the investigation of the differential activity of membrane-bound catechol-O-methyltransferase (MB-COMT) due to altered promoter methylation and the nature of the contribution of COMT Val158Met polymorphism as risk factors for schizophrenia and bipolar disorder by analyzing 115 post-mortem brain samples from the frontal lobe. These studies are the first to reveal that the MB-COMT promoter DNA is frequently hypomethylated in schizophrenia and bipolar disorder patients, compared with the controls (methylation rate: 26 and 29 versus 60%; P=0.004 and 0.008, respectively), particularly in the left frontal lobes (methylation rate: 29 and 30 versus 81%; P=0.003 and 0.002, respectively). Quantitative gene-expression analyses showed a corresponding increase in transcript levels of MB-COMT in schizophrenia and bipolar disorder patients compared with the controls (P=0.02) with an accompanying inverse correlation between MB-COMT and DRD1 expression. Furthermore, there was a tendency for the enrichment of the Val allele of the COMT Val158Met polymorphism with MB-COMT hypomethylation in the patients. These findings suggest that MB-COMT over-expression due to promoter hypomethylation and/or hyperactive allele of COMT may increase dopamine degradation in the frontal lobe providing a molecular basis for the shared symptoms of schizophrenia and bipolar disorder.
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PMID:Hypomethylation of MB-COMT promoter is a major risk factor for schizophrenia and bipolar disorder. 1698 65

Hemizygous deletion of a 3 Mb region of 22q11.2 is found in 1/4000 humans and produces 22q11 deletion syndrome (22q11DS). Up to 35% of 22q11DS patients develop schizophrenia, making it the second highest risk factor for schizophrenia. A mouse model for 22q11DS, the Df1/+ mouse, carries a hemizygous deletion in a region syntenic with the human deletion. Df1/+ mice are mostly viable but display deficits in prepulse inhibition and learning and memory, two common traits of schizophrenia thought to result, at least in part, from defects in hippocampal neurons. We used oligonucleotide microarrays and QRT-PCR to evaluate gene expression changes in hippocampal dentate granule neurons of Df1/+ mice versus wild-type littermates (n=12/group). The expression of only 287 genes changed with p value significance below 0.05 by microarray, yet 12 of the 21 Df1 region genes represented on the array showed highly significantly reduced expression compared to wild-type controls (33% on average, p values from 10(-3) to 10(-7)). Variants in two of these genes, COMT and PRODH, have been linked with schizophrenia. Overlap of the 287 genes with the reportedly reduced expression of mitochondrial, ubiquitin/proteasome, and synaptic plasticity genes in schizophrenia dentate granule neurons, was not significant. However, modest increases in expression of mitochondrial electron transport genes were observed in the Df1/+ mice. This perhaps indicates a compensation for mitochondrial dysfunction caused by the strongly reduced expression of the Df1 region-encoded mitochondrial enzymes proline dehydrogenase (Prodh) and thioredoxin reductase 2 (Txnrd2).
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PMID:Altered expression of hippocampal dentate granule neuron genes in a mouse model of human 22q11 deletion syndrome. 1700 57

With its hallucinations, delusions, thought disorder, and cognitive deficits, schizophrenia affects the most basic human processes of perception, emotion, and judgment. Evidence increasingly suggests that schizophrenia is a subtle disorder of brain development and plasticity. Genetic studies are beginning to identify proteins of candidate genetic risk factors for schizophrenia, including dysbindin, neuregulin 1, DAOA, COMT, and DISC1, and neurobiological studies of the normal and variant forms of these genes are now well justified. We suggest that DISC1 may offer especially valuable insights. Mechanistic studies of the properties of these candidate genes and their protein products should clarify the molecular, cellular, and systems-level pathogenesis of schizophrenia. This can help redefine the schizophrenia phenotype and shed light on the relationship between schizophrenia and other major psychiatric disorders. Understanding these basic pathologic processes may yield novel targets for the development of more effective treatments.
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PMID:Neurobiology of schizophrenia. 1701 32

22q11 Deletion syndrome (22q11DS) is a common microdeletion syndrome with variable expression, including congenital and later onset conditions such as schizophrenia. Most studies indicate that expression does not appear to be related to length of the deletion but there is limited information on the endpoints of even the common deletion breakpoint regions in adults. We used a real-time quantitative PCR (qPCR) approach to fine map 22q11.2 deletions in 44 adults with 22q11DS, 22 with schizophrenia (SZ; 12 M, 10 F; mean age 35.7 SD 8.0 years) and 22 with no history of psychosis (NP; 8 M, 14 F; mean age 27.1 SD 8.6 years). QPCR data were consistent with clinical FISH results using the TUPLE1 or N25 probes. Two subjects (one SZ, one NP) negative for clinical FISH had atypical 22q11.2 deletions confirmed by FISH using the RP11-138C22 probe. Most (n = 34; 18 SZ, 16 NP) subjects shared a common 3 Mb hemizygous 22q11.2 deletion. However, eight subjects showed breakpoint variability: a more telomeric proximal breakpoint (n = 2), or more centromeric (n = 3) or more telomeric distal breakpoint (n = 3). One NP subject had a proximal nested 1.4 Mb deletion. COMT and TBX1 were deleted in all 44 subjects, and PRODH in 40 subjects (19 SZ, 21 NP). The results delineate proximal and distal breakpoint variants in 22q11DS. Neither deletion extent nor PRODH haploinsufficiency appeared to explain the clinical expression of schizophrenia in the present study. Further studies are needed to elucidate the molecular basis of schizophrenia and clinical heterogeneity in 22q11DS.
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PMID:Molecular characterization of deletion breakpoints in adults with 22q11 deletion syndrome. 1702 64

Although current psychiatric nosology separates bipolar disorder and schizophrenia into non-overlapping categories, there is growing evidence of a partial aetiological overlap between them from linkage, genetic epidemiology and molecular genetics studies. Thus, it is important to determine whether genes implicated in the aetiology of schizophrenia play a role in bipolar disorder, and vice versa. In this study we investigated a total of 15 single nucleotide polymorphisms (SNPs), and all possible haplotypes, of genes that have been previously implicated in schizophrenia or bipolar disorder - RGS4, PRODH, COMT and GRK3 - in a sample of 213 cases with bipolar affective disorder type 1 and 197 controls from Scotland. We analysed the polymorphisms allele-wise, genotype-wise and, for each gene, haplotype-wise but obtained no result that reached nominal significance (p<0.05) for an association with the disease status. In conclusion, we could not find evidence of association between RGS4, PRODH, COMT and GRK3 genes and bipolar affective disorder 1 in the Scottish population.
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PMID:Bipolar 1 disorder is not associated with the RGS4, PRODH, COMT and GRK3 genes. 1710 20

The Val158Met polymorphism of the COMT gene is functional, easily detectable, and significantly related to metabolism of catecholamines, which underlie pathogenesis of a significant number of mental disorders. Evidence for the role of this polymorphism in schizophrenia, substance dependence, bipolar disorder, obsessive-compulsive disorder, anorexia nervosa and attention deficit hyperactivity disorder is summed up in this review article. The results make it unlikely that the COMT gene plays an important role in these mental disorders, although a minor effect can not be excluded. Future studies on the COMT gene in mentally ill subjects should be stratified by clinical subtypes of the disorder, gender and ethnicity. Studies of endophenotypes instead of the complex disorder seem to be another promising research strategy. Gene-gene and gene-environment interactions should also be considered. The COMT gene is probably not "a gene for" any mental disorder, but the Val158Met polymorphism appears to have pleiotropic effects on human behavior.
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PMID:Role of the COMT gene Val158Met polymorphism in mental disorders: a review. 1741 9

The author reviews relevant data on the neuropathology and molecular genetics of schizophrenia. Anatomical alterations are localized mainly in the hippocampus, dorsal thalamus and dorsolateral prefrontal cortex, and involve the morphology and molecular structure of the neurons and synapses. Several susceptibility genes [including COMT, dysbindin, neuregulin, DISCI, RGS4, GRM3, G72, PPP3CC, CHRNA7, PRODH2, Aktl, 5qGABA(A)] having physiological function in the brain have been identified and this supports the view of schizophrenia as a disorder of cerebral synaptic function. NMDA receptor-mediated glutamate transmission may be particularly involved, but disturbances of dopamine and GABA signalling seem to be linked as well. Based on recent data, an agreement is emerging between the roles of the genes on the molecular and synaptic levels and the understanding of the disorder at the neural systems level.
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PMID:[Gene polymorphism and gene expression in schizophrenia]. 1743 57

The early recognition of schizophrenia seems crucial; various studies relate a longer duration-of-untreated-psychosis to a worse prognosis. We give an overview over common psychopathological early recognition instruments (BSABS, CAARMS, SIPS, IRAOS, ERIraos). However, many clinical symptoms of prodromal schizophrenia stages are not sufficiently specific. Thus we review recent contributions of neuroimaging and electrophysiological as well as genetic studies: which new diagnostic perspectives offer endophenotypes (such as P300, P50 sensory gating, MMN, smooth pursuit eye movements; indicating a specific genetic vulnerability) together with a better understanding of schizophrenic pathophysiology (state-dependent biological markers, e.g. aggravated motor neurological soft signs during psychosis) in prodromal schizophrenia when still ambiguous clinical symptoms are present. Several examples (e.g. from COMT polymorphisms to working memory deficits) illustrate more specific underlying neuronal mechanisms behind behavioural symptoms. This way, a characteristic pattern of disturbed cerebral maturation might be distinguished in order to complement clinical instruments of early schizophrenia detection.
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PMID:Which perspectives can endophenotypes and biological markers offer in the early recognition of schizophrenia? 1751 28


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