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)

Schizophrenia is hypothesized as a neurodevelopmental and neurodegenerative disorder based on the following findings. 1. MRI studies have revealed brain structural abnormalities from the onset of schizophrenia and the progress of these structural abnormalities. 2. Histopathological studies have elucidated cytoarchitectural abnormalities in schizophrenic brains without gliosis. 3. Obstetric complications are one of the risk factors for schizophrenia. 4. Relapse of schizophrenia results in a deteriorating progress of the disorder. Furthermore, data from family, twin and adoption studies show evidence of a substantial genetic component in schizophrenia, Thus, a molecular genetic study combined with a neurodevelopmental and neurodegenerative hypothesis is required to elucidate the pathophysiology of schizophrenia. The positive association between neuregulin 1 and Icelandic schizophrenia that has been reproduced in Scottish and North European schizophrenia is one of the intriguing examples of this type of research. Neuregulin 1 regulates the cytoarchitecture of brain. Mice mutated for neuregulin 1 show a behavioral phenotype that overlaps with mouse models for schizophrenia. Furthermore, the behavioral phenotypes of the neuregulin 1 hypomorphs are reversible with clozapine. We also demonstrated a positive association between schizophrenia and a 5-HT5A receptor polymorphism, Pro15Ser, that may have role in cell differentiation in the brain.
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PMID:[Bridging the genomic approach and the neurodevelopmental and neurodenerative hypothesis of schizophrenia]. 1548 22

Neuregulin 1 is involved both in neurodevelopment and neurotransmitter mechanisms in the brain. There is evidence of an association between neuregulin 1 genotype and schizophrenia. We compared neuregulin 1 genotypes in patients with schizophrenia (n=94) and control subjects (n=395) of Finnish origin by using one SNP (SNP8NRG221533) as a genetic marker. We also analyzed NRG1 genotype with regard to age at onset and between responders and non-responders to conventional antipsychotics. The NRG1 genotype or allele frequencies showed similar distributions between patient and control groups. Age at onset was not associated with NRG1 genotype. The TT genotype was overrepresented in the non-responders group compared with the responders (p=0.013). Further studies are needed to ascertain the significance of neuregulin genotype in medication response to schizophrenia.
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PMID:Neuregulin genotype and medication response in Finnish patients with schizophrenia. 1553 86

Schizophrenia is a common, multigenic psychiatric disorder. Linkage studies, including a recent meta-analysis of genome scans, have repeatedly implicated chromosome 8p12-p23.1 in schizophrenia susceptibility. More recently, significant association with a candidate gene on 8p12, neuregulin 1 (NRG1), has been reported in several European and Chinese samples. We investigated NRG1 for association in schizophrenia patients of Portuguese descent to determine whether this gene is a risk factor in this population. We tested NRG1 markers and haplotypes for association in 111 parent-proband trios, 321 unrelated cases, and 242 control individuals. Associations were found with a haplotype that overlaps the risk haplotype originally reported in the Icelandic population ("Hap(ICE)"), and two haplotypes located in the 3' end of NRG1 (all P<0.05). However, association was not detected with Hap(ICE) itself. Comparison of NRG1 transcript expression in peripheral leukocytes from schizophrenia patients and unaffected siblings identified 3.8-fold higher levels of the SMDF variant in patients (P=0.039). Significant positive correlations (P<0.001) were found between SMDF and HRG-beta 2 expression and between HRG-gamma and ndf43 expression, suggesting common transcriptional regulation of NRG1 variants. In summary, our results suggest that haplotypes across NRG1 and multiple NRG1 variants are involved in schizophrenia.
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PMID:Support for involvement of neuregulin 1 in schizophrenia pathophysiology. 1554 78

The S100B gene locates in 21q22.3 and produces neurotrophin mainly in astrocytes of CNS which can act as an extensive marker of glial cell integrity. The synaptic destabilization hypothesis (GGF/SD) suggests that the functional deficiency of growth factors like S100B is involved in the etiology of schizophrenia and the S100B serum concentration is reported to be significantly increased in patients with acute schizophrenia and decreased in chronic schizophrenia patients. To validate the association between S100B and schizophrenia, 384 cases and 401 controls, all Chinese Han subjects, were recruited. Four SNPs V1 (-960C>G), V2 (-111C>T), V3 (2757C>G, rs1051169), and V4 (5748C>T, rs9722) were studied. And haplotype V3-V4 (G-C) showed a significant association with schizophrenia. Our study showed an association between schizophrenia and a possible susceptible haplotype V3-V4 (G-C) which possesses a genetic tendency for increased S100B expression. Our results suggest that S100B could be a susceptible gene for schizophrenia and provide indirect evidence for the GGF/SD hypothesis.
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PMID:SNPs and haplotypes in the S100B gene reveal association with schizophrenia. 1567 Jul 88

Positive linkage of schizophrenia to chromosome 8p22-21 loci had been reported in the Caucasian samples. This study was designed to replicate this finding by using eleven microsatellite markers on chromosome 8p22-21 in 52 Taiwanese schizophrenic families with at least two affected siblings. Two phenotype models (narrow: DSM-IV schizophrenia only; and broad: including schizophrenia, schizoaffective, and other non-affective psychotic disorders) were used to define the disease phenotype. Maximum non-parametric linkage scores (NPL score) of 2.45 (P = 0.008) and 1.89 (P = 0.02) were obtained for the marker D8S1222 under the broad and narrow models, respectively. Positive linkage was found across about a 4-cM region. The marker D8S1222 was about 400 kbp distal to the exon 1 of glial growth factor 2 (GGF2), an isoform of Neuregulin 1 gene (NRG1), which has been highly suggested to be a candidate gene for schizophrenia. The results provide suggestive linkage evidence of schizophrenia to loci near NRG1 on chromosome 8p21 in an ethnically distinct Taiwanese sample. Further exploration of the candidate gene and nearby chromosome regions is warranted.
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PMID:Linkage evidence of schizophrenia to loci near neuregulin 1 gene on chromosome 8p21 in Taiwanese families. 1570 28

Genetic epidemiological studies suggest that individual variation in susceptibility to schizophrenia is largely genetic, reflecting alleles of moderate to small effect in multiple genes. Molecular genetic studies have identified several potential regions of linkage and two associated chromosomal abnormalities, and evidence is accumulating in favour of several positional candidate genes. Currently, the positional candidate genes for which we consider the evidence to be strong are those encoding dysbindin (DTNBP1) and neuregulin 1 (NRG1). For other genes, disrupted in schizophrenia 1 (DISC1), D-amino-acid oxidase (DAO), D-amino-acid oxidase activator (DAOA, formerly known as G72) and regulator of G-protein signalling 4 (RGS4), the data are promising but not yet compelling. The identification of these, and other susceptibility genes, will open up new avenues for research aimed at understanding the pathogenesis of schizophrenia, and will catalyse a re-appraisal of the classification of psychiatric disorders.
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PMID:Schizophrenia: genes at last? 1600 49

Chromosome 8p22-p11 has been identified as a locus for schizophrenia in several genome-wide scans, which has been confirmed by meta-analysis of published linkage data. It appears to be 1 of the most robust linkage findings in psychosis. Several attempts have been made to identify the underlying genetic variation that gives rise to this linkage peak, including systematic fine mapping using extended Icelandic pedigrees that have identified an associated haplotype (HAP(ICE)) in the gene neuregulin 1, also known as heuregulin, glial growth factor, NDF43, and ARIA. Neuregulin 1 (NRG1) is a plausible susceptibility gene because of its involvement in neurodevelopment, regulation of glutamate and other neurotransmitter receptor expression, and synaptic plasticity. Encouragingly, this finding was quickly and directly replicated in a Scottish case-control sample by the same investigators with the same approximately 300 kb associated haplotype. Although in Caucasian populations subsequent attempts at replication of this finding have been difficult to interpret, and no individual functional or causative genetic variants have yet been identified, a summary of HAP(ICE) association results in about 4,500 subjects is consistent with a small (odds ratio approximately 1.5) but significant effect of this haplotype on schizophrenia risk. In Chinese Han populations, where HAP(ICE) is not found, there is good evidence from several studies of association with other markers in the same region. Overall, there is convincing but not yet compelling evidence for a role for NRG1 in susceptibility to schizophrenia. Other genes from this region have also been implicated in schizophrenia, not by systematic mapping but by positional candidate gene analysis; these include MSTP131, frizzled-3, and the calcineurin A gamma subunit gene. Not only are these alternative explanations for the linkage seen between chromosome 8p and schizophrenia, but it is equally possible that there is more than 1 susceptibility gene at this locus.
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PMID:Association between the neuregulin 1 gene and schizophrenia: a systematic review. 1608 9

The high pathogenetic relevance of genetic factors in schizophrenia is beyond doubt based on the findings of epidemiological studies. By means of a complex mode of transmission, it is likely that several genes with weak to moderate effect jointly constitute a genetic basis for a vulnerability to schizophrenia that may well vary for different individuals. Other organic and psychosocial factors also play an individually different -- in some cases significant -- role in terms of pathogenesis, as a result of which an oligogenic/polygenic multifactor model is assumed from the standpoint of aetiopathogenetics. Molecular genetic methods consist in linkage analyses and association analyses. Positive linkage findings accumulate particularly for the chromosomes 1q, 6p, 8p, 13q and 22q. By themselves, individual mutations contribute little to the range of schizophrenic feature characteristics, it was not possible -- irrespective of some subtypes -- to replicate genes of major effect. From the large number of possible candidate genes, although studies on DRD3, DRD2 and HTR2A produced positive results, the magnitudes of effect were low. The findings for alleles of dysbindin, neuregulin 1, DAO, COMT, PRODH, ZDHHC and DISC are less clear. The search for schizophrenia-relevant mutations is hampered by the possibility of a heterogeneous phenotype of schizophrenia in case of a homogeneous genotype as much as by the possibility of inter-individually homogeneous phenotypical characteristics in case of schizophrenia-relevant heterotype in the genome. With the aid of the concept of endo-phenotypes, based on neurobiological phenomena, it might be possible to take a more direct approach that leads from relevant mutations to the risk of schizophrenias. However, replacing schizophrenic alienation with neurobiological aspects leads to difficulties in explaining these complex disorder profiles. Schizophrenic diseases require an explanatory approach that also incorporates personality and developmental psychological aspects from the outset, if the aim is not to restrict type of schizophrenic disease exclusively to loci of molecular genetic changes.
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PMID:[Genetic risk factors in schizophrenia]. 1627 Feb 44

Linkage analysis and association studies have pointed to neuregulin 1 (NRG1) as the prime candidate for 8p-linked schizophrenia (SZ). However, so far, no specific functional alleles in the gene's exons, intron-exon junctions and promoters have been identified that are unequivocally associated with SZ. In this study, we analyzed several NRG1 polymorphisms that affect ATTT motifs and AT-rich regions of the gene. We have previously identified a number of such polymorphisms in the promoters of other SZ and bipolar disorder (BD) candidate genes and found positive associations to several of them. In addition, allele specific differences in the binding of brain proteins have been found for many of the polymorphisms. A case control design was used to compare allele frequencies in Caucasian and African American patients with SZ and controls. In the African American group, a significant difference was found in the allele and genotype distribution for several of the markers and haplotype blocks located in the 5'- and 3'-ends of the gene. The most significant result was obtained for rs6150532, an insertion/deletion variant in a conserved region of an intron that separates two small, alternatively spliced exons. Allele-specific and developmental differences were detected in the binding of a brain protein using newborn rat pups when probes containing the two rs6150532 alleles were used in electromobility gel shift assays. There were no significant differences in allele or genotype distribution found for any of the markers in the Caucasian sample. Although the samples size is relatively small, the findings support a role for NRG1 in SZ in African Americans and suggest that polymorphic differences in regions of the gene that recognize AT-binding proteins may be a factor in disease pathogenesis.
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PMID:Analysis of polymorphisms in AT-rich domains of neuregulin 1 gene in schizophrenia. 1628 46

Dysfunction of glial lipid metabolism and abnormal myelination has recently been reported in both schizophrenia and bipolar disorder. Cholesterol is a major component of myelin, and glia-produced cholesterol serves as a glial growth factor in synaptogenesis. We have recently demonstrated that antipsychotic drugs activate the sterol regulatory element-binding protein (SREBP) transcription factors in human and rat glial cells, with subsequent up-regulation of numerous downstream genes involved in cholesterol and fatty acid biosynthesis. Since this stimulation of cellular lipogenesis could represent a new mechanism of action of psychotropic drugs, we investigated whether antidepressants and mood-stabilizers were able to induce a similar activation of SREBP-controlled lipid biosynthesis. Cultured human glioma cells (GaMg) were exposed to the antidepressant drugs imipramine, amitriptyline, clomipramine, citalopram, fluoxetine, mirtazapine and bupropion and the mood-stabilizers/antiepileptics lithium, valproate and carbamazepine. All antidepressant drugs activated the SREBP system with subsequent up-regulation of the downstream lipogenesis-related genes, although to a markedly different extent. The mood-stabilizers did not affect the SREBPs or the downstream genes. These results link antidepressant drugs, but not mood-stabilizers, to SREBP-mediated activation of cellular lipogenesis, and demonstrate a functional similarity between antipsychotic and antidepressant molecular drug action.
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PMID:Antidepressant drugs activate SREBP and up-regulate cholesterol and fatty acid biosynthesis in human glial cells. 1632 87


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