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)

Dysbindin gene (DTNBP1) has been associated with schizophrenia, but literature findings are inconsistent, and further analyses are required. This study is aimed to investigate if a set of DTNBP1 variations might influence clinic psychotic phenotype or treatment response in a sample of 240 Korean schizophrenic in-patients. Four variants have been selected (rs3213207; rs1011313; rs16876759; rs2619522) on the basis of previous findings of association with schizophrenia, bipolar disorder and antidepressant response. Single marker analysis gave marginal results. Haplotype analysis identified a significant association between A-A (rs3213207(A/G), rs1011313(A/G)) haplotype and lower PANSS total and positive scores at baseline (p=0.01; 0.02) and at discharge (p=0.008; 0.005). Covariate analysis revealed a more stable significant association between A-A haplotype and baseline scores. These results suggest a protective effect of A-A haplotype on psychotic positive symptoms at baseline.
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PMID:DTNBP1 haplotype influences baseline assessment scores of schizophrenic in-patients. 1856

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.
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PMID:Systematic meta-analyses and field synopsis of genetic association studies in schizophrenia: the SzGene database. 1858 79

Schizophrenia (SCZ) is a complex trait with a high heritability. The DTNBP1 gene (encoding dysbindin) is one of the leading susceptible genes of SCZ. This risk gene has been reported to be associated with clinical symptoms such as negative symptoms and cognitive deficits. Although reduction of dysbindin expression in schizophrenic brain tissue has been reported, how this contributes to its symptomatology remains uncertain. The sandy (sdy) mouse, which harbors a spontaneously occurring deletion in the Dtnbp1 gene and expresses no dysbindin protein, provides a unique tool to study the role of dysbindin in SCZ. Our recent findings reveal that the sdy mice exhibit specific defects of neurosecretion and synaptic morphology in hippocampal neurons. We here further described that sdy manifested schizophrenia-like behaviors such as social withdrawal and cognitive deficits. In sdy hippocampus, the steady-state level of snapin (a SNAP25-binding protein and a synaptic priming regulator) was reduced due to loss of dysbindin. We further characterized that a 30-residue peptide in dysbindin (90-119 amino acids) mediated the interaction with snapin. Our results suggest that the destabilization of snapin in sdy mice may lead to abnormal neurotransmission and therefore abnormal behaviors. This further defines the sdy mutant as a potential model in schizophrenia research.
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PMID:Dysbindin deficiency in sandy mice causes reduction of snapin and displays behaviors related to schizophrenia. 1877 65

Schizophrenia is a common psychotic mental disorder that is believed to result from the effects of multiple genetic and environmental factors. In this study, we explored gene-gene interactions and main effects in both case-control (657 cases and 411 controls) and family-based (273 families, 1,350 subjects) datasets of English or Irish ancestry. Fifty three markers in 8 genes were genotyped in the family sample and 44 markers in 7 genes were genotyped in the case-control sample. The Multifactor Dimensionality Reduction Pedigree Disequilibrium Test (MDR-PDT) was used to examine epistasis in the family dataset and a 3-locus model was identified (permuted p=0.003). The 3-locus model involved the IL3 (rs2069803), RGS4 (rs2661319), and DTNBP1 (rs2619539) genes. We used MDR to analyze the case-control dataset containing the same markers typed in the RGS4, IL3 and DTNBP1 genes and found evidence of a joint effect between IL3 (rs31400) and DTNBP1 (rs760761) (cross-validation consistency 4/5, balanced prediction accuracy=56.84%, p=0.019). While this is not a direct replication, the results obtained from both the family and case-control samples collectively suggest that IL3 and DTNBP1 are likely to interact and jointly contribute to increase risk for schizophrenia. We also observed a significant main effect in DTNBP1, which survived correction for multiple comparisons, and numerous nominally significant effects in several genes.
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PMID:Interaction between interleukin 3 and dystrobrevin-binding protein 1 in schizophrenia. 1880 46

A number of reports have provided genetic evidence for an association between the DTNBP1 gene (coding dysbindin) and schizophrenia. In addition, sandy mice, which harbor a deletion in the DTNBP1 gene and lack dysbindin, display behavioral abnormalities suggestive of an association with schizophrenia. However, the mechanism by which the loss of dysbindin induces schizophrenia-like behaviors remains unclear. Here, we report that small interfering RNA-mediated knockdown of dysbindin resulted in the aberrant organization of actin cytoskeleton in SH-SY5Y cells. Furthermore, we show that morphological abnormalities of the actin cytoskeleton were similarly observed in growth cones of cultured hippocampal neurons derived from sandy mice. Moreover, we report a significant correlation between dysbindin expression level and the phosphorylation level of c-Jun N-terminal kinase (JNK), which is implicated in the regulation of cytoskeletal organization. These findings suggest that dysbindin plays a key role in coordinating JNK signaling and actin cytoskeleton required for neural development.
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PMID:Dysbindin engages in c-Jun N-terminal kinase activity and cytoskeletal organization. 1909 65

Synaptosomal Associated Protein 25 kDa (SNAP25) has been implicated in the pathogenesis of schizophrenia by numerous neuropathological studies and genetic variation at SNAP25 has been reported to be associated with ADHD. Expression levels of the putative schizophrenia susceptibility gene DTNBP1 has been shown to influence the levels of SNAP25 in vitro. We undertook directed mutation screening of SNAP25 in UK schizophrenic cases followed by direct association analysis of all variants identified and identified known exonic SNPs that showed evidence for association (rs3746544 P = 0.004 OR = 1.26, rs8636 P = 0.003 OR = 1.27), although these SNPs are highly correlated (r(2) > 0.99). We additionally genotyped a further 31 tag SNPs spanning the SNAP25 locus and identified several independent SNPs that were nominally associated with schizophrenia (strongest association at rs3787283, P = 0.006, OR = 1.25) however, due to the number of tests performed no SNP met experiment-wise significance (minimum permuted P-value = 0.1). Post hoc analysis revealed that the SNPs nominally associated with schizophrenia (rs3787283, rs3746544) were the same as those previously demonstrated to be associated with ADHD but with the opposite alleles, allowing the intriguing hypothesis that genetic variation at SNAP25 may be differentially associated with both schizophrenia and ADHD.
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PMID:Evidence that putative ADHD low risk alleles at SNAP25 may increase the risk of schizophrenia. 1913 10

DTNBP1 has been recognized as a schizophrenia susceptible gene, and its protein product, dysbindin-1, is down-regulated in the brains of schizophrenic patients. However, little is known about the physiological role of dysbindin-1 in the central nervous system. We hypothesized that disruption of dysbindin-1 with unidentified proteins could contribute to pathogenesis and the symptoms of schizophrenia. GST pull-down from human neuroblastoma lysates showed an association of dysbindin-1 with the DNA-dependent protein kinase (DNA-PK) complex. The DNA-PK complex interacts only with splice isoforms A and B, but not with C. We found that isoforms A and B localized in nucleus, where the kinase complex exist, whereas the isoform C was found exclusively in cytosol. Furthermore, results of phosphorylation assay suggest that the DNA-PK complex phosphorylated dysbindin-1 isoforms A and B in cells. These observations suggest that DNA-PK regulates the dysbindin-1 isoforms A and B by phosphorylation in nucleus. Isoform C does not contain exons from 1 to 6. Since schizophrenia-related single nucleotide polymorphisms (SNPs) occur in these introns between exon 1 and exon 6, we suggest that these SNPs might affect splicing of DTNBP1, which leads to impairment of the functional interaction between dysbindin-1 and DNA-PK in schizophrenic patients.
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PMID:Dysbindin-1, a schizophrenia-related protein, functionally interacts with the DNA- dependent protein kinase complex in an isoform-dependent manner. 1914 23

It has been difficult to identify disease-causing alleles in schizophrenia (SZ) and bipolar disorder (BD) candidate genes. One reason is that responsible functional variants may exist in unidentified regulatory domains. With the advent of microarray technology and high throughput sequencing, however, it is now feasible to screen genes for such regulatory domains relatively easily by using chromatin immunoprecipitation-based methodologies, such as ChIP-chip and ChIP-seq. In ChIP-chip, regulatory sequences can be captured from chromatin immunoprecipitates prepared with antibodies against covalently modified histones that mark certain regulatory domains; DNA extracted from such immunoprecipitates can then be used as microarray probes. As a first step toward demonstrating the feasibility of this approach in psychiatric genetics, we used ChIP-chip to identify regulatory domains in several candidate genes: NRG1, DTNBP1, DISC1, DAO, DAOA, PDE4B, and COMT. Immunoprecipitates were generated with antibodies to histone H3 acetylated at lysine 9 (H3K9Ac) and histone H3 monomethylated at lysine 4 (H3K4me1), which mark promoters and some enhancers, using fetal brain chromatin as a substrate. Several novel putative regulatory elements, as well as the core and proximal promoters for each gene, were enriched in the immunoprecipitates. Genetic variants within these regions would be of interest to study as potential disease-associated alleles.
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PMID:Survey of schizophrenia and bipolar disorder candidate genes using chromatin immunoprecipitation and tiled microarrays (ChIP-chip). 1922 52

Dysbindin gene (DTNBP1) has been consistently reported to be associated with schizophrenia. However data from East Asian population has been sparse and inconsistent till today. This study tried to replicate the genetic association of DTNBP1 with schizophrenia in a large Korean sample, as well as analyzing the association of DTNBP1 with clinical variables. Nine hundred and eight (908) patients with schizophrenia and 601 controls were investigated. The high-throughput genotyping method using pyrosequencer (Biotage AB, Sweden) was used for genotyping 4 SNPs (rs3213207, rs1011313, rs760761, and rs2619522). Haplotype analyses revealed a significant association with schizophrenia (P < 0.0001) with the haplotypes A-C-C-C and A-C-T-A having an eminent protective effect toward schizophrenia. The major contribution to the difference in the haplotype distribution between patients and the controls was the rs760761 (C/T) and rs2619522 (A/C) haplotypes (P < 0.0001). No association of DTNBP1 with other clinical variables was found. In conclusion, the present study suggests a possible protective effect of rare DTNBP1 variants in schizophrenia, although subsequent studies in different ethnic groups are warranted.
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PMID:Dysbindin gene (DTNBP1) and schizophrenia in Korean population. 1925 39

Schizophrenia is a common psychiatric disorder characterized by disturbances of cognition, emotion and social functioning. There are few studies investigating a possible genetic basis for the underlying mechanism of cognitive dysfunctions. A genetic variation in the dysbindin gene (DTNBP1: dystrobrevin binding protein 1), a susceptibility gene for schizophrenia, has been reported to be associated with general cognitive ability and cognitive decline in patients with schizophrenia. Although profound disturbances of memory performance are observed in schizophrenia, only one study has reported a relationship between this gene and spatial working memory in a Caucasian population. We examined a possible association between a protective haplotype of DTNBP1 for developing schizophrenia and memory performance measured by the Wechsler Memory Scale-Revised (WMS-R) and the Wechsler Adult Intelligence Scale-Revised (WAIS-R) in 165 healthy volunteers and 70 patients with schizophrenia in a Japanese population. Healthy controls that carry the protective haplotype showed higher performance in several memory domains measured by the WMS-R than those who did not. Genotype effect on memory performance was not observed in patients with schizophrenia. This haplotype did not affect IQ and its sub-scores as measured by the Wechsler Adult Intelligence Scale-Revised in both groups. These data suggest that DTNBP1 may have impact on parts of memory functions.
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PMID:A genetic variation in the dysbindin gene (DTNBP1) is associated with memory performance in healthy controls. 1935 85


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