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

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.
 ...
PMID:Schizophrenia: genes at last? 1600 49

The disrupted in schizophrenia 1 (DISC1) gene is a candidate susceptibility factor for schizophrenia, but its mechanistic role in the disorder is unknown. Here we report that the gene encoding phosphodiesterase 4B (PDE4B) is disrupted by a balanced translocation in a subject diagnosed with schizophrenia and a relative with chronic psychiatric illness. The PDEs inactivate adenosine 3',5'-monophosphate (cAMP), a second messenger implicated in learning, memory, and mood. We show that DISC1 interacts with the UCR2 domain of PDE4B and that elevation of cellular cAMP leads to dissociation of PDE4B from DISC1 and an increase in PDE4B activity. We propose a mechanistic model whereby DISC1 sequesters PDE4B in resting cells and releases it in an activated state in response to elevated cAMP.
 ...
PMID:DISC1 and PDE4B are interacting genetic factors in schizophrenia that regulate cAMP signaling. 1629 46

Several lines of evidence support the involvement of the disrupted in schizophrenia 1 (DISC1) gene in schizophrenia susceptibility, including its original identification in a schizophrenia family with a chromosome translocation, several genetic association studies, and functional characterization of the gene product. In the present study, we have genotyped multiple SNP and microsatellite markers in a large Scottish case-control sample. We identified two SNPs and one microsatellite that show significant association with schizophrenia. The strongest association is with a haplotype of SNPs rs751229 and rs3738401, located at the 5' end of the gene; the C-A haplotype of these SNPs is associated with a relative risk of schizophrenia of 5 in our population. We also observe association with a microsatellite in intron 7, but no association with markers toward the 3' end of the gene. The results are in broad agreement with those of other genetic studies, but there are differences in terms of the precise patterns of association. This analysis further strengthens the candidacy of DISC1 as a risk factor for schizophrenia in the general population, and suggests that more intensive searching for causative variants is justified.
 ...
PMID:Genetic association between schizophrenia and the DISC1 gene in the Scottish population. 1638 90

Schizophrenia and bipolar affective disorder are common, debilitating, and poorly understood and treated disorders. Both conditions are highly heritable. Recent genetic studies have suggested that the gene disrupted in schizophrenia 1 (DISC1) is an important risk factor. DISC1 seems to have a key role in building the brain and memories by interacting with other proteins, including nuclear distribution E-like protein and phosphodiesterase 4B. Here, we review the current knowledge, highlight some key unanswered questions and propose ways forward towards a better understanding of normal and abnormal brain development and function. In the long term, this might lead to the discovery of drugs that are more efficacious and safer than currently available ones.
 ...
PMID:Disrupted in schizophrenia 1: building brains and memories. 1667 65

The disrupted in schizophrenia 1 (DISC1) gene has been identified as a schizophrenia susceptibility gene based on linkage and single nucleotide polymorphism (SNP) association studies and clinical data, suggesting that risk SNPs impact on hippocampal structure and function. We hypothesized that altered expression of DISC1 and/or its molecular partners (nuclear distribution element-like [NUDEL], fasciculation and elongation protein zeta-i [FEZ1], and lissencephaly 1 [LIS1]) may underlie its pathogenic role in schizophrenia and explain its genetic association. We examined the expression of DISC1 and its binding partners in the hippocampus and dorsolateral prefrontal cortex of postmortem human brains of schizophrenic patients and controls. We found no difference in the expression of DISC1 mRNA in schizophrenia, and no association with previously identified risk SNPs. However, the expression of NUDEL, FEZ1, and LIS1 was significantly reduced in tissue from schizophrenic subjects, and the expression of each showed association with high-risk DISC1 polymorphisms. These data suggest involvement of genetically linked abnormalities in the DISC1 molecular pathway in the pathophysiology of schizophrenia.
 ...
PMID:Functional genomics in postmortem human brain: abnormalities in a DISC1 molecular pathway in schizophrenia. 1711 17

The disrupted in schizophrenia 1 (DISC1) gene has been linked to schizophrenia and other serious mental illnesses in multiple pedigrees. This article will review the neurobiology of DISC1 in normal developing and adult brain and the putative role of the mutant form in major mental illness, particularly schizophrenia. The initial genetic finding of an association between DISC1 and schizophrenia in a Scottish population has now been replicated in Finnish, American, Japanese, and Taiwanese populations. DISC1 is present throughout the brain of a variety of species during development and adulthood, including many of the brain regions known to be abnormal in schizophrenia, such as the prefrontal cortex, hippocampus, and thalamus. The functions of DISC1 in the developing brain include neuronal migration, neurite outgrowth, and neurite extension. In the adult, DISC1 has been identified in multiple populations of neurons and in structures associated with synaptic function, suggesting that one of its adult functions may be synaptic plasticity. DISC1 is associated with numerous cognitive functions that are abnormal in schizophrenia. Converging evidence from cell culture, mice mutants, postmortem brain, and genetics implicates mutant DISC1 in the pathophysiology of schizophrenia and other mental illnesses.
 ...
PMID:Schizophrenia in translation: disrupted in schizophrenia (DISC1): integrating clinical and basic findings. 1713 82

To further clarify schizophrenia (SCZ), disrupted in schizophrenia 1 (DISC1) is a promising candidate gene expressed predominantly within the hippocampus. Several lines of evidence suggest that DISC1 may be involved in susceptibility to SCZ. In this study, we investigated whether genetic polymorphisms in the coding region of DISC1 were associated with several SCZ clinical phenotypes in a Korean population. To examine any association between DISC1 and SCZ, we genotyped three clinical single nucleotide polymorphisms (SNPs) (rs3738401, R264Q; rs3738402, L465L; rs821616, S704C) in the coding region of the DISC1 gene using the Illumina Sentrix Array Matrix chip and direct sequencing in 303 patients with SCZ and 300 healthy controls. Our case-control analysis showed that none of these SNPs was associated with SCZ. In further endophenotype stratification, however, we found a significant association between rs821616 and the poor concentration subgroup of SCZ, determined using the Operational Criteria Checklist (codominant model, p=0.015). Our results suggest that DISC1 may be a susceptibility gene for poor concentration among Korean patients with SCZ.
 ...
PMID:Association study of polymorphisms between DISC1 and schizophrenia in a Korean population. 1799 36

There is current interest in understanding genetic influences on both healthy and disordered brain function. We assessed brain function with functional magnetic resonance imaging (fMRI) data collected during an auditory oddball task--detecting an infrequent sound within a series of frequent sounds. Then, task-related imaging findings were utilized as potential intermediate phenotypes (endophenotypes) to investigate genomic factors derived from a single nucleotide polymorphism (SNP) array. Our target is the linkage of these genomic factors to normal/abnormal brain functionality. We explored parallel independent component analysis (paraICA) as a new method for analyzing multimodal data. The method was aimed to identify simultaneously independent components of each modality and the relationships between them. When 43 healthy controls and 20 schizophrenia patients, all Caucasian, were studied, we found a correlation of 0.38 between one fMRI component and one SNP component. This fMRI component consisted mainly of parietal lobe activations. The relevant SNP component was contributed to significantly by 10 SNPs located in genes, including those coding for the nicotinic alpha-7 cholinergic receptor, aromatic amino acid decarboxylase, disrupted in schizophrenia 1, among others. Both fMRI and SNP components showed significant differences in loading parameters between the schizophrenia and control groups (P = 0.0006 for the fMRI component; P = 0.001 for the SNP component). In summary, we constructed a framework to identify interactions between brain functional and genetic information; our findings provide a proof-of-concept that genomic SNP factors can be investigated by using endophenotypic imaging findings in a multivariate format.
 ...
PMID:Combining fMRI and SNP data to investigate connections between brain function and genetics using parallel ICA. 1807 79

Activating transcription factor 4 (ATF4) is considered as a positional candidate gene for schizophrenia due to its location at chromosome 22q13, a region linked to schizophrenia. Furthermore, as protein interaction partner of ATF4, disrupted in schizophrenia 1 (DISC1) and its signal pathway implicated in the pathophysiology of schizophrenia have been widely supported by a number of genetic and neurobiological studies. Our aim was to investigate whether ATF4 is associated with schizophrenia in case-control samples of Han Chinese subjects consisting of 352 schizophrenia patients and 357 healthy controls. We detected 18 single nucleotide polymorphisms (SNPs) in ATF4 locus, two of which were analyzed, including one insertion at the putative core promoter region (rs17001266, -/C) and one nonsynonymous variant in exon 1 (rs4894, C/A, Pro22Gln). Allele distributions of two SNPs showed significant associations with schizophrenia in male subjects (respectively, rs17001266: P = 0.021, OR = 1.58, 95% CI = 1.07-2.33; rs4894: P = 0.004, OR = 1.78, 95% CI = 1.19-2.67), but not in female subjects as well as the entire population. Two haplotypes CC and -A constructed of rs17001266-rs4894 also revealed significant associations with schizophrenia in male group (global P = 0.0097). These findings support that ATF4 gene may be involved in susceptibility to schizophrenia with sex-dependent effect in the Chinese Han population and suggest that further functional assays are needed to verify their relevance to the pathogenesis of schizophrenia.
 ...
PMID:Associations of ATF4 gene polymorphisms with schizophrenia in male patients. 1816 33

FEZ1 (fasciculation and elongation protein zeta 1), a mammalian ortholog of Caenorhabditis elegans UNC-76, interacts with DISC1 (disrupted in schizophrenia 1), a schizophrenia susceptibility gene product, and polymorphisms of human FEZ1 have been associated with schizophrenia. We have now investigated the role of FEZ1 in brain development and the pathogenesis of schizophrenia by generating mice that lack Fez1. Immunofluorescence staining revealed FEZ1 to be located predominantly in gamma-aminobutyric acid-containing interneurons. The Fez1(-/-) mice showed marked hyperactivity in a variety of behavioral tests as well as enhanced behavioral responses to the psychostimulants MK-801 and methamphetamine. In vivo microdialysis revealed that the methamphetamine-induced release of dopamine in the nucleus accumbens was exaggerated in the mutant mice, suggesting that enhanced mesolimbic dopaminergic transmission contributes to their hyperactivity phenotype. These observations implicate impairment of FEZ1 function in the pathogenesis of schizophrenia.
 ...
PMID:Mice lacking the schizophrenia-associated protein FEZ1 manifest hyperactivity and enhanced responsiveness to psychostimulants. 1864 54


1 2 3 4 5 Next >>