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)

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

Genome-scans performed in schizophrenia families have provided evidence for region 6p24-21 where variability may confer susceptibility to schizophrenia. Recent studies have implicated that gene DTNBP1 (dysbindin) in this region is strongly associated with schizophrenia. In a family based association study we investigated three markers located in the untranslated region of the DTNBP1 gene: rs909706, rs1047631 and rs742106. The sample size of our study is 117 families. No biased transmission towards the disorder was detected by haplotype analysis using TRANSMIT.
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PMID:Untranslated region haplotype in dysbindin gene: analysis in schizophrenia. 1613 86

Over recent years the gene DTNBP1 (chromosome 6p24-22) has emerged as one of the most promising candidate genes for schizophrenia. In this article, we review the current genetic evidence that implicates DTNBP1 as a schizophrenia-susceptibility gene. While there is now impressive support from genetic association studies, it is important to remain aware that the actual DTNBP1 susceptibility variants have not been identified. While functional analyses have allowed us to speculate their likely function, only when they are identified will we be able to confidently specify the type of altered gene function that is relevant to schizophrenia pathogenesis. This we hope will then open up new vistas for neurobiological research, allowing us to study the exact contribution of DTNBP1 in schizophrenia, its relationships with various aspects of the phenotype, and the potential of epistatic interactions with other genes, as well as functional interactions between the gene products.
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PMID:Is the dysbindin gene (DTNBP1) a susceptibility gene for schizophrenia? 1616 6

Straub et al. (2002) recently identified the 6p22.3 gene dysbindin (DTNBP1) through positional cloning as a schizophrenia susceptibility gene. We studied a rare cohort of 102 children with onset of psychosis before age 13. Standardized ratings of early development, medication response, neuropsychological and cognitive performance, premorbid dysfunction and clinical follow-up were obtained. Fourteen SNPs were genotyped in the gene DTNBP1. Family-based pairwise and haplotype transmission disequilibrium test (TDT) analysis with the clinical phenotype, and quantitative transmission disequilibrium test (QTDT) explored endophenotype relationships. One SNP was associated with diagnosis (TDT p=.01). The QTDT analyses showed several significant relationships. Four adjacent SNPs were associated (p values=.0009-.003) with poor premorbid functioning. These findings support the hypothesis that this and other schizophrenia susceptibility genes contribute to early neurodevelopmental impairment.
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PMID:Dysbindin (DTNBP1, 6p22.3) is associated with childhood-onset psychosis and endophenotypes measured by the Premorbid Adjustment Scale (PAS). 1628 82

It has been conventional for psychiatric research, including the search for predisposing genes, to proceed under the assumption that schizophrenia and bipolar disorder are separate disease entities with different underlying etiologies. These represent Emil Kraepelin's traditional dichotomous classification of the so-called "functional" psychoses and form the basis of modern diagnostic practice. However, findings emerging from many fields of psychiatric research do not fit well with this model. In particular, the pattern of findings emerging from genetic studies shows increasing evidence for an overlap in genetic susceptibility across the traditional classification categories-including association findings at DAOA(G72), DTNBP1 (dysbindin), COMT, BDNF, DISC1, and NRG1. The emerging evidence suggests the possibility of relatively specific relationships between genotype and psychopathology. For example, DISC1 and NRG1 may confer susceptibility to a form of illness with mixed features of schizophrenia and mania. The elucidation of genotype-phenotype relationships is at an early stage, but current findings highlight the need to consider alternative approaches to classification and conceptualization for psychiatric research rather than continuing to rely heavily on the traditional Kraepelinian dichotomy. As psychosis susceptibility genes are identified and characterized over the next few years, this will have a major impact on our understanding of disease pathophysiology and will lead to changes in classification and the clinical practice of psychiatry.
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PMID:Genes for schizophrenia and bipolar disorder? Implications for psychiatric nosology. 1631 75

Impressive advances in the last decade have been made in the genetics and neuroscience of neuropsychiatric illness. Synergies between complex genetics, elaboration of intermediate phenotypes (Egan et al. (2004) Schizophrenia. London: Blackwell) and novel applications in neuroimaging (Bookheimer et al. (2000) N Engl J Med, 343, 450-456) are revealing the effects of positively associated disease alleles on aspects of neurological function. Genes such as NRG-1, DISC1, RGS4, COMT, PRODH, DTNBP1, G72, DAAO, GRM3 (Harrison and Weinberger (2005) Mol Psychiatry, 10, 40-68) and others have been implicated in schizophrenia along with 5-HTTPR (Ogilvie et al. (1996) Lancet, 347, 731-733; Caspi et al. (2003) Science, 301, 386-389) and BDNF (Geller et al. (2004) Am J Psychiatry, 161, 1698-1700) in affective disorders. As the genetics and complex neurocircuits of these and disorders are being untangled, parallel applications in pharmacogenomics and gene-based drug metabolism are shaping a drive for personalized medicine. Genetic research and pharmacogenomics suggest that the subcategorization of individuals based on various sets of susceptibility alleles will make the treatment of neuropsychiatric and other illnesses more predictable and effective.
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PMID:Psychiatric genetics--the new era: genetic research and some clinical implications. 1636 81

Bipolar, schizophrenia, and schizoaffective disorders are common, highly heritable psychiatric disorders, for which familial coaggregation, as well as epidemiological and genetic evidence, suggests overlapping etiologies. No definitive susceptibility genes have yet been identified for any of these disorders. Genetic heterogeneity, combined with phenotypic imprecision and poor marker coverage, has contributed to the difficulty in defining risk variants. We focused on families of Ashkenazi Jewish descent, to reduce genetic heterogeneity, and, as a precursor to genomewide association studies, we undertook a single-nucleotide polymorphism (SNP) genotyping screen of 64 candidate genes (440 SNPs) chosen on the basis of previous linkage or of association and/or biological relevance. We genotyped an average of 6.9 SNPs per gene, with an average density of 1 SNP per 11.9 kb in 323 bipolar I disorder and 274 schizophrenia or schizoaffective Ashkenazi case-parent trios. Using single-SNP and haplotype-based transmission/disequilibrium tests, we ranked genes on the basis of strength of association (P<.01). Six genes (DAO, GRM3, GRM4, GRIN2B, IL2RB, and TUBA8) met this criterion for bipolar I disorder; only DAO has been previously associated with bipolar disorder. Six genes (RGS4, SCA1, GRM4, DPYSL2, NOS1, and GRID1) met this criterion for schizophrenia or schizoaffective disorder; five replicate previous associations, and one, GRID1, shows a novel association with schizophrenia. In addition, six genes (DPYSL2, DTNBP1, G30/G72, GRID1, GRM4, and NOS1) showed overlapping suggestive evidence of association in both disorders. These results may help to prioritize candidate genes for future study from among the many suspected/proposed for schizophrenia and bipolar disorders. They provide further support for shared genetic susceptibility between these two disorders that involve glutamate-signaling pathways.
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PMID:Bipolar I disorder and schizophrenia: a 440-single-nucleotide polymorphism screen of 64 candidate genes among Ashkenazi Jewish case-parent trios. 1638 Sep 5

DTNBP1 (dysbindin) is one of the several putative schizophrenia genes supported by association, neuroanatomical, and cellular studies. These suggest an involvement of DTNBP1 in the prefrontal cortex and cognitive functions mediated by interaction with neurotransmitter systems, in particular glutamate. The influence of DTNBP1 gene variation on prefrontal brain function at the systemic neurophysiological level, though, has not been characterized. The NoGo-anteriorization (NGA) as an event-related potential (ERP) measure elicited during the continuous performance test (CPT) has been established as a valid neurophysiological parameter for prefrontal brain function in healthy individuals and patients with schizophrenias. In the present study, we therefore investigated the influence of eight dysbindin gene variants on the NGA as a marker of prefrontal brain function in 48 healthy individuals. Two DTNBP1 polymorphisms previously linked to schizophrenia (P1765 and P1320) were found associated with changes in the NGA. Post hoc analysis showing an influence of genetic variation at these loci on the Go centroid and frontal amplitudes suggest that this might be due to modification of the execution of motor processes by the prefrontal cortex. This is the first report on a role of DTNBP1 gene variation for prefrontal brain function at a systemic neurophysiological level in healthy humans. Future studies will have to address the relevance of this observation for patients with schizophrenias.
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PMID:DTNBP1 (dysbindin) gene variants modulate prefrontal brain function in healthy individuals. 1640

Human intelligence is a trait that is known to be significantly influenced by genetic factors, and recent linkage data provide positional evidence to suggest that a region on chromosome 6p, previously associated with schizophrenia, may be linked to variation in intelligence. The gene for dysbindin-1 (DTNBP1) is located at 6p and has also been implicated in schizophrenia, a neuropsychiatric disorder characterized by cognitive dysfunction. We report an association between DTNBP1 genotype and general cognitive ability (g) in two independent cohorts, including 213 patients with schizophrenia or schizo-affective disorder and 126 healthy volunteers. These data suggest that DTNBP1 genetic variation influences human intelligence.
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PMID:Genetic variation in DTNBP1 influences general cognitive ability. 1641 41

Dysbindin was identified as a dystrobrevin-binding protein potentially involved in the pathogenesis of muscular dystrophy. Subsequently, genetic studies have implicated variants of the human dysbindin-encoding gene, DTNBP1, in the pathogeneses of Hermansky-Pudlak syndrome and schizophrenia. The protein is a stable component of a multisubunit complex termed BLOC-1 (biogenesis of lysosome-related organelles complex-1). In the present study, the significance of the dystrobrevin-dysbindin interaction for BLOC-1 function was examined. Yeast two-hybrid analyses, and binding assays using recombinant proteins, demonstrated direct interaction involving coiled-coil-forming regions in both dysbindin and the dystrobrevins. However, recombinant proteins bearing the coiled-coil-forming regions of the dystrobrevins failed to bind endogenous BLOC-1 from HeLa cells or mouse brain or muscle, under conditions in which they bound the Dp71 isoform of dystrophin. Immunoprecipitation of endogenous dysbindin from brain or muscle resulted in robust co-immunoprecipitation of the pallidin subunit of BLOC-1 but no specific co-immunoprecipitation of dystrobrevin isoforms. Within BLOC-1, dysbindin is engaged in interactions with three other subunits, named pallidin, snapin and muted. We herein provide evidence that the same 69-residue region of dysbindin that is sufficient for dystrobrevin binding in vitro also contains the binding sites for pallidin and snapin, and at least part of the muted-binding interface. Functional, histological and immunohistochemical analyses failed to detect any sign of muscle pathology in BLOC-1-deficient, homozygous pallid mice. Taken together, these results suggest that dysbindin assembled into BLOC-1 is not a physiological binding partner of the dystrobrevins, likely due to engagement of its dystrobrevin-binding region in interactions with other subunits.
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PMID:Reinvestigation of the dysbindin subunit of BLOC-1 (biogenesis of lysosome-related organelles complex-1) as a dystrobrevin-binding protein. 1644 87


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