Bray NJ, Preece A, Williams NM, Moskvina V, Buckland PR, Owen MJ et al. Haplotypes at the dystrobrevin binding protein 1 (DTNBP1) gene locus mediate risk for schizophrenia through reduced DTNBP1 expression. Hum Mol Genet 14: 1947-1954

Department of Psychological Medicine, School of Medicine, Cardiff University, Heath Park, UK.
Human Molecular Genetics (Impact Factor: 6.39). 08/2005; 14(14):1947-54. DOI: 10.1093/hmg/ddi199
Source: PubMed


The DTNBP1 gene, encoding dysbindin, is now generally considered to be a susceptibility gene for schizophrenia. However, the confidence with which this hypothesis can be held has to be tempered by the poor reproducibility between studies in terms of the exact nature of the associated haplotypes, by the failure so far to identify any specific susceptibility variants and by the absence of any demonstrated function associated with any of the risk haplotypes. In the present study, we show that a defined schizophrenia risk haplotype tags one or more cis-acting variants that results in a relative reduction in DTNBP1 mRNA expression in human cerebral cortex. Subsidiary analyses suggest that risk haplotypes identified in other sample groups of white European ancestry also index lower DTNBP1 expression, whereas putative 'protective' haplotypes index high DTNBP1 expression. Our data indicate that variation in the DTNBP1 gene confers susceptibility to schizophrenia through reduced expression, and that this, therefore, represents a primary aetiological mechanism in the disorder.

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Available from: Nicholas J Bray, May 19, 2015
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    • "In particular, individuals homozygous for COMT Met alleles (i.e., with relative reduction in COMT) and having no " Bray " DTNBP1 haplotype performed more efficiently than other COMT genotypes, consistent with many earlier studies (Mier et al., 2010). This " Bray " haplotype has been suggested previously to result in reduced levels of dysbindin-1 (Bray et al., 2005). In contrast, as predicted by the mouse studies, individuals with COMT Met/Met genotypes and who were also homozygous for the " Bray " low dysbindin-1 expression-associated haplotype were the most inefficient compared with other COMT genotypes (Papaleo et al., 2014). "
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    ABSTRACT: Mutant mice play an increasingly important role in understanding disease processes at multiple levels. In particular, they illuminate the impact of risk genes for disease on such processes. This article reviews recent advances in the application of mutant mice to study the intricacies of dopaminergic (DAergic) function in relation to the putative pathophysiology of psychotic illness, particularly schizophrenia, and antipsychotic drug action. It considers models for understanding the role(s) of risk genes, with a particular focus on DTNBP1 and NRG1, their interactions with environmental factors, and with each other (epistasis). In overview, it considers new schemas for understanding psychotic illness that integrate DAergic pathophysiology with developmental, social, and cognitive processes, and how mutant mouse models can reflect and inform on such schemas.
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    • "We selected rs2619538 because it was the only best associated single nucleotide polymorphism (SNP) from a previous UK-based study of schizophrenia and was also present on all haplotypes showing association with the disorder in that study (Williams et al., 2004). The SNP, which lies about 2 kb 5¢ to the start of DTNBP1 transcript NM_183041, was associated in a UK sample with psychotic mania (Raybould et al., 2005) and is carried on the haplotype that is most strongly associated with cis-acting variants that influence DTNBP1 expression (Bray et al., 2005), on a haplotype showing evidence for association in a second UK schizophrenia sample (Li et al., 2005). It has also been reported to be associated with methamphetamine psychosis (Kishimoto et al., 2008), and to show a trend for association to severe and persistent pathology in schizophrenia (Tosato et al., 2007). "
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    ABSTRACT: Schizophrenia is a neurodevelopmental disorder, and risk genes are thought to act through disruption of brain development. Several genetic studies have identified dystrobrevin-binding protein 1 (DTNBP1, also known as dysbindin) as a potential susceptibility gene for schizophrenia, but its impact on brain development is poorly understood. The present investigation examined for the first time the effects of DTNBP1 on brain structure in children. Our hypothesis was that a genetic variation in DTNBP1 (i.e., the single nucleotide polymorphism rs2619538) would be associated with differences in both gray and white matter brain regions previously implicated in schizophrenia. Magnetic resonance imaging and voxel-based morphometry were used to examine brain structure in 52 male children aged between 10 and 12 years. Statistical inferences on the effects of DTNBP1 genotype on gray and white matter volume (GMV and WMV) were made at p < .05 after family-wise error correction for multiple comparisons across the whole brain. Individuals homozygous for the schizophrenia high-risk allele (AA) compared with those homozygous for the low-risk allele (TT) expressed reduced GMV in the left anterior cingulate gyrus and reduced WMV in the left medial frontal area. Our results suggest that genetic variation in DTNBP1 is associated with differences in gray and white matter; and that these effects are already evident in children as young as 10-12 years. These findings are consistent with the notion that the DTNBP1 genotype influences brain development and may thereby modulate vulnerability to schizophrenia.
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    • "Furthermore, several studies have implicated the involvement of many different alleles and haplotypes as susceptibility variants. These polymorphisms, however, may modulate dysbindin-1 expression levels since reduced dysbindin message and/or protein levels have been found in schizophrenic brains such as prefrontal cortex and hippocampal formation, brain areas commonly affected by the disorder [6], [7], [8]. In the hippocampus of schizophrenic patients, dysbindin-1 reductions occur in the synaptic terminal fields of glutamatergic neurons, especially those located in the DGiml [7]. "
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    ABSTRACT: Genetic variations in the gene encoding dysbindin has consistently been associated with schizophrenia and bipolar disorder, although little is known about the neural functions carried out by dysbindin. To gain some insight into this area, we took advantage of the readily available dysbindin-null mouse sandy (sdy-/-) and studied hippocampal neurogenesis using thymidine analogue bromodeoxuridine (BrdU). No significant differences were found in the proliferation (4 hours) or survival (1, 4 and 8 weeks after the last BrdU injection) of progenitors in the subgranular regions of the dentate gyrus between sdy-/- and sdy+/+ (control) mice. However, 4 weeks after the last BrdU injection, a significant reduction was observed in the ratio of neuronal differentiation in sdy-/- when compared to that of sdy+/+ (sdy+/+  = 87.0 ± 5.3% vs. sdy-/-  = 71.3 ± 8.3%, p = 0.01). These findings suggest that dysbindin plays a role during differentiation process in the adult hippocampal neurogenesis and that its deficit may negatively affect neurogenesis-related functions such as cognition and mood.
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