| 1 | Mol. Psychiatry 2006 Dec 11: 1126-38 |
|---|---|
| PMID | 16924267 |
| Title | Evidence implicating BRD1 with brain development and susceptibility to both schizophrenia and bipolar affective disorder. |
| Abstract | Linkage studies suggest that chromosome 22q12-13 may contain one or more shared susceptibility genes for schizophrenia (SZ) and bipolar affective disorder (BPD). In a Faeroese sample, we previously reported association between microsatellite markers located at 22q13.31-qtel and both disorders. The present study reports an association analysis across five genes (including 14 single nucleotide and two microsatellite polymorphisms) in this interval using a case-control sample of 162 BPD, 103 SZ patients and 200 controls. The bromodomain-containing 1 gene (BRD1), which encodes a putative regulator of transcription showed association with both disorders with minimal P-values of 0.0046 and 0.00001 for single marker and overall haplotype analysis, respectively. A specific BRD1 2-marker 'risk' haplotype showed a frequency of approximately 10% in the combined case group versus approximately 1% in controls (P-value 2.8 x 10(-7)). Expression analysis of BRD1 mRNA revealed widespread expression in mammalian brain tissue, which was substantiated by immunohistochemical detection of BRD1 protein in the nucleus, perikaryal cytosol and proximal dendrites of the neurons in the adult rat, rabbit and human CNS. Quantitative mRNA analysis in developing fetal pig brain revealed spatiotemporal differences with high expression at early embryonic stages, with intense nuclear and cytosolar immunohistochemical staining of the neuroepithelial layer and early neuroblasts, whilst more mature neurons at later embryonic stages had less nuclear staining. The results implicate BRD1 with SZ and BPD susceptibility and provide evidence that suggests a role for BRD1 in neurodevelopment. |
| SCZ Keywords | schizophrenia |
| 2 | Brain Struct Funct 2009 Dec 214: 37-47 |
| PMID | 19763615 |
| Title | Further immunohistochemical characterization of BRD1 a new susceptibility gene for schizophrenia and bipolar affective disorder. |
| Abstract | We have recently shown that the gene BRD1 is associated with schizophrenia and bipolar affective disorder and that the BRD1 protein (BRD1) which is expressed in neurons may occur in a short and a long variant. The aim of the study was to generate polyclonal antibodies against new BRD1 epitopes enabling discrimination between the long and short BRD1 variants, and elucidate the BRD1 distribution in several human tissues, including the CNS. Polyclonal rabbit antibodies were raised against three different BRD1 epitopes. One (67) was specific for the long BRD1 variant, whereas the two others (63/64 and 65/66) like the original monoclonal mouse antibody (K22) were predicted to stain both variants. Immunohistochemical staining procedures were subsequently performed on paraffin-embedded human cerebral cortex and microarray slides containing 30 different human tissues. Western blotting confirmed the predicted specificity of the developed antibodies. K22, 63/64 and 65/66 displayed a similar neuronal staining pattern characterized by a distinct but weak nuclear staining, while the surrounding cytoplasm and proximal dendrites were more intensely stained. Interestingly, staining with 67 generated in contrast primarily an intense nuclear staining. The new antibodies resulted, furthermore, in a prominent neuroglial reaction characterized by staining of cell bodies, nuclei and glial processes. The tissue microarray analysis revealed that BRD1 was widely distributed in human tissues. The particular expression profile, e.g., the degree of nuclear and/or cytoplasmatic staining, seemed, however, to be highly tissue dependent. These results suggest a general role of BRD1 in the cell and stress that the two BRD1 variants may play different roles in the etiology of psychiatric disease. |
| SCZ Keywords | schizophrenia |
| 3 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2010 Mar 153B: 582-91 |
| PMID | 19693800 |
| Title | Support of association between BRD1 and both schizophrenia and bipolar affective disorder. |
| Abstract | A recent study published by our group implicated the bromodomain containing protein 1 (BRD1) gene located at chromosome 22q13.33 with schizophrenia (SZ) and bipolar affective disorder (BPD) susceptibility and provided evidence suggesting a possible role for BRD1 in neurodevelopment. The present study reports an association analysis of BRD1 and the neighboring gene ZBED4 using a Caucasian case-control sample from Denmark and England (UK/DK sample: 490 patients with BPD, 527 patients with SZ, and 601 control individuals), and genotypes obtained from a BPD genome wide association (GWA) study of an overlapping English sample comprising 506 patients with BPD and 510 control individuals (UCL sample). In the UK/DK sample we genotyped 11 SNPs in the BRD1 region, of which six showed association with SZ (minimal single marker P-values of 0.0014), including two SNPs that previously showed association in a Scottish population [Severinsen et al. (2006); Mol Psychiatry 11(12): 1126-1138]. Haplotype analysis revealed specific risk as well as protective haplotypes with a minimal P-value of 0.0027. None of the 11 SNPs showed association with BPD. However, analyzing seven BRD1 SNPs obtained from the BPD GWA study, positive associations with BPD was observed with all markers (minimal P-value of 0.0014). The associations reported add further support for the implication of BRD1 with SZ and BPD susceptibility. |
| SCZ Keywords | schizophrenia |
| 4 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2010 Apr 153B: 786-91 |
| PMID | 19908236 |
| Title | Association study of bromodomain-containing 1 gene with schizophrenia in Japanese population. |
| Abstract | Chromosome 22q13 region has been implicated in schizophrenia in several linkage studies. Genes within this locus are therefore promising genetic and biologic candidate genes for schizophrenia if they are expressed in the brain or predicted to have some role in brain development. A recent study reported that bromodomain-containing 1 gene (BRD1), located in 22q13, showed an association with schizophrenia in a Scottish population. Except for being a putative regulator of transcription, the precise function of BRD1 is not clear; however, expression analysis of BRD1 mRNA revealed widespread expression in mammalian brains. In our study, we explored the association of BRD1 with schizophrenia in a Japanese population (626 cases and 770 controls). In this association analysis, we first examined 10 directly genotyped single-nucleotide polymorphisms (SNPs) and 20 imputed SNPs. Second, we compared the BRD1 mRNA levels between cases and controls using lymphoblastoid cell lines (LCLs) derived from 29 cases and 30 controls. Although the SNP (rs138880) that previously has been associated with schizophrenia showed the same trend in the Japanese population, no significant association was detected between BRD1 and schizophrenia in our study. Similarly, no significant differences in BRD1 mRNA levels in LCLs were detected. Taken together, we could not strongly show that common SNPs in the BRD1 gene account for a substantial proportion of the genetic risk for schizophrenia in the Japanese population. |
| SCZ Keywords | schizophrenia |
| 5 | Neurosci. Lett. 2012 May 516: 110-3 |
| PMID | 22675730 |
| Title | Electroconvulsive seizures regulates the Brd1 gene in the frontal cortex and hippocampus of the adult rat. |
| Abstract | Depressive disorders represent a significant health concern as they are associated with high social and physical dysfunction and increased risk for suicide. Electroconvulsive therapy (ECT) is the most effective treatment for patients with drug-resistant severe depressive disorders. However, the underlying biological mechanisms of ECT are not well characterized. In particular, the regulation of transcription factors upon ECT has only just started to be unveiled. The schizophrenia and bipolar disorder associated bromodomain containing 1 (BRD1) gene is important for the acetylation of histone H3K14 and holds a key role in normal embryonic development and survival. In this study, we have measured BRD1 mRNA in the hippocampus and the frontal cortex of male Sprague-Dawley rats upon acute and repeated electroconvulsive seizures (ECS) over a period of 10 days. We found an increase in the general expression of BRD1 mRNA in the hippocampus after repeated ECS compared to sham (F = 8.108, P = 0.003). Furthermore, we provide evidence suggesting a decrease in the expression of the BRD1 mRNA variant comprising an extended version of exon 7 (BRD1-L) in the frontal cortex after repeated ECS compared to sham (F = 6.225, P = 0.023). These findings indicate that regulation of the BRD1 gene is part of the biological response to ECS and that splice variants are induced differentially in different brain regions. |
| SCZ Keywords | schizophrenia |
| 6 | Eur Neuropsychopharmacol 2012 Sep 22: 651-6 |
| PMID | 22341945 |
| Title | The Schizophrenia and Bipolar Disorder associated BRD1 gene is regulated upon chronic restraint stress. |
| Abstract | Recent genetic evidence has implicated the bromodomain containing 1 gene (BRD1) with brain development and susceptibility to schizophrenia and Bipolar Disorder. The BRD1 protein, which is essential for acetylation of histone H3K14, is a putative regulator of transcription during brain development and in the mature CNS. However, several issues remain to be clarified for example regarding the regulation of the BRD1 gene upon environmental interventions. Chronic restraint stress (CRS) in rats represents an environmental method for induction of morphological and functional changes in the hippocampus and the prefrontal cortex. In order to investigate whether the expression of the rat BRD1 gene may be regulated during such conditions, BRD1 mRNA and protein levels in hippocampus and prefrontal cortex extracts from rats subjected to either 1/2 or 6h of CRS per day for 21days were measured. We found a significant 2-fold up-regulation of long exon 7 splice variants of the BRD1 gene (BRD1-L) in hippocampus in both groups of CRS rats compared to controls. Concomitantly, we found a similar up-regulation of the BRD1 protein. In prefrontal cortex, we found no significant differences in BRD1 mRNA or protein levels. As selective histone deacetylase (HDAC) inhibitors not only preserve stress-induced hyperacetylation of histone H3K14 but also have hippocampal-dependent antidepressant-like activity, we propose that BRD1 by its intrinsic acetylation activity towards histone H3K14 is a player in the regulatory processes underlying adaptation to stress in the mature CNS. |
| SCZ Keywords | schizophrenia |
| 7 | Genome Med 2016 -1 8: 53 |
| PMID | 27142060 |
| Title | Identification of the BRD1 interaction network and its impact on mental disorder risk. |
| Abstract | The bromodomain containing 1 (BRD1) gene has been implicated with transcriptional regulation, brain development, and susceptibility to schizophrenia and bipolar disorder. To advance the understanding of BRD1 and its role in mental disorders, we characterized the protein and chromatin interactions of the BRD1 isoforms, BRD1-S and BRD1-L. Stable human cell lines expressing epitope tagged BRD1-S and BRD1-L were generated and used as discovery systems for identifying protein and chromatin interactions. Protein-protein interactions were identified using co-immunoprecipitation followed by mass spectrometry and chromatin interactions were identified using chromatin immunoprecipitation followed by next generation sequencing. Gene expression profiles and differentially expressed genes were identified after upregulating and downregulating BRD1 expression using microarrays. The presented functional molecular data were integrated with human genomic and transcriptomic data using available GWAS, exome-sequencing datasets as well as spatiotemporal transcriptomic datasets from the human brain. We present several novel protein interactions of BRD1, including isoform-specific interactions as well as proteins previously implicated with mental disorders. By BRD1-S and BRD1-L chromatin immunoprecipitation followed by next generation sequencing we identified binding to promoter regions of 1540 and 823 genes, respectively, and showed correlation between BRD1-S and BRD1-L binding and regulation of gene expression. The identified BRD1 interaction network was found to be predominantly co-expressed with BRD1 mRNA in the human brain and enriched for pathways involved in gene expression and brain function. By interrogation of large datasets from genome-wide association studies, we further demonstrate that the BRD1 interaction network is enriched for schizophrenia risk. Our results show that BRD1 interacts with chromatin remodeling proteins, e.g. PBRM1, as well as histone modifiers, e.g. MYST2 and SUV420H1. We find that BRD1 primarily binds in close proximity to transcription start sites and regulates expression of numerous genes, many of which are involved with brain development and susceptibility to mental disorders. Our findings indicate that BRD1 acts as a regulatory hub in a comprehensive schizophrenia risk network which plays a role in many brain regions throughout life, implicating e.g. striatum, hippocampus, and amygdala at mid-fetal stages. |
| SCZ Keywords | schizophrenia |