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 B10% in the combined case group versus B1% in controls (P-value 2.8 Â 10 À7 ). 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.

The MYST family of histone acetyltransferases and their intimate links to cancer

“…The presence of several domains typically associated with chromatin binding within the BRPF proteins suggests that they are responsible for recruiting the MOZ/MORF complexes to their sites of action. Interestingly, the Caenorhabditis elegans homologue of BRPF has been observed to influence gene expression and development (Chamberlin and Thomas, 2000;Chang et al, 2003), whereas a recent study has implicated BRPF2 (BRD1) in human neurodevelopment and neurological disorders (Severinsen et al, 2006).…”

Recognition of Unmodified Histone H3 by the First PHD Finger of Bromodomain-PHD Finger Protein 2 Provides Insights into the Regulation of Histone Acetyltransferases Monocytic Leukemic Zinc-finger Protein (MOZ) and MOZ-related factor (MORF)

“…2, and the structural statistics are given in Table 2. The structural coordinates of human BRPF2-PHD1, both free and fused to unH3 (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12), have been deposited into the Protein Data Bank with accession codes 2KU3 and 2L43, respectively.…”

“…Despite its identification almost 10 years ago, there has been little information about the biological role of BRPF2 in vertebrate systems. Studies have suggested that BRPF2 expression is highly regulated in the embryonic brain and that the BRPF2 gene is associated with schizophrenia and bipolar affective disorder (9). In a population-based screening study of 446 consecutive childhood acute lymphoblastic leukemia cases, it was found that the entire BRPF2 protein was fused to PAX5 (10), a master regulator of B-cell development.…”

A genome-wide study of panic disorder suggests the amiloride-sensitive cation channel 1 as a candidate gene

“…14,15 The isolate has formerly been used to locate chromosomal regions associated with other complex disorders, 16,17 which has lead to identification of genes for schizophrenia and bipolar disorder in larger outbred populations. [18][19][20] We present the results from a three-stage genetic investigation of PD ( Figure 1). First, we conducted a genome-wide scan on 13 distantly related patients with PD and 43 control individuals from the Faroe Islands.…”