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Evidence implicating BRD1 with brain development and susceptibility to both schizophrenia and bipolar affective disorder

Molecular Psychiatry volume 11, pages 1126–1138 (2006)Cite this article

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 ∼10% in the combined case group versus ∼1% in controls (P-value 2.8 × 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.

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Acknowledgements

The authors acknowledge with gratitude the skillful assistance of Ms HG Binderup, Mr C Westberg, Ms D Jensen, Ms L Munkøe, and Ms K Jensen.

The Danish Medical Research Council, The Faculty of Health Sciences, University of Aarhus, The Desirée and Niels Yde's Foundation, the Psychiatric Research Foundation, The Aarhus University Research Foundation, The Alice Brenaa Foundation, The Foundation for the Advancement of Medical Science, The Lily Benthine Lund Foundation, The Medical Society of Aarhus County, The Research Foundation of the Danish Medical Association, Pulje til styrkelse af Psykiatrisk Forskning, The Novo Nordic Foundation, The Aase and Ejnar Danielsen Foundation, The Foundation of Direktør Ib Henriksen, The Foundation of Jacob Madsen and Wife, The Foundation of consultant Dr med E Geert-Jørgensen and Wife, and The Foundation of King Christian the 10th supported the study. The Scottish sample collection was funded by grants from the Scottish Executive, the Medical Research Council and the Wellcome Trust.

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Authors and Affiliations

  1. Institute of Human Genetics, University of Aarhus, Aarhus, Denmark

    J E Severinsen, S Kiar-Larsen, I M Olsen, M M Nielsen, J Blechingberg, A L Nielsen, T J Corydon & A D Borglum

  2. Institute of Anatomy, University of Aarhus, Aarhus, Denmark

    C R Bjarkam

  3. Centre for Basic Psychiatric Research, Psychiatric Hospital in Aarhus, Aarhus University Hospital, Aarhus, Denmark

    I M Olsen, L Foldager & O Mors

  4. Department of Pathology, Aalborg Hospital, Aarhus University Hospital, Aalberg, Denmark

    I E Holm

  5. Department of Medical Oncology, Cancer Research UK, St Bartholmew's and the Royal London School of Medicine and Dentistry, London, UK

    B D Young

  6. Division of Psychiatry, University of Edinburgh, Royal Edinburgh Hospital, Edinburgh, Scotland

    W J Muir & D H R Blackwood

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Severinsen, J., Bjarkam, C., Kiar-Larsen, S. et al. Evidence implicating BRD1 with brain development and susceptibility to both schizophrenia and bipolar affective disorder. Mol Psychiatry 11, 1126–1138 (2006). https://doi.org/10.1038/sj.mp.4001885

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