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Gene expression analysis of bipolar disorder reveals downregulation of the ubiquitin cycle and alterations in synaptic genes

Molecular Psychiatry volume 11, pages 965–978 (2006)Cite this article

Abstract

Bipolar affective disorder is a severe psychiatric disorder with a strong genetic component but unknown pathophysiology. We used microarray technology to determine the expression of approximately 22 000 mRNA transcripts in post-mortem tissue from two brain regions in patients with bipolar disorder and matched healthy controls. Dorsolateral prefrontal cortex tissue from a cohort of 70 subjects and orbitofrontal cortex tissue from a separate cohort of 30 subjects was investigated. The final analysis included 30 bipolar and 31 control subjects for the dorsolateral prefrontal cortex and 10 bipolar and 11 control subjects for the orbitofrontal cortex. Differences between disease and control groups were identified using a rigorous statistical analysis with correction for confounding variables and multiple testing. In the orbitofrontal cortex, 393 differentially expressed transcripts were identified by microarray analysis and a representative subset was validated by quantitative real-time PCR. Pathway analysis revealed significant upregulation of genes involved in G-protein coupled receptor signalling and response to stimulus (in particular the immune response), while genes relating to the ubiquitin cycle and intracellular transport showed coordinated downregulation in bipolar disorder. Additionally, several genes involved in synaptic function were significantly downregulated in bipolar disorder. No significant changes in gene expression were observed in the dorsolateral prefrontal cortex using microarray analysis or quantitative real-time PCR. Our findings implicate the orbitofrontal cortex as a region prominently involved in bipolar disorder and indicate that diverse processes are affected. Overall, our results suggest that dysregulation of the ubiquitin pathway and synaptic function may be central to the disease process.

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Acknowledgements

This research was supported by the Stanley Medical Research Institute (SMRI) and the donations of the Stanley brain collection courtesy of Drs Michael B Knable, E Fuller Torrey, Serge Weis and Robert H Yolken. We gratefully acknowledge SMRI centre support. We thank MRC Geneservice for hybridisation of the arrays, Dr Rachel Craddock for her contribution to the immune response discussion and all other members of the Bahn laboratory for their support. Margaret Ryan is a recipient of a Young Investigator Award from the National Alliance for Research of Schizophrenia and Depression (NARSAD). Stephen Huffaker is supported by the National Institutes of Health-Cambridge Health Science Scholars Program.

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  1. M M Ryan, H E Lockstone and S J Huffaker: These authors contributed equally to this work.

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  1. Cambridge Centre for Neuropsychiatric Research, Institute of Biotechnology, University of Cambridge, Cambridge, UK

    M M Ryan, H E Lockstone, S J Huffaker, M T Wayland & S Bahn

  2. Department of Psychiatry, Stanley Laboratory of Brain Research, Uniformed Services, University for the Health Sciences, Bethesda, MD, USA

    M J Webster

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Ryan, M., Lockstone, H., Huffaker, S. et al. Gene expression analysis of bipolar disorder reveals downregulation of the ubiquitin cycle and alterations in synaptic genes. Mol Psychiatry 11, 965–978 (2006). https://doi.org/10.1038/sj.mp.4001875

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