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A complex polymorphic region in the brain-derived neurotrophic factor (BDNF) gene confers susceptibility to bipolar disorder and affects transcriptional activity

Molecular Psychiatry volume 11, pages 695–703 (2006)Cite this article

Abstract

Previous studies have suggested that genetic variations in the brain-derived neurotrophic factor (BDNF) gene may be associated with several neuropsychiatric diseases including bipolar disorder. The present study examined a microsatellite polymorphism located approximately 1.0 kb upstream of the translation initiation site of the BDNF gene for novel sequence variations, association with bipolar disorder, and effects on transcriptional activity. Detailed sequencing analysis revealed that this polymorphism is not a simple dinucleotide repeat, but it is highly polymorphic with a complex structure containing three types of dinucleotide repeats, insertion/deletion, and nucleotide substitutions that gives rise to a total of 23 novel allelic variants. We obtained evidence supporting the association between this polymorphic region (designated as BDNF-linked complex polymorphic region (BDNF-LCPR)) and bipolar disorder. One of the major alleles (‘A1’ allele) was significantly more common in patients than in controls (odds ratio 2.8, 95% confidential interval 1.5–5.3, P=0.001). Furthermore, a luciferase reporter gene assay in rat primary cultured neurons suggests that this risk allele (A1) has a lower-transcription activity, compared to the other alleles. Our results suggest that the BDNF-LCPR is a functional variation that confers susceptibility to bipolar disorder and affects transcriptional activity of the BDNF gene.

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Acknowledgements

We thank Shizuno T and Okada K for their technical assistance in laboratory. This study was supported by the Health and Labor Sciences Research Grants (Research on Psychiatric and Neurological Diseases and Mental Health), the Japan Health Sciences Foundation (Research on Health Sciences focusing on Drug innovation) and Mitsubishi Pharma Research Foundation (HK).

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Authors and Affiliations

  1. Department of Mental Disorder Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan

    T Okada, R Hashimoto, T Numakawa, Y Iijima & H Kunugi

  2. Department of Psychiatry, Showa University School of Medicine, Tokyo, Japan

    A Kosuga, M Tatsumi & K Kamijima

  3. Yokohama Shinryo Clinic, Kanagawa, Japan

    M Tatsumi

  4. Laboratory for Molecular Dynamics of Mental Disorders, Brain Science Institute, RIKEN, Saitama, Japan

    T Kato

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  1. T Okada
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  2. R Hashimoto
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Correspondence to H Kunugi.

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Supplementary Information accompanies the paper on the Molecular Psychiatry website (http://www.nature.com/mp).

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Okada, T., Hashimoto, R., Numakawa, T. et al. A complex polymorphic region in the brain-derived neurotrophic factor (BDNF) gene confers susceptibility to bipolar disorder and affects transcriptional activity. Mol Psychiatry 11, 695–703 (2006). https://doi.org/10.1038/sj.mp.4001822

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