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Impaired feedback regulation of XBP1 as a genetic risk factor for bipolar disorder

Nature Genetics volume 35, pages 171–175 (2003)Cite this article

Abstract

The pathophysiology of bipolar disorder is still unclear, although family, twin and linkage studies implicate genetic factors1. Here we identified XBP1, a pivotal gene in the endoplasmic reticulum (ER) stress response, as contributing to the genetic risk factor for bipolar disorder. Using DNA microarray analysis of lymphoblastoid cells derived from two pairs of twins discordant with respect to the illness, we found downregulated expression of genes related to ER stress response in both affected twins. A polymorphism (−116C→G) in the promoter region of XBP1, affecting the putative binding site of XBP1, was significantly more common in Japanese patients (odds ratio = 4.6) and overtransmitted to affected offspring in trio samples of the NIMH Bipolar Disorder Genetics Initiative. XBP1-dependent transcription activity of the −116G allele was lower than that of the −116C allele, and in the cells with the G allele, induction of XBP1 expression after ER stress was markedly reduced. Valproate, one of three mood stabilizers, rescued the impaired response by inducing ATF6, the gene upstream of XBP1. These results indicate that the −116C→G polymorphism in XBP1 causes an impairment of its positive feedback system and increases the risk of bipolar disorder.

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Figure 1: −116C→G polymorphism in XBP1 is a risk factor for bipolar disorder.
Figure 2: Effects of three mood stabilizers on ER stress response cascade.

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Acknowledgements

We thank the individuals with bipolar disorder and unaffected volunteers who participated in this study. Data and biomaterials of the National Institute of Mental Health (NIMH) pedigrees were collected in four projects that participated in the NIMH Bipolar Disorder Genetics Initiative. From 1991 to 1998, the Principal Investigators and Co-Investigators were as follows: Indiana University, Indianapolis, Indiana, USA, J. Nurnberger, M. Miller and E. Bowman; Washington University, St. Louis, Missouri, USA, T. Reich, A. Goate and J. Rice; Johns Hopkins University, Baltimore, Maryland, USA, J. R. DePaulo, Jr., S. Simpson and C. Stine; NIMH Intramural Research Program, Clinical Neurogenetics Branch, Bethesda, Maryland, USA, E. Gershon, D. Kazuba and E. Maxwell.

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Authors and Affiliations

  1. Laboratory for Molecular Dynamics of Mental Disorders, Brain Science Institute, RIKEN, Wako-shi, 351-0198, Saitama, Japan

    Chihiro Kakiuchi, Kazuya Iwamoto, Mizuho Ishiwata, Miki Bundo, Takaoki Kasahara & Tadafumi Kato

  2. Department of Psychiatry, Hokkaido University, Sapporo-shi, 060-8648, Hokkaido, Japan

    Ichiro Kusumi

  3. Department of Psychiatry, Nagasaki University, Nagasaki-shi, 852-8523, Nagasaki, Japan

    Takahiro Tsujita

  4. Department of Psychiatry, Mie University, Tsu-shi, 514-8507, Mie, Japan

    Yuji Okazaki

  5. Department of Psychiatry, Teikyo University School of Medicine, Itabashi-ku, Tokyo, 173-8605, Japan

    Shinichiro Nanko

  6. Department of Mental Disorder Research, National Institute of Neuroscience, Kodaira-shi, Tokyo, 187-8502, Japan

    Hiroshi Kunugi

  7. Department of Psychiatry, Health Service Center, University of Tokyo, Bunkyo-ku, Tokyo, 113-0033, Japan

    Tsukasa Sasaki

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  1. Chihiro Kakiuchi
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Correspondence to Tadafumi Kato.

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RIKEN, the employer of C.K., K.I., M.I., M.B., T. Kasahara and T. Kato, has a pending patent on the results of this paper.

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Kakiuchi, C., Iwamoto, K., Ishiwata, M. et al. Impaired feedback regulation of XBP1 as a genetic risk factor for bipolar disorder. Nat Genet 35, 171–175 (2003). https://doi.org/10.1038/ng1235

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