1. ¹Laboratory for Molecular Dynamics of Mental Disorders, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan
2. ²Department of Psychiatry and Genome Research Center, Teikyo University School of Medicine, Tokyo, Japan
3. ³Department of Mental Disorder Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan
4. ⁴Department of Psychiatry and Neurobiology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan
5. ⁵Department of Psychiatry, Hamamatsu University School of Medicine, Hamamatsu, Japan
6. ⁶Department of Psychiatry, Shiga University of Medical Science, Otsu, Japan
7. ⁷Department of Psychiatry, Health Service Center, University of Tokyo, Tokyo, Japan
8. ⁸Department of Neuropsychiatry, Faculty of Medicine, University of Tokyo, Bunkyo, Tokyo, Japan
9. ⁹Department of Physiology, Keio University School of Medicine, Tokyo, Japan
10. ¹⁰Laboratory for Molecular Psychiatry, RIKEN Brain Science Institute, Wako, Japan

Correspondence: Tadafumi Kato, Laboratory for Molecular Dynamics of Mental Disorders, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan. E-mail: kato@brain.riken.jp

Received 24 May 2007; Accepted 24 July 2007; Published online 4 September 2007.

Abstract

Pathophysiological role of endoplasmic reticulum (ER) stress response signaling has been suggested for bipolar disorder. The goal of this study was to test the genetic association between bipolar disorder and an ER chaperone gene, HSP90B1 (GRP94/gp96), which is located on a candidate locus, 12q23.3. We tested the genetic association between bipolar disorder and HSP90B1 by case-control studies in two independent Japanese sample sets and by a transmission disequilibrium test (TDT) in NIMH Genetics initiative bipolar trio samples (NIMH trios). We also performed gene expression analysis of HSP90B1 in lymphoblastoid cells. Among the 11 SNPs tested, rs17034977 showed significant association in both Japanese sample sets. The frequency of the SNP was lower in NIMH samples than in Japanese samples and there was no significant association in NIMH trios. Gene expression analysis of HSP90B1 in lymphoblastoid cells suggested a possible relationship between the associated SNP and mRNA levels. HSP90B1 may have a pathophysiological role in bipolar disorder in the Japanese population, though further study will be needed to understand the underlying functional mechanisms.