1. ¹Laboratory for Molecular Dynamics of Mental Disorders, Brain Science Institute, RIKEN, Hirosawa, Wako, Saitama, Japan
2. ²Department of Neuropsychiatry, Faculty of Medicine, University of Tokyo, Hongo, Bunkyo-ku, Tokyo, Japan
3. ³Department of Psychiatry, Hokkaido University Graduate School of Medicine, Kita-ku, Sapporo, Hokkaido, Japan
4. ⁴Department of Psychiatry, Fujita Health University School of Medicine, Toyoake, Aichi, Japan
5. ⁵Department of Psychiatry, Nagoya University Faculty of Medicine, Nagoya, Aichi, Japan

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

Received 11 September 2006; Revised 6 February 2007; Accepted 8 February 2007; Published online 1 May 2007.

Abstract

To search DNA methylation difference between monozygotic twins discordant for bipolar disorder, we applied a comprehensive genome scan method, methylation-sensitive representational difference analysis (MS-RDA) to lymphoblastoid cells derived from the twins. MS-RDA isolated 10 DNA fragments derived from 5' region of known genes/ESTs. Among these 10 regions, four regions showed DNA methylation differences between bipolar twin and control co-twin confirmed by bisulfite sequencing. We performed a case–control study of DNA methylation status of these four regions by pyrosequencing. Two regions, upstream regions of spermine synthase (SMS) and peptidylprolyl isomerase E-like (PPIEL) (CN265253), showed aberrant DNA methylation status in bipolar disorder. SMS, a gene on X chromosome, showed significantly higher DNA methylation level in female patients with bipolar disorder compared with control females. However, there was no difference of mRNA expression. In PPIEL, DNA methylation level was significantly lower in patients with bipolar II disorder than in controls. The expression level of PPIEL was significantly higher in bipolar II disorder than in controls. We found strong inverse correlation between gene expression and DNA methylation levels of PPIEL. These results suggest that altered DNA methylation statuses of PPIEL might have some significance in pathophysiology of bipolar disorder.