1. ¹Laboratory for Molecular Psychiatry, RIKEN Brain Science Institute, Saitama, Japan
2. ²Teikyo University School of Medicine Chiba Medical Center, Chiba, Japan
3. ³Department of Mental Disorder Research, National Institute of Neuroscience, Tokyo, Japan
4. ⁴Yokohama Shinryo Clinic, Kanagawa, Japan
5. ⁵Department of Psychiatry, Faculty of Medicine, Nagoya University, Nagoya, Japan
6. ⁶Department of Psychiatry, Faculty of Medicine, Fujita Health University, Nagoya, Japan
7. ⁷Department of Psychiatry, Tokyo Women's Medical College, Tokyo, Japan
8. ⁸Department of Psychiatry and Neurology, Hamamatsu University School of Medicine, Shizuoka, Japan
9. ⁹Department of Psychiatry, Teikyo University School of Medicine, Tokyo, Japan
10. ¹⁰Division of Developmental Neuroscience, Center for Translational and Advanced Animal Research, Tohoku University School of Medicine, Miyagi, Japan
11. ¹¹CREST, Japan Science and Technology Agency, Saitama, Japan
12. ¹²Mood and Anxiety Disorders Program, National Institute of Mental Health, Bethesda, MD, USA
13. ¹³Laboratory for Molecular Dynamics of Mental Disorders, RIKEN Brain Science Institute, Saitama, Japan

Correspondence: Dr T Yoshikawa, Laboratory for Molecular Psychiatry, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako-city, Saitama 351-0198, Japan. Tel: +81 48 467 5968; Fax: +81 48 467 7462; E-mail: takeo@brain.riken.go.jp

Received 31 July 2006; Revised 24 October 2006; Accepted 14 November 2006; Published online 24 January 2007.

Abstract

Lithium is an effective mood stabilizer for bipolar disorder patients and its therapeutic effect may involve inhibition of inositol monophosphatase activity. In humans, the enzyme is encoded by two genes, IMPA1 and IMPA2. IMPA2 maps to 18p11.2, a genomic interval for which evidence of linkage to bipolar disorder has been supported by several reports. We performed a genetic association study in Japanese cohorts (496 patients with bipolar disorder and 543 control subjects). Interestingly, we observed association of IMPA2 promoter single nucleotide polymorphisms (SNPs) (-461C and -207T) with bipolar disorder, the identical SNPs reported previously in a different population. In vitro promoter assay and genetic haplotype analysis showed that the combination of (-461C)–(-207T)–(-185A) drove enhanced transcription and the haplotypes containing (-461C)–(-207T)–(-185A) contributed to risk for bipolar disorder. Expression study on post-mortem brains revealed increased transcription from the IMPA2 allele that harbored (-461C)–(-207T)–(-185A) in the frontal cortex of bipolar disorder patients. The examination of allele-specific expressions in post-mortem brains did not support genomic imprinting of IMPA2, which was suggested nearby genomic locus. Contrasting to a prior report, therapeutic concentrations of lithium could not suppress the transcription of IMPA2 mRNA, and the mood-stabilizing effect of lithium is, if IMPA2 was one of the targets of lithium, deemed to be generated via inhibition of enzymatic reaction rather than transcriptional suppression. In conclusion, the present study suggests that a promoter haplotype of IMPA2 possibly contributes to risk for bipolar disorder by elevating IMPA2 levels in the brain, albeit the genetic effect varies among populations.