1. ¹Dr Einar Martens' Research Group for Biological Psychiatry and Locus on Neuroscience, Center for Medical Genetics and Molecular Medicine, University of Bergen, Norway
2. ²Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Helse Bergen HF, Norway
3. ³Herzog Hospital, Jerusalem, Israel
4. ⁴Section for Medical Statistics, Department of Public Health and Primary Health Care, University of Bergen, Norway
5. ⁵Department of Psychiatry, University of Bergen, Norway
6. ⁶Laboratoire de Genetique Moleculaire de la Neurotransmission et des Processus Neurodegeneratifs (LGN), CNRS, Paris, France
7. ⁷Aventis, Ivry, France
8. ⁸Department of Psychiatry and Center for Neurobiology and Behavior, University of Pennsylvania School of Medicine, Philadelphia, PA, USA
9. ⁹Dr Kemal Psychiatric Hospital, Palestinian Authority, Bethlehem, Israel
10. ¹⁰Department of Pathology, The Gade Institute, University of Bergen, Norway

Correspondence: VM Steen, Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen N-5021, Norway. E-mail: vidar.steen@haukeland.no

Received 9 January 2003; Revised 25 September 2003; Accepted 21 October 2003; Published online 23 December 2003.

Abstract

Manic-depressive (bipolar) illness is a serious psychiatric disorder with a strong genetic predisposition. The disorder is likely to be multifactorial and etiologically complex, and the causes of genetic susceptibility have been difficult to unveil. Lithium therapy is a widely used pharmacological treatment of manic-depressive illness, which both stabilizes the ongoing episodes and prevents relapses. A putative target of lithium treatment has been the inhibition of the myo-inositol monophosphatase (IMPase) enzyme, which dephosphorylates myo-inositol monophosphate in the phosphatidylinositol signaling system. Two genes encoding human IMPases have so far been isolated, namely myo-inositol monophosphatase 1 (IMPA1) on chromosome 8q21.13–21.3 and myo-inositol monophosphatase 2 (IMPA2) on chromosome 18p11.2. In the present study, we have scanned for DNA variants in the human IMPA1 and IMPA2 genes in a pilot sample of Norwegian manic-depressive patients, followed by examination of selected polymorphisms and haplotypes in a family-based bipolar sample of Palestinian Arab proband–parent trios. Intriguingly, two frequent single-nucleotide polymorphisms (-461C>T and -207T>C) in the IMPA2 promoter sequence and their corresponding haplotypes showed transmission disequilibrium in the Palestinian Arab trios. No association was found between the IMPA1 polymorphisms and bipolar disorder, neither with respect to disease susceptibility nor with variation in lithium treatment response. The association between manic-depressive illness and IMPA2 variants supports several reports on the linkage of bipolar disorder to chromosome 18p11.2, and sustains the possible role of IMPA2 as a susceptibility gene in bipolar disorder.