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Examination of IMPA1 and IMPA2 genes in manic-depressive patients: association between IMPA2 promoter polymorphisms and bipolar disorder

Molecular Psychiatry volume 9, pages 621–629 (2004)Cite this article

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.

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Acknowledgements

We would like to thank the anonymous reviewers for very valuable comments on this manuscript. We also thank Anne-Karin Gulbrandsen for assisting in the genotyping of the DNA polymorphisms. This work was supported by Dr Einar Martens' Research Fund and the Research Council of Norway (Mental Health Programme).

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Authors and Affiliations

  1. Dr Einar Martens' Research Group for Biological Psychiatry and Locus on Neuroscience, Center for Medical Genetics and Molecular Medicine, University of Bergen, Norway

    G Sjøholt & V M Steen

  2. Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Helse Bergen HF, Norway

    G Sjøholt & V M Steen

  3. Herzog Hospital, Jerusalem, Israel

    R P Ebstein

  4. Department of Public Health and Primary Health Care, Section for Medical Statistics, University of Bergen, Norway

    R T Lie

  5. Department of Psychiatry, University of Bergen, Norway

    J Ø Berle

  6. Laboratoire de Genetique Moleculaire de la Neurotransmission et des Processus Neurodegeneratifs (LGN), CNRS, Paris, France

    J Mallet & C Laurent

  7. Aventis, Ivry, France

    J F Deleuze

  8. Department of Psychiatry and Center for Neurobiology and Behavior, University of Pennsylvania School of Medicine, Philadelphia, PA, USA

    D F Levinson

  9. Dr Kemal Psychiatric Hospital, Palestinian Authority, Bethlehem, Israel

    M Mujahed, I Bannoura & I Murad

  10. Department of Pathology, The Gade Institute, University of Bergen, Norway

    A Molven

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Correspondence to V M Steen.

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Sjøholt, G., Ebstein, R., Lie, R. et al. Examination of IMPA1 and IMPA2 genes in manic-depressive patients: association between IMPA2 promoter polymorphisms and bipolar disorder. Mol Psychiatry 9, 621–629 (2004). https://doi.org/10.1038/sj.mp.4001460

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  • DOI: https://doi.org/10.1038/sj.mp.4001460

Keywords

  • inositol monophosphatase
  • chromosome 18p11.2
  • transmission disequilibrium
  • SNP haplotypes
  • TDT
  • proband–parent trios

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