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.