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

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 (À461C4T and À207T4C) 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.

Association study of myo-inositol monophosphatase 2 (IMPA2) polymorphisms with bipolar affective disorder and response to lithium treatment

“…Indeed, the frequency of the C allele was different in the two populations: 69% in the parents in the Arab sample, and 76.6 and 78% in the parents of the UK and Bulgarian trios. The level of LD in the IMPA2 gene is very low, as can be seen from Table 2, and a low LD was reported in Sjoholt et al 17 Indeed, the only strong marker-marker LD in our sample was between 599_97G4A and 599_99G4A, which are just 2 bp from each other, as well as for the very rare 443G4A. This indicates that if there are susceptibility SNPs in this gene, their signals might not be captured by the common SNPs investigated, or they might be captured in one population, but not in another one.…”

“…All three SNPs appeared to have minor allele frequencies B30% and we could be confident that they were going to be informative in our populations. Towards the end of the project, we became aware of a new paper 17 that described data on four common polymorphisms identified in the promoter of IMPA2. Two of these showed preferential transmission in 92 Palestinian Arab trios affected with BP.…”

“…Our study cannot replicate or reject these results because the minor allele frequencies of these SNPs were very low in the two European populations (Table 1). Sjoholt et al 17 recently reported preferential transmission of two promoter SNPs in a sample of 92 Palestinian Arab trios. The two SNPs were in nearly complete LD and had identical allele frequencies, so we genotyped only one of them: -461C4T.…”

“…They reported significant genotypic association (P-values between 0.031 and 0.0001) with schizophrenia, but not with bipolar disorder. Towards the end of our project, a family-based association study on 92 trios of Arab ethnicity was reported by Sjoholt et al, 17 who found that two SNPs in the IMPA2 promoter sequence (À461C4T and À207T4C) were preferentially transmitted to affected offspring (P-values of 0.006 and 0.002, respectively).…”

“…Finally, À461C4T was added at the end of the study, as it had shown a statistically significant result with BP in a recent publication. 17 Bulgaria was funded by the Janssen Research Foundation (Beerse, Belgium). The work of AD was funded by the Socrates/Erasmus European programme.…”