Gene expression and association analyses of the phosphodiesterase 4B (PDE4B) gene in major depressive disorder in the Japanese population

Abstract

The phosphodiesterase 4B (PDE4B) interacts with disrupted-in-schizophrenia 1 (DISC1), which is a known genetic risk factor for schizophrenia, bipolar disorder and major depressive disorder (MDD). PDE4B is also important in the regulation of cAMP signaling, a second messenger implicated in learning, memory, and mood. In this study, we determined mRNA expression levels of the PDE4B gene in the peripheral blood leukocytes of patients with MDD and control subjects (n = 33, each). Next we performed two-stage case-controlled association analyses (first set; case = 174, controls = 348; second set; case = 481, controls = 812) in the Japanese population to determine if the PDE4B gene is implicated in MDD. In the leukocytes, a significantly higher expression of the PDE4B mRNA was observed in the drug-naïve MDD patients compared with control subjects (P < 0.0001) and the expression of the MDD patients significantly decreased after antidepressant treatment (P = 0.030). In the association analysis, we observed significant allelic associations of four SNPs (the most significant, rs472952; P = 0.002) and a significant haplotypic association (permutation P = 0.019) between the PDE4B gene and MDD in the first-set samples. However, we could not confirm these significant associations in the following independent second-set of samples. Our results suggest that the PDE4B gene itself does not link to MDD but the elevated mRNA levels of PDE4B might be implicated in the pathophysiology of MDD.

Alterations in Expression and Function of Phosphodiesterases in Huntington’s Disease

“…They found four variants in the PDE4B3 isoform nominally associated with schizophrenia in females, and four additional single nucleotide polymorphisms associated with positive symptom scores according to Positive And Negative Symptoms Scale (PANSS) testing of patients. Similar results were found in the PDE4B gene in a Japanese population, lending further support to the theory that certain PDE4B variants have a positive association with schizophrenia (Numata et al, 2009). Up-regulation of PDE4A and 4B mRNA has been observed in the frontal cortex of patients with schizophrenia (Fatemi et al, 2009).…”

“…The Hdh mouse models of HD exhibit anhedonia and decreased socializing behaviours, which are considered to be analogous to human depression (Kennedy et al, 2005). Genetic factors, or heritability, contribute 40 -50% to the probability a person will suffer major depressive disorder (Numata et al, 2009). Changes in the mRNA expression or the activity of certain PDEs can contribute to major depressive disorder etiology.…”

“…Changes in the mRNA expression or the activity of certain PDEs can contribute to major depressive disorder etiology. PDE4B mRNA expression, single nucleotide polymorphisms, and haplotype variants were examined in a large Japanese population (655) suffering major depressive disorder (Numata et al, 2009). No significant correlation between allelic variation and major depressive disorder was found.…”

Association study of PDE4B gene variants in scandinavian schizophrenia and bipolar disorder multicenter case–control samples

“…However, the present study sample was reasonable stable receiving mostly outpatient treatment, which makes such type 1 errors less likely, and genetic associations to subgroups of SZ based on PANSS scores have been reported earlier [DeRosse et al, 2006]. At the time of choosing the tagSNPs in this study, the three other association studies investigating PDE4B and SZ had not been published [Pickard et al, 2007;Fatemi et al, 2008;Numata et al, 2008a]. Therefore, the overlap between SNPs investigated in the present and published PDE4B studies is limited.…”

Venlafaxine increases cell proliferation and regulates DISC1, PDE4B and NMDA receptor 2B expression in the hippocampus in chronic mild stress mice

“…PDE4B is highly expressed in blood fractions and nervous system tissues in humans (Cheung et al, 2007). Some clinical studies have shown that PDE4B mRNA levels in patients with MDD were down-regulated after chronic treatment with a selective serotonin re-uptake inhibitor (fluoxetine) or tricyclic antidepressant (desipramine, rolipram) (Dlaboga et al, 2006;Numata et al, 2009). In addition, chronic administration of fluoxetine increased hippocampal neurogenesis and decreased the expression of PDE4B in mice and rats (Encinas et al, 2006).…”