Article

Gene Expression and Association Analyses of the Phosphodiesterase 4B (PDE4B) Gene in Major Depressive Disorder in the Japanese Population

Department of Psychiatry, Course of Integrated Brain Sciences, Medical Informatics, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
American Journal of Medical Genetics Part B Neuropsychiatric Genetics (Impact Factor: 3.27). 06/2009; 150B(4):527-34. DOI: 10.1002/ajmg.b.30852
Source: PubMed

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.

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    ABSTRACT: Schizophrenia is a severe psychotic disorder affecting 0.5-1 % of the population. The disorder is characterized by hallucinations; delusions; disorganized behavior and speech; avolition; anhedonia; flattened affect and cognitive deficits. The etiology of the disorder is complex with evidence for multiple genes contributing to the onset of the disorder along with environmental factors. DISC1 is one of the most promising candidate genes for schizophrenia. It codes for a protein which takes part in numerous molecular interactions along several pathways. This network, termed as the DISC1 pathway, is evidently important for the development and maturation of the central nervous system from the embryo until young adulthood. Disruption at these pathways is thought to predispose schizophrenia. In the present study, we have studied the DISC1 pathway in the etiology of schizophrenia in the Finnish population. We have utilized large Finnish samples; the schizophrenia family sample where DISC1 was originally shown to associate with schizophrenia and the Northern Finland birth cohort 1966 (NFBC66). Several DISC1 binding partners displayed evidence for association in the family sample along with DISC1. Through a genome-wide linkage study, we found a significant linkage signal to a locus where a DISC1 binding partner NDE1 is located at the carriers of a certain DISC1 risk variant. In a follow-up study, genetic markers in NDE1 displayed significant evidence for association with schizophrenia. Further exploration of association between 11 genes of the DISC1 pathway and schizophrenia led to recognition of novel variants in NDEL1, PDE4B and PDE4D that significantly either increased or decreased the risk for schizophrenia. Further, we found evidence that DISC1 itself has a significant role in the human mental functioning even in the healthy population. Variants in DISC1 had a significant effect on anhedonia which is a trait present at everybody but is in its severe form one of the main symptoms of schizophrenia and correlates with the risk of developing the disorder. Further, utilizing genome-wide marker data, we recognized three genes; MIR620; CCDC141 and LCT; that are closely related to the DISC1 pathway but which effects on anhedonia were observable only at the individuals who carried these specific DISC1 variants. Our findings significantly add up to the previous evidence for the involvement of DISC1 and the DISC1 pathway in the etiology of schizophrenia and psychosis. Our results support the concept of a number of DISC1 pathway related genes contributing in the etiology of schizophrenia along with DISC1 and provide new candidates for the studies of schizophrenia. Our findings also significantly increase the importance of DISC1 itself as having a role in psychological functioning in the general population. Skitsofrenia on vakava psykoottinen mielenterveyden häiriö, jota sairastaa 0.5-1 % väestöstä. Skitsofrenian tyypillisiin oireisiin kuuluvat aistiharhat, harhaluulot, hajanainen puhe ja käytös, kiinnostuksen puute, vähentynyt kyky tuntea mielihyvää (anhedonia), tunteiden ilmaisun köyhyys sekä kongtiviivisen kyvyn alentuminen. Skitsofrenian tausta on monitekijäinen, eli sairauden puhkeamiseen vaikuttavat useat geneettiset sekä ympäristötekijät yhdessä. DISC1 on yksi lupaavimmista skitsofrenian ehdokasgeeneistä. DISC1:n koodaama proteiini vuorovaikuttaa monien muiden proteiinien kanssa (DISC1-polku) osallistuen lukuisiin prosesseihin, jotka ovat nykykäsityksen mukaan tärkeitä keskushermoston kehityksessä sikiökaudelta varhaiseen aikuisuuteen ja joiden häiriintyminen voi altistaa skitsofrenialle. Tässä tutkimuksessa olemme kartoittaneet DISC1-polun merkitystä skitsofrenian taustatekijänä suomalaisessa väestössä. Käytössämme on ollut laaja skitsofreniaperheaineisto, jossa aiemmin on havaittu yhteys DISC1:n ja skitsofrenian välillä, sekä suuri pohjoissuomalainen syntymäkohortti vuodelta 1966. Perheaineistossa DISC1:n ohella myös useat muut DISC1-polun geenit osoittautuivat olevan yhteydessä skitsofreniaan. Genominlaajuisessa analyysissä havaitsimme kytkentäsignaalin lähellä DISC1:n kanssa vuorovaikuttavaa NDE1:tä henkilöillä, jotka kantoivat tiettyä DISC1-riskimuotoa. Tarkemmassa assosiaatioanalyysissä kartoitimme tämän ja 11 muun tunnetun DISC1-polun geenin yhteyttä skitsofreniaan ja tunnistimme geeneissä NDE1, NDEL1, PDE4B ja PDE4D uusia variantteja, jotka olivat yhteydessä joko kohonneesseen tai alentuneeseen skitsofreniariskiin. Tulostemme perusteella DISC1:llä näyttää olevan tärkeä rooli myös terveen väestön käyttäytymiselle. Tietyt DISC1:n muodot näyttävät olevan yhteydessä anhedoniaan, joka on kaikilta mitattavissa oleva ominaisuus, mutta joka vaikeassa muodossaan on yksi skitsofrenian pääoireista ja korreloi skitsofreniaan sairastumisen riskin kanssa. Lisäksi genominlaajuisessa aineistossa tunnistimme kolme geeniä, MIR620, CCDC141 ja LCT, jotka läheisesti liittyvät DISC1-polkuun ja joiden yhteys anhedoniaan oli havaittavissa vain näiden tiettyjen DISC1-muotojen kantajilla. Löydöksemme tuovat uutta tietoa DISC1:n ja DISC1-polun merkityksestä skitsofrenian ja psykoosialttiuden taustatekijänä suomalaisessa väestössä. Tuloksemme tukevat aiempaa käsitystä siitä, että useat DISC1-polun geenit vaikuttavat skitsofrenia-alttiuteen DISC1:n ohella ja tarjoavat uusia ehdokasgeenejä tarkempia jatkotutkimuksia varten. Se, että DISC1:llä näyttää olevan yhteys käyttäytymiseen myös väestötasolla, tekee DISC1:stä entistäkin merkityksellisemmän ihmisen psyykkisten toimintojen kannalta.
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