AKT1 Is Associated with Schizophrenia Across Multiple Symptom Dimensions in the Irish Study of High Density Schizophrenia Families

Background The phosphatidylinositol 3-kinase (PI3K)-AKT signal transduction pathway is critical to cell growth and survival. In vitro functional studies indicate that the candidate schizophrenia susceptibility gene DTNBP1 influences AKT signaling to promote neuronal viability. The AKT1 gene has also...

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Bibliographic Details
Published in:Biological psychiatry (1969) 2008-03, Vol.63 (5), p.449-457
Main Authors: Thiselton, Dawn L, Vladimirov, Vladimir I, Kuo, Po-Hsiu, McClay, Joseph, Wormley, Brandon, Fanous, Ayman, O’Neill, Francis A, Walsh, Dermot, Van den Oord, Edwin J.C.G, Kendler, Kenneth S, Riley, Brien P
Format: Article
Language:English
Subjects:
5' Flanking Region - genetics
Affect
AKT1
Alleles
association
Bipolar Disorder - diagnosis
Bipolar Disorder - genetics
Brain - pathology
Carrier Proteins - genetics
Case-Control Studies
clinical features
Dysbindin
Dystrophin-Associated Proteins
Female
gene expression
Gene Frequency - genetics
Genetic Markers - genetics
Genetic Predisposition to Disease - genetics
Genetic Testing
Genetics, Population
Genotype
Haplotypes - genetics
Humans
Ireland
Linkage Disequilibrium - genetics
Male
Northern Ireland
Phenotype
Polymorphism, Single Nucleotide - genetics
Proto-Oncogene Proteins c-akt - genetics
Psychiatry
RNA, Messenger - genetics
schizophrenia
Schizophrenia - diagnosis
Schizophrenia - genetics
Signal Transduction - genetics
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Summary:Background The phosphatidylinositol 3-kinase (PI3K)-AKT signal transduction pathway is critical to cell growth and survival. In vitro functional studies indicate that the candidate schizophrenia susceptibility gene DTNBP1 influences AKT signaling to promote neuronal viability. The AKT1 gene has also been implicated in schizophrenia by association studies and decreased protein expression in the brains of schizophrenic patients. Methods The association of DTNBP1 in the Irish Study of High Density Schizophrenia Families (ISHDSF) prompted our investigation of AKT1 for association with disease in this sample. Eight single nucleotide polymorphisms spanning AKT1 were analyzed for association with schizophrenia across four definitions of affection and according to Operational Criteria Checklist of Psychotic Illness (OPCRIT) symptom scales. We examined expression of AKT1 messenger RNA from postmortem brain tissue of schizophrenic, bipolar, and control individuals. Results No single marker showed significant association, but the risk haplotype previously found over-transmitted to Caucasian schizophrenic patients was significantly under-transmitted in the ISHDSF (.01 < p < .05), across all OPCRIT symptom dimensions. Exploratory haplotype analysis confirmed association with schizophrenia toward the 5’ end of AKT1 (.008 < p < .049, uncorrected). We found significantly decreased RNA levels in prefrontal cortex of schizophrenic individuals, consistent with reduced AKT1 protein levels reported in schizophrenic brain. Conclusions The replication of association of AKT1 gene variants in a further Caucasian family sample adds support for involvement of AKT signaling in schizophrenia, perhaps encompassing a broader clinical phenotype that includes mood dysregulation. We show that AKT signaling might be compromised in schizophrenic and bipolar patients via reduced RNA expression of specific AKT isoforms.
ISSN:0006-3223
1873-2402
DOI:10.1016/j.biopsych.2007.06.005