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 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.
Thiselton
Dawn L
DL
Department of Psychiatry, Virginia Commonwealth University, Richmond, Virginia 23298-0424, USA. dlthiselton@vcu.edu
Vladimirov
Vladimir I
VI
Kuo
Po-Hsiu
PH
McClay
Joseph
J
Wormley
Brandon
B
Fanous
Ayman
A
O'Neill
Francis A
FA
Walsh
Dermot
D
Van den Oord
Edwin J C G
EJ
Kendler
Kenneth S
KS
Riley
Brien P
BP
D024506:5' Flanking Region / Q000235:genetics*; D000339:Affect; D000483:Alleles; D001714:Bipolar Disorder / Q000175:diagnosis / Q000235:genetics; D001921:Brain / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics; D016022:Case-Control Studies; D000074765:Dysbindin; D049029:Dystrophin-Associated Proteins; D005260:Female; D005787:Gene Frequency / Q000235:genetics; D005819:Genetic Markers / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005820:Genetic Testing; D005828:Genetics, Population; D005838:Genotype; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D007494:Ireland; D015810:Linkage Disequilibrium / Q000235:genetics; D008297:Male; D009660:Northern Ireland; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D012559:Schizophrenia / Q000175:diagnosis / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics