Elsevier

Biological Psychiatry

Volume 63, Issue 5, 1 March 2008, Pages 449-457
Biological Psychiatry

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

https://doi.org/10.1016/j.biopsych.2007.06.005Get rights and content

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.

Section snippets

Subjects and Phenotypes

The ISHDSF sample comprises 265 high-density schizophrenia families with 1408 individuals available for genotyping (22). All participating individuals gave appropriate informed consent to the study. The sample was divided into four concentric diagnostic categories for analysis purposes, ranging from narrow to very broad spectrum disease. Briefly, D2 (core schizophrenia) includes schizophrenia, poor-outcome schizoaffective disorder, and simple schizophrenia; D5 (narrow psychosis spectrum)

Results

Table 1 lists the AKT1 SNP locations and allele frequencies in the ISHDSF, which are similar to those of Emamian et al. (6). AKT1 has 14–15 known exons (depending on splice variant) spanning approximately 24.2 kilobases (kb) (Figure 1). Genotype frequencies of all SNPs were in HWE (data not shown).

Discussion

As is increasingly observed in complex disease association studies, reports on AKT1 and schizophrenia reveal inconsistent replication of a particular allele combination, yet replication at a broader level, i.e. the SNP or haplotype and ultimately the gene itself (43, 44). Potential reasons for such diverse findings are sample size, heterogenous phenotypes, marker sets, allele frequencies or LD structure, genetic admixture, multiple testing issues, and indeed true heterogeneity in variants that

References (53)

  • D. Clayton

    A generalization of the transmission/disequilibrium test for uncertain-haplotype transmission

    Am J Hum Genet

    (1999)
  • E.R. Martin et al.

    A test for linkage and association in general pedigrees: The pedigree disequilibrium test

    Am J Hum Genet

    (2000)
  • K.J. Livak et al.

    Analysis of relative gene expression data using real-time quantitative PCR and the 2-ΔΔCT method

    Methods

    (2001)
  • E.J.C.G. Van den Oord et al.

    False discoveries and models for gene discovery

    Trends Genet

    (2003)
  • B.M. Neale et al.

    The future of association studies: Gene-based analysis and replication

    Am J Hum Genet

    (2004)
  • P.-I. Lin et al.

    No gene is an island: The flip-flop phenomenon

    Am J Hum Genet

    (2007)
  • P.F. Sullivan

    Spurious genetic associations

    Biol Psychiatry

    (2007)
  • K.K. Nicodemus et al.

    An evaluation of power and type I error of single-nucleotide polymorphism transmission/disequilibrium-based statistical methods under different family structures, missing parental data, and population stratification

    Am J Hum Genet

    (2007)
  • R.M. Murray et al.

    A developmental model for similarities and dissimilarities between schizophrenia and bipolar disorder

    Schizophrenia Res

    (2004)
  • P. Mäki et al.

    Predictors of schizophrenia—a review

    Brit Med Bull

    (2005)
  • K.S. Kendler et al.

    The genetics of schizophrenia: A current, genetic-epidemiologic perspective

    Schizophr Bull

    (1993)
  • P.J. Harrison et al.

    Schizophrenia genes, gene expression, and neuropathology: On the matter of their convergence

    Mol Psychiatry

    (2005)
  • J.M. Beaulieu et al.

    Lithium antagonizes dopamine-dependent behaviors mediated by an AKT/glycogen synthase kinase 3 signaling cascade

    Proc Natl Acad Sci U S A

    (2004)
  • E.S. Emamian et al.

    Convergent evidence for impaired AKT1-GSK3B signaling in schizophrenia

    Nat Genet

    (2004)
  • G. Song et al.

    The activation of Akt/PKB signaling pathway and cell survival

    J Cell Mol Med

    (2005)
  • W.-S. Lai et al.

    Akt1 deficiency affects neuronal morphology and predisposes to abnormalities in prefrontal cortex functioning

    Proc Natl Acad Sci U S A

    (2006)
  • Cited by (131)

    • Receptor tyrosine kinases (RTKs): from biology to pathophysiology

      2023, Receptor Tyrosine Kinases in Neurodegenerative and Psychiatric Disorders
    View all citing articles on Scopus
    View full text