Association of AKT1 with schizophrenia confirmed in a Japanese population

Ikeda, Masashi; Iwata, Nakao; Suzuki, Tatsuyo; Kitajima, Tsuyoshi; Yamanouchi, Yoshio; Kinoshita, Yoko; Inada, Toshiya; Ozaki, Norio

doi:10.1016/j.biopsych.2004.07.023

Cited by 143 publications

(112 citation statements)

References 15 publications

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“…We see a similarly complex LD structure to that reported in cases by Ikeda et al (13), with low LD between rs3803304-rs2498799 (SNPs 4-6 in Fig.1) in the midst of otherwise high intermarker LD. This may contribute to the haplotypic diversity of AKT1 and underlie the lack of tag SNPs for either block (Fig.2).…”

Section: Linkage Disequilibrium (Ld) Mapsupporting

confidence: 52%

“…Several AKT1 haplotypes have been associated with schizophrenia: in Caucasians (6,12), haplotype [rs1130214-rs3730358]-rs2498799 (T-C-G, SNPs [1-3]-4 in our study; Fig.1) and in a Japanese sample (13), association is more pronounced toward 3' AKT1 (Fig.1). Given the ethnicity of our sample, we focused on the Caucasian over-transmitted risk haplotype T-C-G (rs1130214-rs3730358-rs2498799; 6).…”

Section: Haplotype Replicationsupporting

confidence: 46%

“…Most significant association was detected with haplotype rs3803300-rs10149779-rs3730358 (p=0.001), although others were also over-transmitted to affected offspring, including the T-C-G risk haplotype of Emamian et al (6; Fig.1). Ikeda et al (13) found most significant association with rs2494732, in intron 7 (p=0.004), and with haplotypes overlapping the Emamian et al 'risk' haplotype at the 3' end (Fig.1). The most significant haplotype rs3730358-rs2498799-rs2494732 (C-G-A) was more frequent in controls than cases, indicative of a 'protective' effect.…”

Section: Introductionmentioning

confidence: 84%

“…Association between AKT1 and schizophrenia has been replicated in 3 independent studies: 79 Caucasian sib-pair families (12), a Japanese 507 case −437 control sample (13) and an Iranian 321 case −383 control sample (14). Schwab et al (12) found association with rs3730358 (p=0.027), but more significantly with 5'UTR SNPs, rs1130214 (p=0.011) and rs10149779 (p=0.002).…”

Section: Introductionmentioning

confidence: 90%

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

Thiselton

Vladimirov²,

Kuo³

et al. 2008

Biological Psychiatry

149

111

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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.

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Section: Linkage Disequilibrium (Ld) Mapsupporting

confidence: 52%

Section: Haplotype Replicationsupporting

confidence: 46%

Section: Introductionmentioning

confidence: 84%

Section: Introductionmentioning

confidence: 90%

See 2 more Smart Citations

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

Thiselton

Vladimirov²,

Kuo³

et al. 2008

Biological Psychiatry

149

111

View full text Add to dashboard Cite

show abstract

“…The gene coding for AKT1 (14q32.32) has also been associated with schizophrenia (31,32,(34)(35)(36)(37). Importantly, the A allele in a synonymous SNP in AKT1 (rs1130233 − G > A) is associated with reduced AKT1 protein levels in lymphoblasts (38,39), reduced cognitive performance, inefficient prefronto-striatal activity during cognition (39), as well as with diagnosis of schizophrenia (39).…”

mentioning

confidence: 99%

DRD2/AKT1interaction on D2 c-AMP independent signaling, attentional processing, and response to olanzapine treatment in schizophrenia

Blasi

Napolitano

Ursini

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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The D2/AKT1/GSK-3β signaling pathway has been involved in the downstream intracellular effects of dopamine, in the pathophysiology of cognitive deficits and related brain activity in schizophrenia, as well as in response to treatment with antipsychotics. Polymorphisms in the D2 (DRD2 rs1076560) and AKT1 (AKT1 rs1130233) genes have been associated with their respective protein expression and with higher-order cognition and brain function, including attention. Given the strong potential for their relationship, we investigated the interaction of these polymorphisms on multiple molecular and in vivo phenotypes associated with this signaling pathway. We measured AKT1 and GSK-3β proteins and phosphorylation in human peripheral blood mononuclear cells, functional MRI cingulate response during attentional control, behavioral accuracy during sustained attention, and response to 8 wk of treatment with olanzapine in a total of 190 healthy subjects and 66 patients with schizophrenia. In healthy subjects, we found that the interaction between the T allele of DRD2 rs1076560 and the A allele of AKT1 rs1130233 was associated with reduced AKT1 protein levels and reduced phosphorylation of GSK-3β, as well as with altered cingulate response and reduced behavioral accuracy during attentional processing. On the other hand, interaction of these two alleles was associated with greater improvement of Positive and Negative Syndrome Scale scores in patients with schizophrenia after treatment with olanzapine. The present results indicate that these functional polymorphisms are epistatically associated with multiple phenotypes of relevance to schizophrenia. Our results also lend support to further investigation of this downstream molecular pathway in the etiology and treatment of this disorder.A large series of experimental data indicate that dopamine D2 receptors and schizophrenia are tightly related. First, these receptors are privileged targets of antipsychotic drugs, which antagonize their activity (1). Second, previous reports have suggested association between psychosis and relatively greater D2 density in striatum, even though change is moderate (2). Third, clinical symptoms and cognitive deficits have been associated with abnormal D2 signaling (3-12). The relationship between D2 receptors and cognitive deficits in schizophrenia is also supported by previous models postulating that relatively excessive D2 signaling may lead to lower cortical signal-to-noise ratio and reduced filtering of information, as well as blocking of distracting inputs (10-12). These brain processes contribute to different higherorder cognitive functions and are strongly involved in top-down modulation of attention (13,14). Consistent with these models, previous data have suggested that attentional behavior is affected by D2 genetic variation (15). Furthermore, deficits in attentional processing are centrally implicated in schizophrenia (16,17). In fact, patients with schizophrenia performing attentional tasks have abnormal activity in the cingulate cortex, a ...

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Family-Based Analysis of Genetic Variation Underlying Psychosis-Inducing Effects of Cannabis<subtitle>Sibling Analysis and Proband Follow-up</subtitle><alt-title>Genetic Variation Underlying Cannabis Effects</alt-title>

Winkel¹

2011

Arch Gen Psychiatry

172

109

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Association of AKT1 with schizophrenia confirmed in a Japanese population

Cited by 143 publications

References 15 publications

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

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

DRD2/AKT1interaction on D2 c-AMP independent signaling, attentional processing, and response to olanzapine treatment in schizophrenia

Family-Based Analysis of Genetic Variation Underlying Psychosis-Inducing Effects of Cannabis<subtitle>Sibling Analysis and Proband Follow-up</subtitle><alt-title>Genetic Variation Underlying Cannabis Effects</alt-title>

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