Association of AKT1 haplotype with the risk of schizophrenia in Iranian population

Bajestan, Sepideh N.; Sabouri, Amir H.; Nakamura, Masayuki; Takashima, Hiroshi; Keikhaee, Mohammad Reza; Behdani, Fatemeh; Fayyazi, Mohammad Reza; Sargolzaee, Mohammad Reza; Bajestan, Mahboobeh N.; Sabouri, Zahra; Khayami, Esmaeil; Haghighi, Sima; Hashemi, Susan Bany; Eiraku, Nobutaka; Tufani, Hamid; Najmabadi, Hossein; Arimura, Kimiyoshi; Sano, Akira; Osame, Mitsuhiro

doi:10.1002/ajmg.b.30291

Cited by 75 publications

(48 citation statements)

References 22 publications

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“…Interestingly, haplotype 1-5 (rs1130214-rs2494732) whose 2 SNPs singly showed trends toward significance (Supplementary Table S1), is most significantly associated with TRANSMIT/PDTPHASE at broadest diagnostic category D9 (0.0002<global p<0.045; Supplementary Table S2). We saw no association with 'risk' haplotypes of Ikeda et al (13), or the tested portion of the Bajestan et al (14) risk haplotype.…”

Section: Exploratory Analysis -All 2-4 Snp Haplotypescontrasting

confidence: 64%

“…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%

“…The most significant haplotype rs3730358-rs2498799-rs2494732 (C-G-A) was more frequent in controls than cases, indicative of a 'protective' effect. Bajestan et al (14) showed modest evidence of association with schizophrenia in the Iranian population with a different haplotype of the 5 original SNPs of Emamian et al (6). Norton et al (15) in a UK 673 case −716 control sample recently reported weak evidence for association (p=0.04, uncorrected) with a 4-marker haplotype encompassing the Emamian et al core haplotype.…”

Section: Introductionmentioning

confidence: 99%

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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

151

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: Exploratory Analysis -All 2-4 Snp Haplotypescontrasting

confidence: 64%

Section: Introductionmentioning

confidence: 90%

Section: Introductionmentioning

confidence: 99%

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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

151

111

View full text Add to dashboard Cite

show abstract

“…It has a basic role in regulating neuronal cell size and survival (Franke, 2008) and is also a key signaling molecule downstream of the dopamine D2 (DRD2) receptor; decreased AKT1 functionality may result in exacerbated responses to DRD2 receptor stimulation (Arguello and Gogos, 2008). Decreased AKT1 levels have been observed in lymphoblasts and postmortem prefrontal cortex of patients with schizophrenia (Emamian et al, 2004;Thiselton et al, 2008), and several studies have shown evidence for genetic association with schizophrenia (Bajestan et al, 2006;Ikeda et al, 2004;Norton et al, 2007;Schwab et al, 2005;Thiselton et al, 2008), although not all studies were able to confirm this (Ide et al, 2006;Liu et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

AKT1 Moderation of Cannabis-Induced Cognitive Alterations in Psychotic Disorder

Winkel

Beveren

Simons

2011

Neuropsychopharmacol

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Genetic variation in AKT1 may be associated with sensitivity to the psychotomimetic effects of cannabis as well as with increased risk for psychotic disorder following cannabis use. Investigation of the effect of this interaction on relevant intermediate phenotypes for psychosis, such as cognition, may help to clarify the underlying mechanism. Thus, verbal memory (visually presented Word Learning Task), sustained attention (Continuous Performance Test, CPT), AKT1 rs2494732 genotype, and cannabis use were examined in a large cohort of patients with psychotic disorder. No evidence was found for AKT1 Â cannabis interaction on verbal memory. Cannabis use preceding onset of psychotic disorder did interact significantly with AKT1 rs2494732 genotype to affect CPT reaction time (b ¼ 8.0, SE 3.9, p ¼ 0.037) and CPT accuracy (b ¼ À1.2, SE 0.4, p ¼ 0.003). Cannabis-using patients with the a priori vulnerability C/C genotype were slower and less accurate on the CPT, whereas cannabis-using patients with the T/T genotype had similar or better performance than non-using patients with psychotic disorder. The interaction was also apparent in patients with psychotic disorder who had not used cannabis in the 12 months preceding assessment, but was absent in the unaffected siblings of these patients and in healthy controls. In conclusion, cannabis use before onset of psychosis may have long-lasting effects on measures of sustained attention, even in the absence of current use, contingent on AKT1 rs2494732 genotype. The results suggest that long-term changes in cognition may mediate the risk-increasing effect of the AKT1 Â cannabis interaction on psychotic disorder.

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“…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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Association of AKT1 haplotype with the risk of schizophrenia in Iranian population

Cited by 75 publications

References 22 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

AKT1 Moderation of Cannabis-Induced Cognitive Alterations in Psychotic Disorder

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

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