The mRNA expression of DRD2, PI3KCB, and AKT1 in the blood of acute schizophrenia patients

Lang, Liang; Yin, Ling; Zhang, Guofu; Jin, Chunhui; Zhou, Zhenhe; Zhang, Cheng; Gao, Yuan

doi:10.1016/j.psychres.2016.07.010

Cited by 14 publications

(14 citation statements)

References 44 publications

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“…Third, we found a significant enrichment of schizophrenia SNPs in postsynaptic protein kinase B (PKB or Akt). AKT1 messenger RNA levels are higher in blood of schizophrenia patients compared to healthy controls and interactions between genetic variation in AKT1 and cannabis use are associated with schizophrenia, possibly mediated through AKT signaling downstream of DRD2 (Liu et al, 2016;van Winkel, 2011). Interestingly, phosphorylation of glycogen synthase kinase 3 beta (Gsk3β) by the antipsychotic aripiprazole is mediated by Akt (Pan et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

Comprehensive pathway analyses of schizophrenia risk loci point to dysfunctional postsynaptic signaling

Schijven

Kofink

Tragante

et al. 2018

Schizophrenia Research

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Large-scale genome-wide association studies (GWAS) have implicated many low-penetrance loci in schizophrenia. However, its pathological mechanisms are poorly understood, which in turn hampers the development of novel pharmacological treatments. Pathway and gene set analyses carry the potential to generate hypotheses about disease mechanisms and have provided biological context to genome-wide data of schizophrenia. We aimed to examine which biological processes are likely candidates to underlie schizophrenia by integrating novel and powerful pathway analysis tools using data from the largest Psychiatric Genomics Consortium schizophrenia GWAS (N=79,845) and the most recent 2018 schizophrenia GWAS (N=105,318). By applying a primary unbiased analysis (Multi-marker Analysis of GenoMic Annotation; MAGMA) to weigh the role of biological processes from the Molecular Signatures Database (MSigDB), we identified enrichment of common variants in synaptic plasticity and neuron differentiation gene sets. We supported these findings using MAGMA, Meta-Analysis Gene-set Enrichment of variaNT Associations (MAGENTA) and Interval Enrichment Analysis (INRICH) on detailed synaptic signaling pathways from the Kyoto Encyclopedia of Genes and Genomes (KEGG) and found enrichment in mainly the dopaminergic and cholinergic synapses. Moreover, shared genes involved in these neurotransmitter systems had a large contribution to the observed enrichment, protein products of top genes in these pathways showed more direct and indirect interactions than expected by chance, and expression profiles of these genes were largely similar among brain tissues. In conclusion, we provide strong and consistent genetics and protein-interaction informed evidence for the role of postsynaptic signaling processes in schizophrenia, opening avenues for future translational and psychopharmacological studies.

show abstract

Section: Discussionmentioning

confidence: 99%

Comprehensive pathway analyses of schizophrenia risk loci point to dysfunctional postsynaptic signaling

Schijven

Kofink

Tragante

et al. 2018

Schizophrenia Research

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“…We recently showed in the same cohort used in the current study, an increased expression of three NRG1 transcripts [i.e., NRG1 -EGFα, NRG1 -EGFβ, and NRG1 -typeI (Ig2) ] in TRS compared to controls ( 24 ). In addition, several studies by others have reported increased expression of specific isoforms of NRG1 ( 18 ) and mRNA of down-stream signaling molecules, including PIK3CD, PIK3CB ( 16 , 22 ), and AKT1 ( 22 , 23 ) in schizophrenia patients. Furthermore, other down-stream signaling molecules, such as mTOR, P70S6K , and eIF4B , have been shown to be increased in major depressive disorder ( 35 ).…”

Section: Discussionmentioning

confidence: 99%

“…Several human postmortem brain studies have shown dysregulation of gene expression of NRG1 , ErbB4 or down-stream targets among individuals with schizophrenia ( 12 – 17 ). Likewise, evidence of dysregulated gene expression of NRG1 ( 18 – 20 ), ErbB1 / ErbB4 ( 21 ), and PI3K /AKT ( 22 , 23 ) in peripheral tissues [i.e., whole blood, peripheral blood mononuclear cells (PBMCs), monocytes] in schizophrenia has also been shown in people with chronic schizophrenia. Treatment-resistant schizophrenia (TRS) patients represent a considerable subgroup who have significant increases in multiple NRG1 splice variants in peripheral blood ( 24 ).…”

Section: Introductionmentioning

confidence: 99%

Peripheral Transcription of NRG-ErbB Pathway Genes Are Upregulated in Treatment-Resistant Schizophrenia

et al. 2017

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Investigation of peripheral gene expression patterns of transcripts within the NRG–ErbB signaling pathway, other than neuregulin-1 (NRG1), among patients with schizophrenia and more specifically treatment-resistant schizophrenia (TRS) is limited. The present study built on our previous work demonstrating elevated levels of NRG1 EGFα, EGFβ, and type I(Ig2) containing transcripts in TRS by investigating 11 NRG–ErbB signaling pathway mRNA transcripts (NRG2, ErbB1, ErbB2, ErbB3, ErbB4, PIK3CD, PIK3R3, AKT1, mTOR, P70S6K, eIF4EBP1) in whole blood of TRS patients (N = 71) and healthy controls (N = 57). We also examined the effect of clozapine exposure on transcript levels using cultured peripheral blood mononuclear cells (PBMCs) from 15 healthy individuals. Five transcripts (ErbB3, PIK3CD, AKT1, P70S6K, eIF4EBP1) were significantly elevated in TRS patients compared to healthy controls but only expression of P70S6K (Pcorrected = 0.018), a protein kinase linked to protein synthesis, cell growth, and cell proliferation, survived correction for multiple testing using the Benjamini–Hochberg method. Investigation of clinical factors revealed that ErbB2, PIK3CD, PIK3R3, AKT1, mTOR, and P70S6K expression were negatively correlated with duration of illness. However, no transcript was associated with chlorpromazine equivalent dose or clozapine plasma levels, the latter supported by our in vitro PBMC clozapine exposure experiment. Taken together with previously published NRG1 results, our findings suggest an overall upregulation of transcripts within the NRG–ErbB signaling pathway among individuals with schizophrenia some of which attenuate over duration of illness. Follow-up studies are needed to determine if the observed peripheral upregulation of transcripts within the NRG–ErbB signaling pathway are specific to TRS or are a general blood-based marker of schizophrenia.

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Section: Discussionmentioning

confidence: 99%

“…AKT1 messenger RNA levels are higher in blood of schizophrenia patients compared to healthy controls and interactions between genetic variation in AKT1 and cannabis use are associated with schizophrenia, possibly mediated through AKT signaling downstream of DRD2. 45,46 Interestingly, phosphorylation of glycogen synthase kinase 3 beta (Gsk3b) by the antipsychotic aripiprazole is mediated by Akt. 47 Finally, we detected an accumulation of SNPs in protein phosphatase 1 (PP1) and protein phosphatase 2A (PP2A).…”

Section: Discussionmentioning

confidence: 99%

Comprehensive pathway analyses of schizophrenia risk loci point to dysfunctional postsynaptic signaling

Schijven

Kofink

Tragante

et al. 2017

Preprint

View full text Add to dashboard Cite

Large-scale genome-wide association studies (GWAS) have implicated many low-penetrance loci in schizophrenia. However, its pathological mechanisms are poorly understood, which in turn hampers the development of novel pharmacological treatments. Pathway and gene set analyses carry the potential to generate hypotheses about disease mechanisms and have provided biological context to genome-wide data of schizophrenia. We aimed to examine which biological processes are likely candidates to underlie schizophrenia by integrating novel and powerful pathway analysis tools using data from the largest published schizophrenia GWAS (N = 79,845). By applying a primary unbiased analysis (Multi-marker Analysis of GenoMic Annotation; MAGMA) to weigh the role of biological processes from the MSigDB database, we identified enrichment of common variants in synaptic plasticity and neuron differentiation gene sets. We supported these findings using MAGMA, MetaAnalysis Gene-set Enrichment of variaNT Associations (MAGENTA) and Interval Enrichment Analysis (INRICH) on detailed synaptic signaling pathways from the Kyoto Encyclopedia of Genes and Genomes (KEGG) and found enrichment in mainly the dopaminergic synapse and long-term potentiation. Moreover, shared genes involved in these neurotransmitter systems had a large contribution to the observed enrichment, protein products of top genes in these pathways showed more direct and indirect interactions than expected by chance, and expression profiles of these genes were largely similar among brain tissues. In conclusion, we provide strong and consistent genetics and protein-interaction informed evidence for the role of postsynaptic signaling processes in schizophrenia, opening avenues for future psychopharmacological studies.

show abstract

The mRNA expression of DRD2, PI3KCB, and AKT1 in the blood of acute schizophrenia patients

Cited by 14 publications

References 44 publications

Comprehensive pathway analyses of schizophrenia risk loci point to dysfunctional postsynaptic signaling

Comprehensive pathway analyses of schizophrenia risk loci point to dysfunctional postsynaptic signaling

Peripheral Transcription of NRG-ErbB Pathway Genes Are Upregulated in Treatment-Resistant Schizophrenia

Comprehensive pathway analyses of schizophrenia risk loci point to dysfunctional postsynaptic signaling

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