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Letters to the Editor   |    
Five New Schizophrenia Loci May Converge on the Same Cellular Mechanism: The AKT Pathway
Zsolt Balog, Ph.D.; Imre Kiss, M.D.; Szabolcs Kéri, M.D., Ph.D., D.Sc.
Am J Psychiatry 2012;169:335-335. doi:10.1176/appi.ajp.2011.11101562
View Author and Article Information
Szeged and Budapest, Hungary

The authors report no financial relationships with commercial interests.

Research supported by Hungarian National Scientific Research Fund grant NF72488.

Accepted for publication in January 2012.

Copyright © American Psychiatric Association

Accepted January , 2012.

To the Editor: The complexity of schizophrenia genetics raises new questions regarding the biological plausibility of findings from association studies (1). Is there a shared cellular mechanism for the diverse proteins encoded by the dozens of “schizophrenia genes”? The Schizophrenia Psychiatric Genome-Wide Association Study Consortium reported significant associations for five new gene loci (2). Here, we show that these loci are all associated with the neuregulin-1-induced activation of the phosphatidylinositol 3-kinase/protein kinase B/AKT1 intracellular system, which is an important convergence point for several putative factors of psychotic disorders including biogenic amines, synaptic proteins, and growth factors (3, 4). Decreased AKT1 protein levels and phosphorylation have been documented in lymphocytes and brains of individuals with schizophrenia (46). We genotyped 115 healthy volunteers for the following five loci: MIR137, PCGEM1, CSMD1, MMP16 (also associated with cancer), and CNNM2 (a metal ion carrier) (2). The AKT1 pathway, similarly to four of the five loci, is implicated in cell proliferation and differentiation. AKT1 activation was determined from peripheral lymphoblasts by using an immunoblot assay (5, 6). We also studied the extracellular signal-regulated kinase kinase (MEK-) extracellular signal-regulated kinase (ERK) pathway. Results revealed that the ratio of phosphorylated AKT1 (Ser473; 60 kDa) to total AKT1 was lower in risk-allele carriers (mean ratio averaged across the five foci, 0.21) relative to noncarriers (mean ratio, 0.39). This result was evident for all five foci (p<0.001 in all cases; Table 1). We did not observe similar changes in the case of ERK ratios. Our findings raise the possibility that the complex array of proteins encoded by “schizophrenia genes” converge on common intracellular molecular pathways that convert information from the environment to the biological system.

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TABLE 1.

AKT and Extracellular Signal-Regulated Kinase (ERK) Activation Relative to the Risk Alleles of Five New Schizophrenia Locia

Table Footer Note

a The table shows data from 115 healthy volunteers of Central-Eastern European descent with a negative family history for schizophrenia and major mood disorders (mean age=45.6 years, SD=8.7; mean education=12.4 years, SD=4.8; 57 female participants). Genotyping was performed using a TaqMan assay (Applied Biosystems, Foster City, Calif.; duplicate run, error rates <2%; no deviation from the Hardy-Weinberg equilibrium). In alleles, the first one is the risk allele from stage 1 of the genome-wide association study (1). “N (Risk)” refers to the number of participants with the risk allele. Means and standard deviations for the ratios of neuregulin-1-induced phosphorylated AKT and ERK (pAKT and pERK) and total AKT and ERK are shown in the case of risk-allele carriers and noncarriers. Groups were compared with Mann-Whitney U tests. In the case of pERK/ERK ratios, risk-allele carriers and noncarriers did not differ (p>0.5 in all cases).

Walsh  CA;  Engle  EC:  Allelic diversity in human developmental neurogenetics: insights into biology and disease.  Neuron 2010; 68:245–253
[CrossRef] | [PubMed]
 
Schizophrenia Psychiatric Genome-Wide Association Study (GWAS) Consortium:  Genome-wide association study identifies five new schizophrenia loci.  Nat Genet 2011; 43:969–976
[CrossRef] | [PubMed]
 
Freyberg  Z;  Ferrando  SJ;  Javitch  JA:  Roles of the Akt/GSK-3 and Wnt signaling pathways in schizophrenia and antipsychotic drug action.  Am J Psychiatry 2010; 167:388–396
[CrossRef] | [PubMed]
 
Emamian  ES;  Hall  D;  Birnbaum  MJ;  Karayiorgou  M;  Gogos  JA:  Convergent evidence for impaired AKT1-GSK3beta signaling in schizophrenia.  Nat Genet 2004; 36:131–137
[CrossRef] | [PubMed]
 
Sei  Y;  Ren-Patterson  R;  Li  Z;  Tunbridge  EM;  Egan  MF;  Kolachana  BS;  Weinberger  DR:  Neuregulin1-induced cell migration is impaired in schizophrenia: association with neuregulin1 and catechol-O-methyltransferase gene polymorphisms.  Mol Psychiatry 2007; 12:946–957
[CrossRef] | [PubMed]
 
Kéri  S;  Beniczky  S;  Kelemen  O:  Suppression of the P50 evoked response and neuregulin 1-induced AKT phosphorylation in first-episode schizophrenia.  Am J Psychiatry 2010; 167:444–450
[CrossRef] | [PubMed]
 
References Container
Anchor for Jump
TABLE 1.

AKT and Extracellular Signal-Regulated Kinase (ERK) Activation Relative to the Risk Alleles of Five New Schizophrenia Locia

Table Footer Note

a The table shows data from 115 healthy volunteers of Central-Eastern European descent with a negative family history for schizophrenia and major mood disorders (mean age=45.6 years, SD=8.7; mean education=12.4 years, SD=4.8; 57 female participants). Genotyping was performed using a TaqMan assay (Applied Biosystems, Foster City, Calif.; duplicate run, error rates <2%; no deviation from the Hardy-Weinberg equilibrium). In alleles, the first one is the risk allele from stage 1 of the genome-wide association study (1). “N (Risk)” refers to the number of participants with the risk allele. Means and standard deviations for the ratios of neuregulin-1-induced phosphorylated AKT and ERK (pAKT and pERK) and total AKT and ERK are shown in the case of risk-allele carriers and noncarriers. Groups were compared with Mann-Whitney U tests. In the case of pERK/ERK ratios, risk-allele carriers and noncarriers did not differ (p>0.5 in all cases).

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References

Walsh  CA;  Engle  EC:  Allelic diversity in human developmental neurogenetics: insights into biology and disease.  Neuron 2010; 68:245–253
[CrossRef] | [PubMed]
 
Schizophrenia Psychiatric Genome-Wide Association Study (GWAS) Consortium:  Genome-wide association study identifies five new schizophrenia loci.  Nat Genet 2011; 43:969–976
[CrossRef] | [PubMed]
 
Freyberg  Z;  Ferrando  SJ;  Javitch  JA:  Roles of the Akt/GSK-3 and Wnt signaling pathways in schizophrenia and antipsychotic drug action.  Am J Psychiatry 2010; 167:388–396
[CrossRef] | [PubMed]
 
Emamian  ES;  Hall  D;  Birnbaum  MJ;  Karayiorgou  M;  Gogos  JA:  Convergent evidence for impaired AKT1-GSK3beta signaling in schizophrenia.  Nat Genet 2004; 36:131–137
[CrossRef] | [PubMed]
 
Sei  Y;  Ren-Patterson  R;  Li  Z;  Tunbridge  EM;  Egan  MF;  Kolachana  BS;  Weinberger  DR:  Neuregulin1-induced cell migration is impaired in schizophrenia: association with neuregulin1 and catechol-O-methyltransferase gene polymorphisms.  Mol Psychiatry 2007; 12:946–957
[CrossRef] | [PubMed]
 
Kéri  S;  Beniczky  S;  Kelemen  O:  Suppression of the P50 evoked response and neuregulin 1-induced AKT phosphorylation in first-episode schizophrenia.  Am J Psychiatry 2010; 167:444–450
[CrossRef] | [PubMed]
 
References Container
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