Genetic association and identification of a functional SNP at GSK3β for schizophrenia susceptibility
Introduction
Schizophrenia (MIM181500) is one of the most severe mental disorders with worldwide lifetime prevalence approaching 1%, and characterized by psychotic features (delusions and hallucinations), disorganization, dysfunction in normal affective responses, and altered cognitive function (Mueser and McGurk, 2004). It has been demonstrated that genetic component plays an important role in the etiology of schizophrenia, but the underlying genetic risk factors are yet to be identified.
The currently prevailing hypothesis has proposed that schizophrenia is a neurodevelopmental disorder, and disturbances in the early stage of brain development may cause abnormal alterations during embryonic neurogenesis, including regulating neuronal progenitor proliferation (Mao et al., 2009), changing synaptic morphology and physiology, altering differentiation, migration and survival of neurons, etc., which may result in impaired neuronal network in the mature brain and eventually lead to schizophrenia (Fatemi and Folsom, 2009).
The GSK3β gene, spanning about 286 kb on human chromosome 3q13.33 with 12 exons, is highly expressed in the brain and plays numerous roles in development, including synaptic plasticity modulation, intracellular trafficking, apoptosis and regulation of gene transcription etc. (Hur and Zhou, 2010). GSK3β is a key player in the Wnt and PI3K/AKT signaling pathways, which are crucially involved in neurodevelopment and also show abnormalities in schizophrenia (Cotter et al., 1998, Emamian et al., 2004, Lie et al., 2005). It has been suggested that GSK-3β is a master regulator of neural progenitor homeostasis, supporting the pivotal role of GSK-3β in brain development and function (Kim et al., 2009). Additionally, there are abundant evidences that GSK3β interacts with many known schizophrenia risk genes during neurodevelopment, implying potential involvement of GSK3β in schizophrenia susceptibility (Figure S1).
The involvement of GSK3β in schizophrenia are also supported by previous association studies, in which several markers have been identified, though the results were inconsistent among different studies (Scassellati et al., 2004, Ikeda et al., 2005, Lee et al., 2006, Szczepankiewicz et al., 2006, Meng et al., 2008, Souza et al., 2008). In addition, the postmortem studies indicated that GSK3β may play an important role in the pathogenesis of schizophrenia, and a reduction of approximately 40% in GSK3β protein, mRNA and kinase activity was reported in the postmortem frontal cortex of schizophrenia patients (Kozlovsky et al., 2000, Kozlovsky et al., 2001, Kozlovsky et al., 2004, Kozlovsky et al., 2005). However, there have been inconsistent reports (Nadri et al., 2004). Collectively, whether GSK3β contributes to schizophrenia susceptibility awaits further studies.
To search for the susceptible genetic variants of GSK3β for schizophrenia, we first conducted a two stage case–control association analysis using samples independently collected from two cities (Kunming and Yuxi) of southwestern China (a total of 2550 subjects), and we identified a risk SNP (rs3755557) which is located in the GSK3β promoter region. With the use of EMSA and reporter gene assays, we proved that rs3755557 is a functional polymorphism.
Section snippets
Subjects
We recruited two case–control samples independently from Kunming (432 cases, mean age 35.5 ± 9.8 years and 568 controls, mean age 36.1 ± 6.8 years) and Yuxi (520 cases, mean age 38.6 ± 10.4 years and 1030 controls, mean age 36.7 ± 6.9 years) of southwestern China. The patients were diagnosed with schizophrenia according to The Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria (Kunming) and The International Classification of Diseases 10 (ICD-10) (Yuxi) respectively.
Case–control association analysis
The genotypic distributions of the 9 SNPs are in Hardy–Weinberg equilibrium in all samples, except for rs7431209 in the Yuxi case sample (p = 0.01). We double checked the eletromorphs of the original genotype data and no calling errors were found (Figure S2).
Table 1 presents the results of allelic association. For the Kunming sample, among the 9 tested SNPs, one SNP (rs13320980) showed nominally significant association with schizophrenia (p = 0.002, uncorrected). There are two SNPs with marginal
Discussion
Previous studies have suggested GSK3β gene as a potential susceptibility gene for schizophrenia due to its critical role in neurodevelopment, and this was supported by the reported aberrant expression of GSK3β in schizophrenia patients. But the efforts in identifying risk genetic variants in GSK3β gene for schizophrenia have harvested little. Potential susceptibility loci for schizophrenia on chromosome 3q was detected by early genome-wide analysis using microsatellite markers, which is
Role of funding source
This work was supported by grants from the National 973 project of China (grant numbers, 2011CBA00401 and 2007CB815705), the National Natural Science Foundation of China (grant numbers, 30871343 and 31071101), and the Natural Science Foundation of Yunnan Province of China (grant number, Y003721111).
Contributors
Authors ML, XJL and BS designed the experiments. Authors ML, YM, XX, XJL, LS and YMP performed the experiments. Authors ML and XX analyzed the data. Authors ML, BS, XX and XJL wrote the paper. Authors YM, XYL, LDY and HBD conducted the sample collection. All authors contributed to and have approved the final manuscript.
Conflict of interest
The authors have no conflicts of interest to declare.
Acknowledgements
We are grateful to the volunteers who participated in the genetic studies summarized in this article. We thank the participating psychiatrists in the Second People's Hospital of Yuxi City for helping with the ascertainment of the study subjects (Drs. Shun-ying Yang, Xing-fu Pu and Jin Yu). We also thank Hui Zhang from Kunming Institute of Zoology for her technical assistance.
References (36)
- et al.
Glycogen synthase kinase-3beta immunoreactivity is reduced in the prefrontal cortex in schizophrenia
Neurosci. Lett.
(2001) - et al.
Low GSK-3 activity in frontal cortex of schizophrenic patients
Schizophr. Res.
(2001) - et al.
Low GSK-3beta in schizophrenia as a consequence of neurodevelopmental insult
Eur. Neuropsychopharmacol.
(2005) - et al.
No association of two common SNPs at position − 1727 A/T, -50 C/T of GSK-3 beta polymorphisms with schizophrenia and bipolar disorder of Korean population
Neurosci. Lett.
(2006) - et al.
Disrupted in schizophrenia 1 regulates neuronal progenitor proliferation via modulation of GSK3beta/beta-catenin signaling
Cell
(2009) - et al.
No significant association between the genetic polymorphisms in the GSK-3 beta gene and schizophrenia in the Chinese population
J. Psychiatr. Res.
(2008) - et al.
Schizophrenia
Lancet
(2004) - et al.
GSK-3 parameters in postmortem frontal cortex and hippocampus of schizophrenic patients
Schizophr. Res.
(2004) - et al.
Positional pathway screen of wnt signaling genes in schizophrenia: association with DKK4
Biol. Psychiatry
(2008) - et al.
PLINK: a tool set for whole-genome association and population-based linkage analyses
Am. J. Hum. Genet.
(2007)
Score tests for association between traits and haplotypes when linkage phase is ambiguous
Am. J. Hum. Genet.
Neonatal neuronal overexpression of glycogen synthase kinase-3 beta reduces brain size in transgenic mice
Neuroscience
Association study of the human FZD3 locus with schizophrenia
Biol. Psychiatry
A genome screen of 13 bipolar affective disorder pedigrees provides evidence for susceptibility loci on chromosome 3 as well as chromosomes 9, 13 and 19
Mol. Psychiatry
Haploview: analysis and visualization of LD and haplotype maps
Bioinformatics
Statistical power analysis for the behavioral sciences
Abnormalities of Wnt signalling in schizophrenia--evidence for neurodevelopmental abnormality
Neuroreport
The tumor suppressor adenomatous polyposis coli gene is associated with susceptibility to schizophrenia
Mol. Psychiatry
Cited by (37)
4-Methoxycinnamic acid attenuates schizophrenia-like behaviors induced by MK-801 in mice
2022, Journal of EthnopharmacologyCitation Excerpt :In schizophrenia patients, dysfunction of PI3K-Akt signaling with the subsequent inactivation of GSK-3β, which is associated with dopamine D1 and D5 receptor signaling, has been reported (Goldman-Rakic et al., 2004). Moreover, several schizophrenia-linked single nucleotide polymorphisms of PI3K (Li et al., 2021), Akt (McGuire et al., 2017), and GSK-3β (Li et al., 2011) were suggested to affect such kinase activities and to induce abnormal intracellular signal transduction, as observed in schizophrenia patients (Zheng et al., 2012). Therefore, regulating the PI3K-Akt-GSK-3β signaling pathway has been suggested as a potential therapeutic strategy against schizophrenia (Freyberg et al., 2010; Luo et al., 2020).
A comprehensive analysis of GSK3B variation for schizophrenia in Han Chinese individuals
2020, Asian Journal of PsychiatryCitation Excerpt :The rs3755557 SNP is located in the promoter region of GSK3B. The functional experiment demonstrated that the rs3755557 polymorphism could influence the transcription factor binding affinities (Li et al., 2011). Therefore, this SNP may have important pathophysiological implications for schizophrenia.
Effects of the antipsychotics haloperidol, clozapine, and aripiprazole on the dendritic spine
2018, European NeuropsychopharmacologyMaslinic acid ameliorates NMDA receptor blockade-induced schizophrenia-like behaviors in mice
2017, NeuropharmacologyCitation Excerpt :For example, the GSK-3β signaling pathway is said to be one of the target signaling molecules (Blasi et al., 2013; Pandey et al., 2015; Peng et al., 2013). GSK-3β has been suggested to be closely related to psychiatric disorders such as schizophrenia, bipolar disorder and Alzheimer's disease (Li et al., 2011; Singh, 2013; Tang et al., 2013). We observed that the increased phosphorylation of Akt and GSK-3β induced by MK-801 in the prefrontal cortex was significantly blocked by a single administration of maslinic acid.
Association of functional genetic variation in PP2A with prefrontal working memory processing
2017, Behavioural Brain ResearchCitation Excerpt :Since PP2A, the protein coded by PPP2R2B gene, is a key partner of D2 receptor in dopamine signaling, it is plausible that genetically determined variation in PPP2R2B prefrontal expression leads to molecular effects along with system level phenotypes associated with modulation of D2 signaling in such a brain area. In particular, PP2A participates to a macromolecular complex including D2 receptor, Akt1 and β-arrestin, which is recruited when D2 is stimulated by dopamine [2,4] and allows an alternate D2 signaling transduction with respect to that mediated by the canonical cAMP dependent pathway [23,18,1,33,25]. Thus, it is possible that variation of PPP2R2B expression associated with rs959627 results in a differential availability of PP2A to activate the cAMP independent D2 signaling, which may represents a switch mechanism between the two pathways of D2 signal transduction.
Dimensions of GSK3 Monoamine-Related Intracellular Signaling in Schizophrenia
2016, Handbook of Behavioral Neuroscience
- 1
These authors contributed equally to the work.