Next Article in Journal
Evaluating the Efficiency of DNA Metabarcoding to Analyze the Diet of Hippocampus guttulatus (Teleostea: Syngnathidae)
Next Article in Special Issue
Stochastic Effects in Retrotransposon Dynamics Revealed by Modeling under Competition for Cellular Resources
Previous Article in Journal
COVID-19 and Antimicrobial Resistance: Data from the Greek Electronic System for the Surveillance of Antimicrobial Resistance—WHONET-Greece (January 2018–March 2021)
Previous Article in Special Issue
Whole-Genome Resequencing Points to Candidate DNA Loci Affecting Body Temperature under Cold Stress in Siberian Cattle Populations
 
 
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Article

Study of Early Onset Schizophrenia: Associations of GRIN2A and GRIN2B Polymorphisms

by
Evgeniya G. Poltavskaya
1,*,
Olga Yu. Fedorenko
1,
Elena G. Kornetova
1,2,
Anton J. M. Loonen
3,
Alexander N. Kornetov
2,
Nikolay A. Bokhan
1,2 and
Svetlana A. Ivanova
1,2
1
Mental Health Research Institute, Tomsk National Research Medical Center of the Russian Academy of Sciences, 634014 Tomsk, Russia
2
Fundamental Psychology and Behavioral Medicine Department, Siberian State Medical University, 634050 Tomsk, Russia
3
Unit of PharmacoTherapy, Epidemiology & Economics, Groningen Research Institute of Pharmacy, University of Groningen, 9713AV Groningen, The Netherlands
*
Author to whom correspondence should be addressed.
Life 2021, 11(10), 997; https://doi.org/10.3390/life11100997
Submission received: 1 August 2021 / Revised: 15 September 2021 / Accepted: 17 September 2021 / Published: 22 September 2021
(This article belongs to the Special Issue Life: Computational Genomics)

Abstract

:
Background: Schizophrenia is a complex mental disorder with a high heritability. Dysfunction of the N-methyl-D-aspartate (NMDA)-type glutamate receptors may be involved in the pathogenesis of schizophrenia. In this study, we examined the contribution of GRIN2A and GRIN2B (Glutamate Ionotropic Receptor NMDA Type Subunit 2A/2B) polymorphisms to the clinical features of schizophrenia, such as the leading symptoms, the type of course, and the age of onset. Methods: A population of 402 Russian patients with schizophrenia from the Siberian region was investigated. Genotyping of seventeen single-nucleotide polymorphisms (SNPs) in GRIN2A and GRIN2B was performed using QuantStudio™ 3D Digital PCR System Life Technologies amplifier using TaqMan Validated SNP Genotyping Assay kits (Applied Biosystems). The results were analyzed using Chi-square and the Fisher’s exact tests. Results: We found an association of GRIN2A rs7206256 and rs11644461 and GRIN2B rs7313149 with the early onset (before the age of 18 years old) schizophrenia. We did not reveal any associations of GRIN2A and GRIN2B polymorphisms with leading (positive vs. negative) symptoms or type of course (continuous vs. episodic) of schizophrenia. Conclusions: In the study, we confirmed the involvement of the GRIN2A and GRIN2B genes in the early onset of schizophrenia in a Russian population of the Siberian region.

1. Introduction

Schizophrenia is a complex mental disorder that seems to originate from disruption of brain development and/or maturation caused by genetic or environmental factors, or both [1]. The family, twin and adoption studies have demonstrated a high heritability of the disease which is not simply defined by several major genes but rather evolves from addition or potentiation of a specific cluster of genes, which subsequently determines the genetic vulnerability of an individual [2].
The oldest and best developed idea for the pathophysiology of schizophrenia is the thought that this disorder is caused by a dysfunction within the dopaminergic system [3]. Now, it is almost impossible to imagine that such a dysfunction would be independent of the dysfunction of the gamma aminobutyric acid (GABA) and glutamate neurotransmitter systems [4]. Involvement of glutamatergic neurotransmission is therefore at the heart of another main hypothesis [5,6]. Glutamate is the most important excitatory neurotransmitter of the central nervous system and affects the transmission of impulses via ionotropic and metabotropic receptors [7]. Ionotropic N-methyl-D-aspartate (NMDA) type glutamate receptors are of particular interest in this context because they increase the sensitivity of certain synapses through long-term potentiation (LTP) and lead to excitotoxicity when stimulated too massively.
Dysfunction of the N-methyl-D-aspartate (NMDA)-type glutamate receptor has been proposed as a mechanism in the etiology of schizophrenia, based on the observation that non-competitive antagonists of the NMDA receptor, such as phencyclidine, induce schizophrenia-like symptoms [5,6]. Psychiatric diseases may occur when genes which encode receptors become dysfunctional [8]. Dysfunction of NMDA receptors may therefore in principle be associated with the occurrence of neurodevelopmental changes that may underlie the pathology of schizophrenia [1]. In addition, neuronal excitotoxicity resulting from hyperactive NMDA receptors is suggested to play a role in many brain disorders, including Alzheimer’s disease and schizophrenia [9,10]. At the same time, in humans, depending on dose, blocking the NMDA receptor with ketamine can cause antidepressant effects [11].
The NMDA receptors are ionotropic glutamate receptors, composed of a heterotetramer of two NMDA 1 (GRIN1) subunits and archetypally two GRIN2 (or GluN2) subunits of which four variants (GRIN2A-GRIN2D) exist, combined in a varying ratio to make up the receptor complex [12]. GluN2A, encoded by the GRIN2A gene, is the most abundant of the GluN2 NMDA receptor subunits in the mammalian CNS. Physiological and genetic evidence implicate GluN2A-containing receptors in susceptibility to autism, schizophrenia, and childhood epilepsy and neurodevelopmental disorders such as Rett Syndrome [13]. A previous study identified a variable (GT)n polymorphism in the promoter region of the GluN2A subunit gene (GRIN2A), and showed its association with schizophrenia in a case–control study, together with a correlation between the length of the repeat and the severity of chronic outcome [14].
The GRIN2B (glutamate receptor, ionotropic, N-methyl-D-aspartate 2B) gene, located in the short arm of chromosome 12, encoding the NR2B subunit of the N-methyl-D-aspartate receptor, has recently been recognized to play an important role in corticogenesis and brain plasticity. Deletions in the short arm of chromosome 12 are rare. Hemizygous loss of function of the GRIN2B gene results in developmental delay, whereas gain of function leads to epilepsy, and infantile spasms in particular. In addition, GRIN2B variants have been associated with autism spectrum disorder and schizophrenia [15]. It has also been demonstrated that the level of an ionotropic N-methyl-D-aspartate 2B subunit (GRIN2B) of the glutamate receptor tends to increase after subchronic administration of clozapine, suggesting that GRIN2B may play an active role in the pathogenesis of schizophrenia and the function of clozapine medication [16].
Earlier, we studied the role of GRIN2A and GRIN2B variants in antipsychotic-induced tardive dyskinesia in schizophrenia in terms of genetically determined increase in vulnerability to NMDA-induced excitotoxicity [17,18,19].
Schizophrenia is highly heterogeneous mental disorder. The course of the disease can be either continuous or episodic, which significantly affects treatment management. Some of the clinical characteristics of the disease act as a poor prognostic sign. Stable negative symptoms are associated with a higher progression of schizophrenia. Also, it is generally accepted that childhood-onset schizophrenia is less benign compared to a debut after puberty. In the long term, many patients with childhood-onset are expected to have poor social adaptability and severe functional impairments [20,21].
In this study, we examined the contribution of GRIN2A and GRIN2B polymorphisms to the clinical features of schizophrenia, specifically the leading symptoms (negative or positive), course type (continuous or episodic), as well as the age of onset of the disease.

2. Materials and Methods

2.1. Patients

This study was carried out in accordance with The Code of Ethics of the World Medical Association (Declaration of Helsinki 1975, revised in Fortaleza, Brazil, 2013) for experiments involving humans and according to the protocol approved by the Bioethical Committee of the Mental Health Research Institute of the Tomsk National Research Medical Center of the Russian Academy of Sciences (protocol N63 of 14.07.2014). We recruited 402 patients with schizophrenia being treated at clinics of the Mental Health Research Institute, Siberian State Medical University, Tomsk Clinical Psychiatric Hospital (Tomsk), Kemerovo Regional Clinical Psychiatric Hospital (Kemerovo) in the Siberian region. The inclusion criteria were a verified clinical diagnosis of schizophrenia (F20) according to the World Health Organization World Mental Health Composite International Diagnostic Interview (WHO WMH-CIDI) for schizophrenia diagnostics [22], age 18–60 years, and the patient’s informed consent. Exclusion criteria for all patients were non-Caucasian physical appearance (e.g., Mongoloid, Buryats or Khakassians), organic mental disorders (e.g., epilepsy, Parkinson’s disease) or somatic disorders in the stage of decompensation. Clinical examination and diagnostic assessment were carried out using the Positive and Negative Syndrome Scale (PANSS) [23]. The total PANSS score in the group of patients with schizophrenia was 102 (92; 109) (median and lower-upper quartiles: Me (Q1; Q3)). The course of schizophrenia (continuous or episodic) was determined by ICD-10—in the classification of ICD-10, the fifth character is used for this.
To study the associations between GRIN2A and GRIN2B polymorphisms and leading symptoms (negative or positive) the total group of 402 patients with schizophrenia was divided into 2 subgroups according to the PANSS survey data: a subgroup of 201 patients with leading negative symptoms and a subgroup of 185 patients with leading positive symptoms. The rest of the patients were not included in the comparison due to mixed symptoms and the lack of prevalence of positive or negative symptoms according to the PANSS. To study the role of GRIN2A and GRIN2B polymorphisms in the development of the course of schizophrenia, the total group of patients with schizophrenia was divided into 2 subgroups: 297 cases were continuously ill while the remaining cohort of 105 patients experienced an episodic course of the disease. To study the associations between the GRIN2A and GRIN2B polymorphisms and the age of onset of schizophrenia, a total group of 402 patients with schizophrenia was divided into subgroups: a subgroup of 71 patients with early onset of the disease (before the age of 18 years old) and a subgroup of 331 people with adult-onset schizophrenia (after the age of 18 years old). The group of patients with schizophrenia was divided according to the age of onset of the disease, since the early onset of schizophrenia is interpreted as a risk factor for a more severe course of the disease [24].

2.2. Genetic Analysis

Blood samples were taken after 8 h overnight fasting in tubes containing EDTA and stored in several aliquots at −20 °C until DNA isolation using the standard phenol-chloroform method.
Inclusion criteria for SNP selection and genotype are described elsewhere [17]. Genotyping of eleven single-nucleotide polymorphisms (SNPs) in GRIN2A (rs7206256, rs1345423, rs8049651, rs9989388, rs7192557, rs9788936, rs9921541, rs11646587, rs1650420, rs11644461, rs4782039) and six SNPs in GRIN2B (rs220599, rs7313149, rs2192970, rs10845838, rs10772715, rs1805481) was carried out using a QuantStudio™ 3D Digital PCR System Life Technologies amplifier (Applied Biosystems, Waltham, MA, USA) using TaqMan Validated SNP Genotyping Assay kits (Applied Biosystems) based at The Core Facility “Medical Genomics”, Tomsk National Research Medical Center of the Russian Academy of Sciences.

2.3. Statistical Analysis

Statistical analysis was performed using SPSS software for Windows, release 21. The genotype frequencies were checked for Hardy–Weinberg equilibrium using the chi-square test. Chi-square test and the Fisher’s exact test, where necessary, were used for between-group comparisons of genotype or allele frequencies at a significance level of p < 0.05. Assessment of the association of genotypes and alleles of the studied polymorphic variants of genes with a pathological phenotype was carried out using the odds ratio (OR) with a 95% confidence interval for the odds ratio (95% CI).

3. Results

Details about the studied patient population are presented in Table 1.
The prevalence of schizophrenia is higher among men than among women. This is probably related to the well-known gender differences in the distribution of the incidence and prevalence of schizophrenia [25]. At a relatively young age, as is the case in our population, men are clearly in excess, but at a later age schizophrenia debuts much more frequently in women then in men
Deviation from the HWE was found for GRIN2A rs7192557 and GRIN2B rs220599; hence, these polymorphisms were excluded from further consideration.

3.1. Association of GRIN2A and GRIN2B Polymorphisms with Leading (Positive vs. Negative) Symptoms of Schizophrenia

The genotypes and alleles frequency analysis of GRIN2A and GRIN2B polymorphisms detected no “modifier loci” regarding positive or negative leading symptoms of schizophrenia.

3.2. Association of GRIN2A and GRIN2B Polymorphisms with Type of Course of Schizophrenia (Continuous Course vs. Episodic Course)

The genotypes and alleles frequency analysis found no difference between GRIN2A and GRIN2B polymorphisms in patients with schizophrenia with a continuous course of schizophrenia and those with an episodic course of schizophrenia.

3.3. Association of GRIN2A and GRIN2B Polymorphisms with Age of Onset of Schizophrenia (Early vs. Adult)

When comparing groups of patients with early age of onset of schizophrenia and adult age of onset of the disease, we found an association of the rs7206256 (p = 0.043 for genotypes, p = 0.020 for alleles) and rs11644461 (p = 0.034 for genotypes, p = 0.030 for alleles) polymorphisms of the GRIN2A gene (Table 2) and the rs7313149 polymorphism of the GRIN2B gene (p = 0.048 for alleles) (Table 3) with the early onset of schizophrenia.
Table 4 shows the odds ratio data calculated for polymorphisms associated with age of onset of schizophrenia. In this connection, a group of patients with an early onset of the disease was taken as the main group in the calculation, since an early onset is considered a negative factor in the prognosis of the disease.
In our study, we identified an association of GRIN2A rs7206256*A, GRIN2A rs1164446*GG/G, and GRIN2B rs7313149*A with the early onset of schizophrenia.

4. Discussion

N-methyl-D-aspartate receptors mediate a slow calcium-permeable component of excitatory synaptic transmission in the central nervous system. The NMDA receptors are very important for proper brain development and neuroplasticity while hyperfunction results in excitotoxicity associated with the genesis of various neurodegenerative diseases [26]. The GRIN2A gene encodes the GluN2A subunit of the NMDA receptor. The GluN2A subunit plays a critical role during postnatal brain development as its expression increases while Glun2B (encoded by the GRIN2B gene) expression decreases. Mutations and polymorphisms in the GRIN2A gene, coding for GluN2A, are linked to developmental brain disorders such as mental retardation, epilepsy, and mental disorders. This might also apply for schizophrenia. Published data suggest that GluN2A is involved in maturation and phenotypic maintenance of parvalbumin interneurons, and these interneurons suffer from a deficient glutamatergic neurotransmission via GluN2A-containing NMDA receptors in schizophrenia [27].
The GRIN2B gene encodes a subunit of the NMDA receptor ion channel, which acts as an agonist binding site for glutamate. The GRIN2B gene plays a crucial role in normal neuronal development and is important for learning and memory. Mutations in human GRIN2B were distributed throughout the entire gene in a number of patients with various neuropsychiatric and developmental disorders [28].
The GRIN2A and GRIN2B genes are being actively investigated as candidate genes for the predisposition of schizophrenia and other neurodevelopmental and/or neurodegenerative disorders.
A review by Myers et al. (2019) compares the available information describing the clinical and functional consequences of genetic variations in GRIN2A and GRIN2B. They showed that GRIN2A variants are commonly associated with an epileptic phenotype but that GRIN2B variants are commonly found in patients with neurodevelopmental disorders [29]. Krzystanek et al. (2021) did not find any associations between selected nucleotide variants in GRIN1, GRIN2A, and GRIN2B and resistance to clozapine and the presence of cognitive deficits in schizophrenia in a targeted group of 45 Polish patients with super clozapine-resistant schizophrenia and cognitive impairment [30]. We have in the past studied the relationship between GRIN2A and GRIN2B variants and the occurrence of drug-induced dyskinesia [17,18]. We revealed the susceptibility to levodopa-induced dyskinesia in patients with Parkinson’s disease to be associated with two NMDA receptor (GRIN2A) variants, identified by SNPs rs7192557 and rs8057394, which were previously found to be associated with the age of dyskinesia onset in Huntington’s disease [17]. We hypothesized that this is related to increased vulnerability to neurotoxic damage [19].
The significance of genetic variation of GRIN2A and GRIN2B fits well with the glutamate hypothesis for the pathophysiology of schizophrenia [5,6]. It is hypothesized that positive psychotic symptoms of schizophrenia are possibly mainly attributed to presynaptic dopaminergic changes, whereas negative and cognitive symptoms could be associated with glutamatergic dysfunction. Now, glutamatergic neurotransmission is one of the most widespread neurotransmission systems in the central nervous system, with, for example, virtually all intracortical and corticofugal connections using this neurotransmitter substance [7]. There are therefore many possibilities for circuits and pathways through which glutamatergic neurotransmission can modulate dopaminergic activity [4] and glutamatergic variation need not exclude mediation via dopaminergic neurotransmission. This also brings into focus our hypothesis about the role of the dorsal diencephalic conduction system (DDCS) in the development of mental illnesses such as schizophrenia [31,32,33]. This pathway, via the habenuloid complex between the forebrain and the ascending dopaminergic, adrenergic and serotonergic pathways from the midbrain, is phylogenetically very old and its caudal part has remained largely unchanged since the earliest vertabrates. Within this DDCS, glutamatergic neurotransmission plays a dominant role and the associated neuroplastic changes lead in the initiation and control of life-determining behaviours. It is quite conceivable that GRIN2A and GRIN2B, via this DDCS, modulate the activity of the ascending monoaminergic pathways and thus cause the ‘positive’ component of schizophrenia [34], while changes in the prefrontal cortex and hippocampus cause negative and cognitive components to arise [5,6]. Whether this involves neurodevelopmental or neurodegenerative changes remains to be seen. Research suggests that cognitive decline does not manifest until puberty/adolescence in schizophrenia patients, although this can be as early as the age of 10 years [35].
Dysfunction of the glutamate receptor N-methyl-D-aspartate is also being studied regarding the particularities of the course of schizophrenia. Thus, previous study has shown a correlation between the duration of the GRIN2A variable polymorphism (GT)n repeat and the severity of the chronic outcome of schizophrenia [3]. This may indicate that dysfunction of NMDA receptor subunits can serve as a trigger for the development of schizophrenia, and significant mutations in the GRIN2A and GRIN2B genes can affect early or late onset. Studies in rat models have shown that GRIN2A and GRIN2B expression is upregulated in the prefrontal cortex during childhood and adolescence, while a model of schizophrenia is characterized by an immature neurobiological phenotype with reduced GRIN2A and GRIN2B expression [36]. This suggests the importance of the age at which dysfunction of the NMDA receptor subunits triggers the pathological defect.
In this study, we did not identify associations of the GRIN2A and GRIN2B genes with leading symptoms or course types of schizophrenia. At the same time, we were the first to obtain data on the association of the GRIN2A (rs7206256, rs11644461) and GRIN2B (rs7313149) genes with early onset of schizophrenia in the Russian population of the Siberian region.
Earlier onset is often associated with a poorer outcome [37]. Promotion of good mental health, prevention, and early intervention before/at the onset of mental disorders improve outcomes [38]. We could speculate that our findings could be potentially useful for families with psychiatric burden when they pass prenatal genetic counseling for psychiatric disorders, although our data need to be confirmed on a larger sample.
Perhaps, in the future our findings will be significant in terms of treatment of early onset schizophrenia. We did not verify the treatment, such as the pharmacological profile of individual drugs including antipsychotics, since we were not able to track treatment throughout the course of the disease. The lack of verification for treatment may act as a limitation of this study in terms of studying the type of schizophrenia course or leading symptoms and, at the same time, does not play a role in studying the onset of the disease.
Converging evidence implicates redox dysregulation as a pathological mechanism driving the emergence of psychosis. Increased oxidative damage and decreased capacity of intracellular redox modulatory systems are consistent findings in persons with schizophrenia as well as in persons at clinical high risk who subsequently developed frank psychosis. Molecules regulating interneuron function under redox control include NMDA receptor subunits [39].

5. Conclusions

Our findings showed no contributions of GRIN2A and GRIN2B polymorphisms into genetic architecture of schizophrenia’s clinical heterogeneity concerning different leading symptoms (negative or positive) or the course of schizophrenia (continuous or episodic) in our Russian population of the Siberian region. However, we found associations of GRIN2A rs7206256 and rs11644461 and GRIN2B rs7313149 with the early onset of the disease.

Author Contributions

Conceptualization, O.Y.F., E.G.K., A.J.M.L. and S.A.I.; methodology, E.G.P., E.G.K.; software, E.G.P.; validation, O.Y.F.; formal analysis, E.G.K., A.N.K.; investigation, E.G.P., E.G.K.; resources, N.A.B., S.A.I.; data curation, E.G.P., E.G.K.; writing—original draft preparation, E.G.P., O.Y.F.; writing—review and editing, O.Y.F., E.G.K., A.J.M.L. and S.A.I.; visualization, E.G.P., A.J.M.L.; supervision, N.A.B., S.A.I.; project administration, O.Y.F.; funding acquisition, O.Y.F. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by the Russian Science Foundation (project no. 21-15-00212).

Institutional Review Board Statement

This study was conducted according to the guidelines of the Declaration of Helsinki and approved by the Ethics Committee of the Mental Health Research Institute of the Tomsk National Research Medical Center of the Russian Academy of Sciences (protocol N63 of 14.07.2014).

Informed Consent Statement

Informed consent was obtained from all subjects involved in the study.

Data Availability Statement

The datasets generated for this study will not be made publicly available, but they are available on reasonable request to Svetlana A. Ivanova ([email protected]), following approval of the Board of Directors of the MHRI, in line with local guidelines and regulations.

Acknowledgments

The authors are grateful to the head doctors Sergey M. Andreev (Tomsk Clinical Psychiatric Hospital), and Veronika A. Sorokina (Kemerovo Regional Clinical Psychiatric Hospital), for their help in recruiting patients for this investigation.

Conflicts of Interest

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.

References

  1. Owen, M.J.; Sawa, A.; Mortensen, P.B. Schizophrenia. Lancet 2016, 388, 86–97. [Google Scholar] [CrossRef] [Green Version]
  2. Lang, U.E.; Puls, I.; Müller, D.J.; Strutz-Seebohm, N.; Gallinat, J. Molecular Mechanisms of Schizophrenia. Cell. Physiol. Biochem. 2007, 20, 687–702. [Google Scholar] [CrossRef] [PubMed]
  3. Howes, O.; Kapur, S. The Dopamine Hypothesis of Schizophrenia: Version III—The Final Common Pathway. Schizophr. Bull. 2009, 35, 549–562. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  4. Carlsson, A. The Neurochemical Circuitry of Schizophrenia. Pharmacopsychiatry 2006, 39 (Suppl. S1), S10–S14. [Google Scholar] [CrossRef]
  5. Howes, O.; McCutcheon, R.; Stone, J. Glutamate and dopamine in schizophrenia: An update for the 21st century. J. Psychopharmacol. 2015, 29, 97–115. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  6. Uno, Y.; Coyle, J.T. Glutamate hypothesis in schizophrenia. Psychiatry Clin. Neurosci. 2019, 73, 204–215. [Google Scholar] [CrossRef] [Green Version]
  7. Loonen, A.J.M. Het Beweeglijke Brein. De Neurowetenschappelijke Achtergrond van de Psychische Functies, 3rd ed.; Mension: Haarlem, The Netherlands, 2021. [Google Scholar]
  8. Li, Z.J.; Wang, B.J.; Ding, M.; Pang, H.; Sun, X.F.; Yang, J. The association between glutamate receptor gene SNP and schizophrenia. Fa Yi Xue Za Zhi 2008, 24, 369–374, 377. [Google Scholar] [PubMed]
  9. Wu, S.-L.; Wang, W.-F.; Shyu, H.-Y.; Ho, Y.-J.; Shieh, J.-C.; Fu, Y.-P.; Wu, S.-T.; Cheng, C.-W. Association analysis of GRIN1 and GRIN2B polymorphisms and Parkinson’s disease in a hospital-based case—Control study. Neurosci. Lett. 2010, 478, 61–65. [Google Scholar] [CrossRef] [PubMed]
  10. Ceylan, H. Integrated Bioinformatics Analysis to Identify Alternative Therapeutic Targets for Alzheimer’s Disease: Insights from a Synaptic Machinery Perspective. J. Mol. Neurosci. 2021, 1–14. [Google Scholar] [CrossRef]
  11. Dean, B.; Gibbons, A.S.; Boer, S.; Uezato, A.; Meador-Woodruff, J.; Scarr, E.; McCullumsmith, R. Changes in cortical N-methyl-d-aspartate receptors and post-synaptic density protein 95 in schizophrenia, mood disorders and suicide. Aust. N. Z. J. Psychiatry 2016, 50, 275–283. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  12. Chiu, H.-J.; Wang, Y.-C.; Liou, Y.-J.; Lai, I.-C.; Chen, J.-Y. Association Analysis of the Genetic Variants of the N-Methyl D-Aspartate Receptor Subunit 2b (NR2b) and Treatment-Refractory Schizophrenia in the Chinese. Neuropsychobiology 2003, 47, 178–181. [Google Scholar] [CrossRef] [PubMed]
  13. Volkmann, R.A.; Fanger, C.M.; Anderson, D.R.; Sirivolu, V.R.; Paschetto, K.; Gordon, E.; Virginio, C.; Gleyzes, M.; Buisson, B.; Steidl, E.; et al. MPX-004 and MPX-007: New Pharmacological Tools to Study the Physiology of NMDA Receptors Containing the GluN2A Subunit. PLoS ONE 2016, 11, e0148129. [Google Scholar] [CrossRef] [Green Version]
  14. Tang, J.; Chen, X.; Xu, X.; Wu, R.; Zhao, J.; Hu, Z.; Xia, K. Significant linkage and association between a functional (GT)n polymorphism in promoter of the N-methyl-d-aspartate receptor subunit gene (GRIN2A) and schizophrenia. Neurosci. Lett. 2006, 409, 80–82. [Google Scholar] [CrossRef]
  15. Mishra, N.; Kouzmitcheva, E.; Orsino, A.; Minassian, B.A. Chromosome 12p Deletion Spanning the GRIN2B Gene Presenting With a Neurodevelopmental Phenotype: A Case Report and Review of Literature. Child Neurol. Open 2016, 3, 2329048x16629980. [Google Scholar] [CrossRef] [Green Version]
  16. Hong, C.-J.; Yu, Y.W.-Y.; Lin, C.-H.; Cheng, C.-Y.; Tsai, S.-J. Association analysis for NMDA receptor subunit 2B (GRIN2B) genetic variants and psychopathology and clozapine response in schizophrenia. Psychiatr. Genet. 2001, 11, 219–222. [Google Scholar] [CrossRef]
  17. Ivanova, S.; Loonen, A.J.M.; Pechlivanoglou, P.; Freidin, M.B.; Al Hadithy, A.F.Y.; Rudikov, E.V.; Zhukova, I.; Govorin, N.V.; Sorokina, V.; Fedorenko, O.Y.; et al. NMDA receptor genotypes associated with the vulnerability to develop dyskinesia. Transl. Psychiatry 2012, 2, e67. [Google Scholar] [CrossRef] [PubMed]
  18. Ivanova, S.; Loonen, A.J.; Bakker, P.R.; Freidin, M.B.; Ter Woerds, N.J.; Al Hadithy, A.F.; Semke, A.V.; Fedorenko, O.Y.; Brouwers, J.R.; Bokhan, N.A.; et al. Likelihood of mechanistic roles for dopaminergic, serotonergic and glutamatergic receptors in tardive dyskinesia: A comparison of genetic variants in two independent patient populations. SAGE Open Med. 2016, 4, 2050312116643673. [Google Scholar] [CrossRef] [PubMed]
  19. Ivanova, S.; Loonen, A.J.M. Levodopa-Induced Dyskinesia Is Related to Indirect Pathway Medium Spiny Neuron Excitotoxicity: A Hypothesis Based on an Unexpected Finding. Park. Dis. 2016, 2016, 6461907. [Google Scholar] [CrossRef] [Green Version]
  20. Davidson, L.; McGlashan, T.H. The Varied Outcomes of Schizophrenia. Can. J. Psychiatry 1997, 42, 34–43. [Google Scholar] [CrossRef] [Green Version]
  21. Mazaeva, N.A. Schizophrenia in adolescence. Zhurnal Nevrol. Psikhiatrii Im. S. S. Korsakova 2015, 115, 20. [Google Scholar] [CrossRef]
  22. World Health Organization. International Statistical Classification of Diseases and Health Related Problems ICD-10; World Health Organization: Geneva, Switzerland, 2004. [Google Scholar]
  23. Kay, S.R.; Fiszbein, A.; Opler, L.A. The Positive and Negative Syndrome Scale (PANSS) for Schizophrenia. Schizophr. Bull. 1987, 13, 261–276. [Google Scholar] [CrossRef]
  24. Coulon, N.; Godin, O.; Bulzacka, E.; Dubertret, C.; Mallet, J.; Fond, G.; Brunel, L.; Andrianarisoa, M.; Anderson, G.; Chereau, I.; et al. Early and very early-onset schizophrenia compared with adult-onset schizophrenia: French FACE-SZ database. Brain Behav. 2020, 10, e01495. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  25. Abel, K.M.; Drake, R.; Goldstein, J.M. Sex differences in schizophrenia. Int. Rev. Psychiatry 2010, 22, 417–428. [Google Scholar] [CrossRef]
  26. Armada-Moreira, A.; Gomes, J.I.; Pina, C.C.; Savchak, O.K.; Gonçalves-Ribeiro, J.; Rei, N.; Pinto, S.; Morais, T.P.; Martins, R.S.; Ribeiro, F.F.; et al. Going the Extra (Synaptic) Mile: Excitotoxicity as the Road Toward Neurodegenerative Diseases. Front. Cell. Neurosci. 2020, 14, 90. [Google Scholar] [CrossRef] [PubMed]
  27. Cardis, R.; Cabungcal, J.-H.; Dwir, D.; Do, K.Q.; Steullet, P. A lack of GluN2A-containing NMDA receptors confers a vulnerability to redox dysregulation: Consequences on parvalbumin interneurons, and their perineuronal nets. Neurobiol. Dis. 2018, 109 Pt A, 64–75. [Google Scholar] [CrossRef]
  28. Hu, C.; Chen, W.; Myers, S.J.; Yuan, H.; Traynelis, S.F. Human GRIN2B variants in neurodevelopmental disorders. J. Pharmacol. Sci. 2016, 132, 115–121. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  29. Myers, S.J.; Yuan, H.; Kang, J.-Q.; Tan, F.C.K.; Traynelis, S.F.; Low, C.-M. Distinct roles of GRIN2A and GRIN2B variants in neurological conditions. F1000Research 2019, 8, 1940. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  30. Krzystanek, M.; Asman, M.; Witecka, J.; Pałasz, A.; Wiaderkiewicz, R. Selected single-nucleotide variants in GRIN1, GRIN2A, and GRIN2B encoding subunits of the NMDA receptor are not biomarkers of schizophrenia resistant to clozapine: Exploratory study. Pharmacol. Rep. 2021, 73, 309–315. [Google Scholar] [CrossRef]
  31. Loonen, A.J.; Ivanova, S. Circuits regulating pleasure and happiness: Evolution and role in mental disorders. Acta Neuropsychiatr. 2018, 30, 29–42. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  32. Loonen, A.J.; Ivanova, S. The evolutionary old forebrain as site of action to develop new psychotropic drugs. J. Psychopharmacol. 2018, 32, 1277–1285. [Google Scholar] [CrossRef]
  33. Loonen, A.J.M.; Ivanova, S.A. Evolution of circuits regulating pleasure and happiness with the habenula in control. CNS Spectr. 2019, 24, 233–238. [Google Scholar] [CrossRef] [Green Version]
  34. Loonen, A.J.M.; Ivanova, S.A. Circuits Regulating Pleasure and Happiness in Schizophrenia: The Neurobiological Mechanism of Delusions. In Schizophrenia Treatment—The New Facets; Shen, Y.C., Ed.; InTech: London, UK, 2016. [Google Scholar] [CrossRef] [Green Version]
  35. Kahn, R.S. On the Origins of Schizophrenia. Am. J. Psychiatry 2020, 177, 291–297. [Google Scholar] [CrossRef] [PubMed]
  36. Elfving, B.; Müller, H.K.; Oliveras, I.; Østerbøg, T.B.; Rio-Alamos, C.; Sanchez-Gonzalez, A.; Tobena, A.; Fernandez-Teruel, A.; Aznar, S. Differential expression of synaptic markers regulated during neurodevelopment in a rat model of schizophrenia-like behavior. Prog. Neuro-Psychopharmacol. Biol. Psychiatry 2019, 95, 109669. [Google Scholar] [CrossRef] [PubMed]
  37. Musket, C.W.; Kuo, S.S.; Rupert, P.E.; Almasy, L.; Gur, R.C.; Prasad, K.; Wood, J.; Roalf, D.R.; Gur, R.E.; Nimgaonkar, V.L.; et al. Why does age of onset predict clinical severity in schizophrenia? A multiplex extended pedigree study. Am. J. Med. Genet. Part B Neuropsychiatr. Genet. 2020, 183, 403–411. [Google Scholar] [CrossRef] [PubMed]
  38. Solmi, M.; Radua, J.; Olivola, M.; Croce, E.; Soardo, L.; de Pablo, G.S.; Shin, J.I.; Kirkbride, J.B.; Jones, P.; Kim, J.H.; et al. Age at onset of mental disorders worldwide: Large-scale meta-analysis of 192 epidemiological studies. Mol. Psychiatry 2021, 1–15. [Google Scholar] [CrossRef]
  39. Perkins, D.O.; Jeffries, C.D.; Do, K.Q. Potential Roles of Redox Dysregulation in the Development of Schizophrenia. Biol. Psychiatry 2020, 88, 326–336. [Google Scholar] [CrossRef] [PubMed]
Table 1. Demographic and clinical parameters of the studied patients.
Table 1. Demographic and clinical parameters of the studied patients.
Sample Size, n402
Gender, n (%)Men: 256 (63.7%)
Women: 146 (36.3%)
Age, years, Me (Q1; Q3)41 (29; 53)
Age at onset, years, Me (Q1; Q3)23 (19; 31)
Duration of illness, years, Me (Q1; Q3).14 (7; 25)
Table 2. Frequency distribution of genotypes and alleles of GRIN2A polymorphisms in patients with schizophrenia with early or adult age of onset of schizophrenia.
Table 2. Frequency distribution of genotypes and alleles of GRIN2A polymorphisms in patients with schizophrenia with early or adult age of onset of schizophrenia.
SNPsGenotypes
and Alleles
Early Onset
(<18 y.o.)
Adult Onset
(≥18 y.o.)
χ2p-Value
rs7206256 AA31 (44.9%)112 (34.1%)6.2790.043 *
AG34 (39.3%)162 (49.4%)
GG4 (5.8%)54 (16.5%)
A96 (69.6%)386 (58.8%)5.4970.020 *
G42 (30.4%)270 (41.2%)
rs1345423 AA22 (31.4%)128 (39.0%)1.8090.405
AC36 (51.4%)158 (48.2%)
CC12 (17.1%)42 (12.8%)
A80 (57.1%)414 (63.1%)1.7450.187
C60 (42.9%)242 (36.9%)
rs8049651 AA5 (7.0%)25 (7.6%)1.2880.525
AG35 (49.3%)139 (42.0%)
GG31 (43.7%)167 (50.5%)
A45 (31.7%)189 (28.5%)0.5590.455
G97 (68.3%)473 (71.5%)
rs9989388 AA5 (7.1%)15 (4.7%)1.0490.592
AG23 (32.9%)120 (37.4%)
GG42 (60.0%)186 (57.9%)
A33 (23.6%)150 (23.4%)0.0030.959
G107 (76.4%)492 (76.6%)
rs9788936 AA49 (72.1%)204 (63.4%)3.1540.207
AG19 (27.9%)109 (33.9%)
GG0 (0%)9 (2.8%)
A117 (86.0%)517 (80.3%)2.4400.119
G19 (14.0%)127 (19.7%)
rs9921541 AA4 (5.9%)13 (4.1%)1.0050.605
AC21 (30.9%)115 (36.4%)
CC43 (63.2%)188 (59.5%)
A29 (21.3%)141 (22.3%)0.0630.802
C107 (78.8%)491 (77.7%)
rs11646587 AA5 (7.1%)21 (6.5%)0.7370.692
AG26 (37.1%)138 (42.7%)
GG39 (55.7%)164 (50.8%)
A36 (25.7%)180 (27.9%)0.2670.606
G104 (74.3%)466 (72.1%)
rs1650420 AA8 (11.3%)56 (17.2%)2.7880.248
AG38 (53.5%)142 (43.6%)
GG25 (35.2%)128 (39.3%)
A54 (38.0%)254 (39.0%)0.0420.837
G88 (62.0%)398 (61.0%)
rs11644461 AA25 (35.2%)143 (43.2%)6.7600.034 *
AG30 (42.3%)151 (45.6%)
GG16 (22.5%)37 (11.2%)
A80 (56.3%)437 (66.0%)4.7670.030 *
G62 (43.7%)225 (34.0%)
rs4782039 AA38 (53.5%)190 (58.1%)0.9150.633
AG31 (43.7%)124 (37.9%)
GG2 (2.8%)13 (4.0%)
A107 (75.4%)504 (77.1%)0.1920.662
G35 (24.6%)150 (22.9%)
*—statistical significance p < 0.05; y.o.—years old.
Table 3. Frequency distribution of genotypes and alleles GRIN2B polymorphisms in patients with schizophrenia with early or adult age of onset of schizophrenia.
Table 3. Frequency distribution of genotypes and alleles GRIN2B polymorphisms in patients with schizophrenia with early or adult age of onset of schizophrenia.
SNPsGenotypes
and Alleles
Early Onset
(<18 y.o.)
Adult Onset
(≥18 y.o.)
χ2p-Value
rs7313149 AA49 (71.0%)192 (60.0%)4.7050.095
AG20 (29.0%)115 (35.9%)
GG0 (0%)13 (4.1%)
A118 (85.5%)499 (78.0%)3.9310.048 *
G20 (14.5%)141 (22.0%)
rs2192970 AA0 (0%)7 (2.2%)1.5370.464
AG21 (30.4%)94 (29.2%)
GG48 (69.6%)221 (68.6%)
A21 (15.2%)108 (16.8%)0.0660.798
G117 (84.8%)563 (83.2%)
rs10845838 AA5 (7.1%)40 (12.3%)1.8320.400
AG32 (45.7%)151 (46.5%)
GG33 (47.1%)134 (41.2%)
A42 (30.0%)231 (35.5%)1.5620.212
G98 (70.0%)419 (64.5%)
rs10772715 AA7 (10.0%)60 (18.3%)3.0890.213
AG36 (51.4%)161 (49.2%)
GG27 (38.6%)106 (32.4%)
A50 (35.7%)281 (43.0%)2.4950.115
G90 (64.3%)373 (57.0%)
rs1805481 AA21 (30.9%)86 (27.0%)1.4360.488
AC38 (55.9%)171 (53.8%)
CC9 (13.2%)61 (19.2%)
A80 (58.8%)343 (53.9%)1.0830.299
C56 (41.2%)293 (46.1%)
*—statistical significance p < 0.05.
Table 4. Odds ratios calculated for GRIN2A and GRIN2B polymorphisms associated with early onset of schizophrenia.
Table 4. Odds ratios calculated for GRIN2A and GRIN2B polymorphisms associated with early onset of schizophrenia.
GeneSNPsGenotypes and AllelesORCl (95%)χ2p-Value
GRIN2Ars7206256 AA1.5730.929–2.6636.2790.043
AG0.9950.592–1.673
GG0.3120.109–0.893
A1.5991.078–2.3725.4970.020
G0.6250.422–0.928
GRIN2Ars11644461 AA0.7150.419–1.2186.7600.034
AG0.8720.519–1.464
GG2.3121.203–4.443
A0.6640.460–0.9604.7670.030
G1.5051.041–2.176
GRIN2Brs7313149 AA1.6330.927–2.8774.7050.095
AG0.7280.412–1.284
GG--
A1.6671.002–2.7753.9310.048
G0.6000.360–0.998
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Poltavskaya, E.G.; Fedorenko, O.Y.; Kornetova, E.G.; Loonen, A.J.M.; Kornetov, A.N.; Bokhan, N.A.; Ivanova, S.A. Study of Early Onset Schizophrenia: Associations of GRIN2A and GRIN2B Polymorphisms. Life 2021, 11, 997. https://doi.org/10.3390/life11100997

AMA Style

Poltavskaya EG, Fedorenko OY, Kornetova EG, Loonen AJM, Kornetov AN, Bokhan NA, Ivanova SA. Study of Early Onset Schizophrenia: Associations of GRIN2A and GRIN2B Polymorphisms. Life. 2021; 11(10):997. https://doi.org/10.3390/life11100997

Chicago/Turabian Style

Poltavskaya, Evgeniya G., Olga Yu. Fedorenko, Elena G. Kornetova, Anton J. M. Loonen, Alexander N. Kornetov, Nikolay A. Bokhan, and Svetlana A. Ivanova. 2021. "Study of Early Onset Schizophrenia: Associations of GRIN2A and GRIN2B Polymorphisms" Life 11, no. 10: 997. https://doi.org/10.3390/life11100997

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop