The Role of Glutamatergic Gene Polymorphisms in the Clinical Phenotypes of Schizophrenia.

BACKGROUND: Personal variations in genetic risk for schizophrenia relate to its phenotypic heterogeneity-both in disorder development and clinical manifestations. Abnormal glutamatergic neurotransmitter system functioning is integrated in the pathogenesis of schizophrenia. METHODS: A sample of 805 Russian schizophrenia patients from the Siberian Federal region was investigated. We examined the association of 39 single nucleotide polymorphisms in eight genes (GRIN2A, GRIN2B, SLC1A2, SLC1A3, SLC17A7, GRM3, GRM7, and GRM8) involved in the glutamatergic system with the development of clinical heterogeneity of schizophrenia. The MassARRAY Analyzer 4 was used for genotyping. RESULTS: GRIN2A rs11644461, rs8057394 and GRIN2B rs7313149 are associated with the continuous type of schizophrenia. The GRIN2A rs8057394*G allele is a relative risk factor (p = 0.019) for developing the continuous type of schizophrenia. We found a nominally significant association between negative symptoms of schizophrenia and SLC17A7 rs62126236. The SLC17A7 rs62126236*T allele has a protective effect (p = 0.039) against predominant negative symptoms in schizophrenia. The total Positive and Negative Syndrome Scale (PANSS) scores were significantly associated with GRIN2A rs9788936 after adjusting for multiple testing (p = 0.001). CONCLUSIONS: In this study the contribution of the glutamatergic gene polymorphisms to the clinical heterogeneity of schizophrenia has been demonstrated.

Genes of the Glutamatergic System and Tardive Dyskinesia in Patients with Schizophrenia.

BACKGROUND: Tardive dyskinesia (TD) is an extrapyramidal side effect of the long-term use of antipsychotics. In the present study, the role of glutamatergic system genes in the pathogenesis of total TD, as well as two phenotypic forms, orofacial TD and limb-truncal TD, was studied. METHODS: A set of 46 SNPs of the glutamatergic system genes (GRIN2A, GRIN2B, GRIK4, GRM3, GRM7, GRM8, SLC1A2, SLC1A3, SLC17A7) was studied in a population of 704 Caucasian patients with schizophrenia. Genotyping was performed using the MassARRAY Analyzer 4 (Agena Bioscience™). Logistic regression analysis was performed to test for the association of TD with the SNPs while adjusting for confounders. RESULTS: No statistically significant associations between the SNPs and TD were found after adjusting for multiple testing. Since three SNPs of the SLC1A2 gene demonstrated nominally significant associations, we carried out a haplotype analysis for these SNPs. This analysis identified a risk haplotype for TD comprising CAT alleles of the SLC1A2 gene SNPs rs1042113, rs10768121, and rs12361171. Nominally significant associations were identified for SLC1A3 rs2229894 and orofacial TD, as well as for GRIN2A rs7192557 and limb-truncal TD. CONCLUSIONS: Genes encoding for mGlu3, EAAT2, and EAAT1 may be involved in the development of TD in schizophrenia patients.

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

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.

Genetic polymorphisms of PIP5K2A and course of schizophrenia.

BACKGROUND: Schizophrenia is a severe highly heritable mental disorder. The clinical heterogeneity of schizophrenia is expressed in the difference in the leading symptoms and course of the disease. Identifying the genetic variants that affect clinical heterogeneity may ultimately reveal the genetic basis of the features of schizophrenia and suggest novel treatment targets. PIP5K2A (Phosphatidylinositol-4-Phosphate 5-Kinase Type II Alpha) has been investigated as a potential susceptibility gene for schizophrenia. METHODS: In this work, we studied the possible association between eleven polymorphic variants of PIP5K2A and the clinical features of schizophrenia in a population of 384 white Siberian patients with schizophrenia. Genotyping was carried out on QuantStudio 5 Real-Time PCR System with a TaqMan Validate SNP Genotyping Assay (Applied Biosystems, USA). RESULTS: PIP5K2A rs8341 (χ2 = 6.559, p = 0.038) and rs946961 (χ2 = 5.976, p = 0.049) showed significant association with course of schizophrenia (continuous or episodic). The rs8341*CT (OR = 1.63, 95% CI: 1.04-2.54) and rs946961*CC (OR = 5.17, 95% CI: 1.20-22.21) genotypes were associated with a continuous type of course, while the rs8341*TT genotype (OR = 0.53, 95% CI: 0.29-0.97) was associated with an episodic type of course of schizophrenia. Therefore rs8341*TT genotype presumably has protective effect against the more severe continuous course of schizophrenia compared to the episodic one. CONCLUSIONS: Our experimental data confirm that PIP5K2A is a genetic factor influencing the type of course of schizophrenia in Siberian population. Disturbances in the phosphatidylinositol pathways may be a possible reason for the transition to a more severe continuous course of schizophrenia.