The study of dopamine receptor genes in patients with schizophrenia

Abstract

Background: Schizophrenia is a severe mental disorder, usually treated with long-term anti-dopaminergic therapy. Although several theories have been lanced, pathophysiology of schizophrenia has not yet been elucidated. Identifying genetic factors contributing to development of schizophrenia would be of considerable interest for personalizing treatment [1]. Most studies in the field of pharmacogenetics of schizophrenia are based on the study of receptor candidate genes or secondary messengers (pharmacodynamic components) and that of drug metabolizing enzymes (pharmacokinetic components), or suspected loci to the disease schizophrenia (pathogenetic components). An important role in personalization of treatment is played by the suitability of drugs targeting dopamine receptors [2]. Objective: to investigate role of 28 SNP s of dopamine receptor genes DRD1, DRD2, DRD2/ANKK1, DRD3, DRD4 as a potential markers of schizophrenia in patients of Russian population. Methods: Fourhundred and seventy (470) patients with schizophrenia and 127 healthy controls were investigated. Mean age was 42.1 ± 12.4 for patients, for healthy group is 38.5 ± 13.2 years. Mean duration of disease was 13 years for schizophrenic patients. The inclusion criteria were a clinical diagnosis of schizophrenia, according to the International Classification of Diseases and Related Health Problems, 10th Revision (ICD-10: F20), and age 18–75 years old. We used the standard phenol-chloroform method for isolation DNA from whole peripheral blood. Genotyping was carried out on 28 SNPs of dopamine receptors (rs6275, rs1801028, rs4245147, rs134655, rs6277, rs1076560, rs2283265, rs179997, rs6279, rs1076562, rs2734842, rs4532, rs936461, rs2734849, rs11721264, rs167770, rs3773678, rs963468, rs7633291, rs2134655, rs9817063, rs324035, rs1800828, rs167771, rs6280, rs1587756, rs3758653, rs11246226). We were employed the MassARRAY® Analyzer 4 (Agena Bioscience™) and using the kit iPLEX Gold 384. Statistical analysis was carried out with SPSS software, release 17. Statistical significance of tested associations was considered for significance at a P-value less than 0.05. Results: 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), established for experiments involving humans. We recruited patients from three psychiatric hospitals located in the Tomsk, Kemerovo, and Chita oblasts (regions) of Siberia, Russia. Healthy control group was recruited from the same region with identical characteristics, comparable in gender and age. The distribution of genotypes of studied genes corresponded to the Hardy-Weinberg equilibrium. We got statistically significant results for alleles of polymorphic variant rs3773678 of DRD3 receptor gene (c2 = 4.940, p = 0.030). We found that allele C are significantly associated with protective effect (odds ratio is 0.53 [95% CI: 0.30 - 0.94]) and allele T are significantly associated with predisposing effect on the development of schizophrenia (odds ratio is 1.88 [95% CI: 1.07 - 3.29]). Conclusion: According to literature data polymorphisms of dopamine receptors genes play important role in the therapy of schizophrenia. A polymorphic variant of one dopamine receptor gene has been identified, whose alleles have predisposing and protective effects for patients in the pathogenesis of schizophrenia. Acknowledgement: This work was supported by the comprehensive program of fundamental scientific research of the SB RAS ``Interdisciplinary Integrated Studies (2018-2020), project No. 30