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Association of purinergic receptor P2RX7 gene polymorphisms with depression symptoms.

Abstract

INTRODUCTION

The activation of the ATP-gated P2RX7 (purinergic receptor P2X, ligand-gated ion channel, 7) produces microglial activation, a process which has been demonstrated in depression, bipolar disorder, and schizophrenia. Emerging data over the last years highlighted the importance of P2X7 cation channel as a potential drug target for these central nervous system disorders. The Gln460Arg (rs2230912) polymorphism of the P2RX7 gene has been widely studied in mood disorders, however the results are still controversial. Therefore, we aimed to investigate the C-terminal region of this gene in major depressive and bipolar disorders (MDD and BD) by studying possibly functional, non-synonymous polymorphisms within a 7 kb long region around the Gln460Arg, including Ala348Thr (rs1718119), Thr357Ser (rs2230911), and Glu496Ala (rs3751143) variants. Since Gln460Arg is located at the 3' end of the P2RX7 gene, we included additional, potentially functional single nucleotide polymorphisms (SNPs) from the 3' untranslated region (UTR), which can be in linkage with Gln460Arg. Based on in silico search, we chose two SNPs in putative microRNA target sites which are located in consecutive positions: rs1653625 and rs1718106.

METHODS

P2RX7 SNPs from the C-terminal region were selected based on previous functional assays, 3' UTR variants were chosen using PolymiRTS and Patrocles databases. The genotyping of the non-synonymous SNPs was carried out by pre-designed TaqMan® kits, while the 3' UTR variants were analyzed by PCR-RFLP method. Case-control analyses were carried out between 315 inpatients with acute major depressive episode (195 MDD, 120 BD) and 406 healthy control subjects. The two subscales of the Hospital Anxiety and Depression Scale (HADS) self-report questionnaire were used for quantitative analyses, including an additional, "at-risk" population of 218 patients with diabetes mellitus. The in vitro reporter gene assays were carried out on HEK and SK-N-FI cells transiently transfected with pMIR vector constructs containing the P2RX7 3' UTR downstream of the luciferase gene.

RESULTS

Haplotype analysis indicated a relatively high linkage between the analyzed P2RX7 SNPs. Our case-control study did not yield any association between P2RX7 gene variants and depression. However, dimensional analyses showed significant associations of the HADS depression severity scores with Gln460Arg (rs2230912) and Ala348Thr (rs1718119) in the depressed and diabetic patient groups. In the in vitro experiments, the P2RX7 3' UTR constructs with the lowest predicted binding efficiency to their miRNAs showed the highest expression of the gene. The combination of the depression-associated P2RX7 C-terminal and 3' UTR SNPs contributed to the highest depression severity score in the haplotype analysis.

CONCLUSION

Based on our findings, we propose that a P2RX7 haplotype combination of the Gln460Arg and neighboring SNPs contribute to the observed genetic association with depressive symptoms.

Authors+Show Affiliations

Department of Medical Chemistry, Molecular Biology and Pathobiochemistry, Semmelweis University, Budapest, Hungary.Department of Medical Chemistry, Molecular Biology and Pathobiochemistry, Semmelweis University, Budapest, Hungary.Department of Psychiatry, Kútvölgyi Clinical Centre, Semmelweis University, Budapest, Hungary; Bhaktivedanta College, Budapest, Hungary.2nd Department of Internal Medicine, Semmelweis University, Budapest, Hungary.Institute of Psychology, Eötvös Loránd University, Budapest, Hungary.2nd Department of Internal Medicine, Semmelweis University, Budapest, Hungary.Department of Psychiatry, Kútvölgyi Clinical Centre, Semmelweis University, Budapest, Hungary.Department of Medical Chemistry, Molecular Biology and Pathobiochemistry, Semmelweis University, Budapest, Hungary. Electronic address: nemoda.zsofia@med.semmelweis-univ.hu.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

30664971

Citation

Vereczkei, Andrea, et al. "Association of Purinergic Receptor P2RX7 Gene Polymorphisms With Depression Symptoms." Progress in Neuro-psychopharmacology & Biological Psychiatry, vol. 92, 2019, pp. 207-216.
Vereczkei A, Abdul-Rahman O, Halmai Z, et al. Association of purinergic receptor P2RX7 gene polymorphisms with depression symptoms. Prog Neuropsychopharmacol Biol Psychiatry. 2019;92:207-216.
Vereczkei, A., Abdul-Rahman, O., Halmai, Z., Nagy, G., Szekely, A., Somogyi, A., Faludi, G., & Nemoda, Z. (2019). Association of purinergic receptor P2RX7 gene polymorphisms with depression symptoms. Progress in Neuro-psychopharmacology & Biological Psychiatry, 92, 207-216. https://doi.org/10.1016/j.pnpbp.2019.01.006
Vereczkei A, et al. Association of Purinergic Receptor P2RX7 Gene Polymorphisms With Depression Symptoms. Prog Neuropsychopharmacol Biol Psychiatry. 2019 06 8;92:207-216. PubMed PMID: 30664971.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Association of purinergic receptor P2RX7 gene polymorphisms with depression symptoms. AU - Vereczkei,Andrea, AU - Abdul-Rahman,Omar, AU - Halmai,Zsuzsa, AU - Nagy,Geza, AU - Szekely,Anna, AU - Somogyi,Aniko, AU - Faludi,Gabor, AU - Nemoda,Zsofia, Y1 - 2019/01/19/ PY - 2018/09/19/received PY - 2019/01/08/revised PY - 2019/01/13/accepted PY - 2019/1/22/pubmed PY - 2019/6/30/medline PY - 2019/1/22/entrez KW - Bipolar disorder KW - Major depressive disorder KW - P2X7R KW - SNP KW - miRNA SP - 207 EP - 216 JF - Progress in neuro-psychopharmacology & biological psychiatry JO - Prog. Neuropsychopharmacol. Biol. Psychiatry VL - 92 N2 - INTRODUCTION: The activation of the ATP-gated P2RX7 (purinergic receptor P2X, ligand-gated ion channel, 7) produces microglial activation, a process which has been demonstrated in depression, bipolar disorder, and schizophrenia. Emerging data over the last years highlighted the importance of P2X7 cation channel as a potential drug target for these central nervous system disorders. The Gln460Arg (rs2230912) polymorphism of the P2RX7 gene has been widely studied in mood disorders, however the results are still controversial. Therefore, we aimed to investigate the C-terminal region of this gene in major depressive and bipolar disorders (MDD and BD) by studying possibly functional, non-synonymous polymorphisms within a 7 kb long region around the Gln460Arg, including Ala348Thr (rs1718119), Thr357Ser (rs2230911), and Glu496Ala (rs3751143) variants. Since Gln460Arg is located at the 3' end of the P2RX7 gene, we included additional, potentially functional single nucleotide polymorphisms (SNPs) from the 3' untranslated region (UTR), which can be in linkage with Gln460Arg. Based on in silico search, we chose two SNPs in putative microRNA target sites which are located in consecutive positions: rs1653625 and rs1718106. METHODS: P2RX7 SNPs from the C-terminal region were selected based on previous functional assays, 3' UTR variants were chosen using PolymiRTS and Patrocles databases. The genotyping of the non-synonymous SNPs was carried out by pre-designed TaqMan® kits, while the 3' UTR variants were analyzed by PCR-RFLP method. Case-control analyses were carried out between 315 inpatients with acute major depressive episode (195 MDD, 120 BD) and 406 healthy control subjects. The two subscales of the Hospital Anxiety and Depression Scale (HADS) self-report questionnaire were used for quantitative analyses, including an additional, "at-risk" population of 218 patients with diabetes mellitus. The in vitro reporter gene assays were carried out on HEK and SK-N-FI cells transiently transfected with pMIR vector constructs containing the P2RX7 3' UTR downstream of the luciferase gene. RESULTS: Haplotype analysis indicated a relatively high linkage between the analyzed P2RX7 SNPs. Our case-control study did not yield any association between P2RX7 gene variants and depression. However, dimensional analyses showed significant associations of the HADS depression severity scores with Gln460Arg (rs2230912) and Ala348Thr (rs1718119) in the depressed and diabetic patient groups. In the in vitro experiments, the P2RX7 3' UTR constructs with the lowest predicted binding efficiency to their miRNAs showed the highest expression of the gene. The combination of the depression-associated P2RX7 C-terminal and 3' UTR SNPs contributed to the highest depression severity score in the haplotype analysis. CONCLUSION: Based on our findings, we propose that a P2RX7 haplotype combination of the Gln460Arg and neighboring SNPs contribute to the observed genetic association with depressive symptoms. SN - 1878-4216 UR - https://www.unboundmedicine.com/medline/citation/30664971/Association_of_purinergic_receptor_P2RX7_gene_polymorphisms_with_depression_symptoms_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0278-5846(18)30729-2 DB - PRIME DP - Unbound Medicine ER -