Association of purinergic receptor P2RX7 gene polymorphisms with depression symptoms

Andrea Vereczkei, Omar Abdul-Rahman, Zsuzsa Halmai, Geza Nagy, A. Székely, A. Somogyi, G. Faludi, Z. Nemoda

Research output: Contribution to journalArticle

1 Citation (Scopus)

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.

Original languageEnglish
Pages (from-to)207-216
Number of pages10
JournalProgress in Neuro-Psychopharmacology and Biological Psychiatry
Volume92
DOIs
Publication statusPublished - Jun 8 2019

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Purinergic Receptors
3' Untranslated Regions
Single Nucleotide Polymorphism
Depression
Genes
Haplotypes
MicroRNAs
Bipolar Disorder
Anxiety
Purinergic P2X7 Receptors
Central Nervous System Diseases
Major Depressive Disorder
Luciferases
Mood Disorders
Reporter Genes
Restriction Fragment Length Polymorphisms
Computer Simulation
Self Report
Cations
Case-Control Studies

Keywords

  • Bipolar disorder
  • Major depressive disorder
  • miRNA
  • P2X7R
  • SNP

ASJC Scopus subject areas

  • Pharmacology
  • Biological Psychiatry

Cite this

Association of purinergic receptor P2RX7 gene polymorphisms with depression symptoms. / Vereczkei, Andrea; Abdul-Rahman, Omar; Halmai, Zsuzsa; Nagy, Geza; Székely, A.; Somogyi, A.; Faludi, G.; Nemoda, Z.

In: Progress in Neuro-Psychopharmacology and Biological Psychiatry, Vol. 92, 08.06.2019, p. 207-216.

Research output: Contribution to journalArticle

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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 - Székely, A.

AU - Somogyi, A.

AU - Faludi, G.

AU - Nemoda, Z.

PY - 2019/6/8

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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.

AB - 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.

KW - Bipolar disorder

KW - Major depressive disorder

KW - miRNA

KW - P2X7R

KW - SNP

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