Relationship between P2XR4 Gene Variants and the Risk of Schizophrenia in South-East of Iran: A Preliminary Case-Control Study and in Silico Analysis

Milad Heidari Nia; Mahdieh Jafari Shahroudi; Ramin Saravani; Saman Sargazi; Mahdiyeh Moudi; Azizollah Mojahed

doi:10.18502/ijph.v50i5.6115

Relationship between P2XR4 Gene Variants and the Risk of Schizophrenia in South-East of Iran: A Preliminary Case-Control Study and in Silico Analysis

Milad Heidari Nia

Mahdieh Jafari Shahroudi

Abstract

Background: Schizophrenia (SZN) is a heterogeneous disorder. Recently, the role of purinergic receptor’s signaling in mental disorders has implicated. There is no evidence regarding the association of P2XR4 single nucleotide polymorphisms (SNPs) and the risk of behavioral disorders. Therefore, this preliminary study, we determined the association of rs1169727A/G and rs25644A/G variants located in P2XR4 gene with the risk of SZN.

Methods: This case-control study was performed on 150 SZN patient referring to Baharan Hospital, Zahedan (Eastern of Iran) in 2018. Genotyping was done by tetra-amplification refractory mutation system polymerase chain reaction (Tetra ARMS-PCR). Different databases were used to determine the effects of the SNPs on the secondary structure of P2XR4 pre-mRNA and protein as well as binding of transcriptional regulators.

Results: The G allele of rs1169727 significantly increased the risk of SZN (OR=1.41, 95%CI=1.02-1.93, P=0.039), but there was no significant association was found between the other SNP and SZN. Moreover, GG model of rs1169727 (OR=2.46, 95%CI= 1.32-4.62, P=0.004) and rs25644 (OR=3.45, 95%CI= 1.12-5.10, P=0.013) increased the risk of SZN. The substitution of A and G alleles of rs1169727 significantly altered the secondary structure of pre-mRNA (P=0.1). In silico analysis revealed that rs25644A/G could act as an intronic cryptic donor site. Screening for flanking sequence of rs1169727A/G and rs25644A/G predicted a novel enhancer and silencer for both SNPs.

Conclusion: rs1169727A/G and rs25644A/G are linked to SZN susceptibility in a sample of the Iranian population. In-silico analysis indicated that rs25644 have substantial roles in determining the pre-mRNA and protein structure of P2XR4 gene.

1. Liu C-M, Liu Y-L, Fann CS-J, et al (2007). No association evidence between schizophrenia and dystrobrevin-binding protein 1 (DTNBP1) in Taiwanese families. Schizophr Res, 93(1-3):391-8.
2. Vrijenhoek T, Buizer-Voskamp JE, van der Stelt I, et al (2008). Recurrent CNVs disrupt three candidate genes in schizophrenia patients. Am J Hum Genet, 83(4):504-10.
3. McGuffin P, Tandon K, Corsico A (2003). Linkage and association studies of schizophrenia. Curr Psychiatry Rep, 5(2):121-7.
4. Hwu HG, Faraone SV, Liu CM, et al (2005). Taiwan schizophrenia linkage study: the field study. Am J Med Genet B Neuropsychiatr Genet, 134(1):30-6.
5. Straub RE, MacLean CJ, O'Neill FA, et al (1995). A potential vulnerability locus for schizophrenia on chromosome 6p24–22: evidence for genetic heterogeneity. Nat Genet, 11(3):287-93.
6. Riley BP, McGuffin P (2000). Linkage and associated studies of schizophrenia. Am J Med Genet, 97(1):23-44.
7. Greenwood TA, Lazzeroni LC, Murray SS, et al (2011). Analysis of 94 candidate genes and 12 endophenotypes for schizophrenia from the Consortium on the Genetics of Schizophrenia. Am J Psychiatry, 168(9):930-46.
8. Abbracchio MP, Burnstock G, Verkhratsky A, et al (2009). Purinergic signalling in the nervous system: an overview. Trends Neurosci, 32(1):19-29.
9. Barden N, Harvey M, Gagné B, et al (2006). Analysis of single nucleotide polymorphisms in genes in the chromosome 12Q24. 31 region points to P2RX7 as a susceptibility gene to bipolar affective disorder. Am J Med Genet B Neuropsychiatr Genet, 141(4):374-82.
10. Burnstock G (2007). Physiology and pathophysiology of purinergic neurotransmission. Physiol Rev, 87(2):659-797.
11. Fagerberg L, Hallström BM, Oksvold P, et al (2014). Analysis of the human tissue-specific expression by genome-wide integration of transcriptomics and antibody-based proteomics. Mol Cell Proteomics, 13(2):397-406.
12. Halmai Z, Dome P, Vereczkei A, et al (2013). Associations between depression severity and purinergic receptor P2RX7 gene polymorphisms. J Affect Disord, 150(1):104-9.
13. Hafner S, Wagner K, Weber S, et al (2017). Role of the purinergic receptor P2XR4 after blunt chest trauma in cigarette smoke-exposed mice. Shock, 47(2):193-199.
14. Iwata M, Ota KT, Li X-Y, et al (2016). Psychological stress activates the inflammasome via release of adenosine triphosphate and stimulation of the purinergic type 2X7 receptor. Biol Psychiatry, 80(1):12-22.
15. Miller S, Dykes D, Polesky H (1988). A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res, 16(3):1215.
16. Sabarinathan R, Tafer H, Seemann SE, et al (2013). RNAsnp: efficient detection of local RNA secondary structure changes induced by SNPs. Hum Mutat, 34(4):546-56.
17. Bromberg Y, Rost B (2007). SNAP: predict effect of non-synonymous polymorphisms on function. Nucleic Acids Res, 35(11):3823-3835.
18. Chen H, Gu F, Huang Z (2006). Improved Chou-Fasman method for protein secondary structure prediction. BMC Bioinformatics, 7:S14.
19. Piva F, Giulietti M, Burini AB, Principato G (2012). SpliceAid 2: A database of human splicing factors expression data and RNA target motifs. Hum Mutat, 33(1):81-5.
20. Crooks GE, Hon G, Chandonia J-M, et al (2004). WebLogo: a sequence logo generator. Genome Res, 14(6):1188-90.
21. Desmet F-O, Hamroun D, Lalande M, et al (2009). Human Splicing Finder: an online bioinformatics tool to predict splicing signals. Nucleic acids Res, 37(9):e67.
22. Harper S, Towers-Evans H, MacCabe J (2015). The aetiology of schizophrenia: what have the Swedish Medical Registers taught us? Soc Psychiatry Psychiatr Epidemiol, 50(10):1471-9.
23. Harrison PJ (2015). Recent genetic findings in schizophrenia and their therapeutic relevance. J Psychopharmacol, 29(2):85-96.
24. Tansey KE, Rees E, Linden D, et al (2016). Common alleles contribute to schizophrenia in CNV carriers. Mol psychiatry, 21(8):1153.
25. Färber K, Kettenmann H (2006). Purinergic signaling and microglia. Pflugers Arch, 452(5):615-21.
26. Cheffer A, Castillo A, Corrêa-Velloso J, et al (2018). Purinergic system in psychiatric diseases. Mol psychiatry, 23(1):94-106.
27. Khoja S, Shah V, Garcia D, et al (2016). Role of purinergic P2X4 receptors in regulating striatal dopamine homeostasis and dependent behaviors. J Neurochem, 139(1):134-48.
28. Lucae S, Salyakina D, Barden N, et al (2006). P2RX7, a gene coding for a purinergic ligand-gated ion channel, is associated with major depressive disorder. Hum Mol Genet, 15(16):2438-45.
29. Todd JN, Poon W, Lyssenko V, et al (2015). Hum Mol Genet. J Clin Endocrinol Metab, 100(5):E688-E96.
30. Wesselius A, Bours MJ, Jørgensen NR, et al (2013). Non-synonymous polymorphisms in the P2RX 4 are related to bone mineral density and osteoporosis risk in a cohort of Dutch fracture patients. Purinergic signal, 9(1):123-30.
31. Romanello M, Codognotto A, Bicego M, et al (2005). Autocrine/paracrine stimulation of purinergic receptors in osteoblasts: contribution of vesicular ATP release. Biochem Biophysl Res Commun, 331(4):1429-38.

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Issue	Vol 50 No 5 (2021)
Section	Original Article(s)
DOI	https://doi.org/10.18502/ijph.v50i5.6115
Keywords
Purinergic receptors Schizophrenia In-silico

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Heidari Nia M, Jafari Shahroudi M, Saravani R, Sargazi S, Moudi M, Mojahed A. Relationship between P2XR4 Gene Variants and the Risk of Schizophrenia in South-East of Iran: A Preliminary Case-Control Study and in Silico Analysis. Iran J Public Health. 2021;50(5):978-989.

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