Journal of Isfahan Medical School

Journal of Isfahan Medical School

In Silico Analysis of SNPs in MicroRNAs Related to Th1/Th2 Differentiation Pathways in Schizophrenia

Document Type : Original Article (s)

Authors
1 Assistant Professor, Endocrinology and Metabolism Research Center, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
2 Associate Professor, Molecular Medicine Research Center, Hormozgan Health Institute, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
10.48305/jims.v44.i875.1543
Abstract
Background: Genetic variations in miRNAs and their binding sites may increase schizophrenia risk by disrupting miRNA-target interactions, impairing brain development, and elevating susceptibility to this disorder. This study employed in silico tools to predict the deleterious effects of single-nucleotide polymorphisms (SNPs) in overlapped miRNAs related to Th1/Th2 differentiation in schizophrenia, focusing on their impact on miRNA stability, structure, and target binding.
Methods: Overlapped miRNAs associated with Th1/Th2 differentiation in schizophrenia were retrieved from miRTarBase and miRWalk databases. To identify and predict the functional effects of SNPs located in the precursor and mature regions of candidate miRNAs, Ensembl, miRNASNP-v4, and SNP2TFBS databases were used. Finally, enrichment analysis of biological pathways was performed using NcPath database.
Findings: miRNASNP-v4 identified multiple SNPs across seven overlapped miRNAs (hsa-miR-107, hsa-miR-1827, hsa-miR-206, hsa-miR-320e, hsa-miR-4429, hsa-miR-4467, and hsa-miR-936), with the highest SNP counts in pre-miRNA and mature miRNA regions, particularly in hsa-miR-320e, hsa-miR-4467, and hsa-miR-936. SNPs rs1350983737 and rs1043872367 in hsa-miR-4467 exhibited the strongest and weakest influences on mature miRNA production, respectively. Notably, miR-4467 and miR-320e harbored the most seed region SNPs, potentially disrupting miRNA binding to 3′UTR of target mRNAs. Several SNPs were also found in miRNA promoter regions, potentially impairing transcription factor binding.
Conclusion: SNPs in miRNAs can affect both their expression and regulatory functions. Genetic variations in schizophrenia-related miRNAs represent important targets for further investigation to elucidate disease molecular mechanisms.

Highlights

Pegah Mousavi: Google Scholar , PubMed

Nahid Davoodian: Google Scholar , PubMed

Keywords
Subjects

1.     Insel TR. Rethinking schizophrenia. Nature 2010; 468(7321): 187-93.
2.     Sullivan PF, Kendler KS, Neale MC. Schizophrenia as a complex trait: evidence from a meta-analysis of twin studies. Arch Gen Psychiatry 2003; 60(12): 1187-92.
3.     Dean K, Murray RM. Environmental risk factors for psychosis. Dialogues Clin Neurosci 2005; 7(1): 69-80.
4.     Papavasiliou FN, Chung YC, Gagnidze K, Hajdarovic KH, Cole DC, Bulloch K. Epigenetic modulators of monocytic function: Implication for steady state and disease in the CNS. Front Immunol 2016; 6: 661.
5.     Prinz M, Priller J. The role of peripheral immune cells in the CNS in steady state and disease. Nat Neurosci 2017; 20(2): 136-44.
6.     Miller BJ, Gassama B, Sebastian D, Buckley P, Mellor A. Meta-analysis of lymphocytes in schizophrenia: clinical status and antipsychotic effects. Biol Psychiatry 2013; 73(10): 993-9.
7.     Zheng Y, Zhang Q, Zhou X, Yao L, Zhu Q, Fu Z. Altered levels of cytokine, T-and B-lymphocytes, and PD-1 expression rates in drug-naïve schizophrenia patients with acute phase. Sci Rep 2023; 13(1): 21711.
8.     Chiang SSW, Riedel M, Schwarz M, Mueller N. Is T‐helper type 2 shift schizophrenia‐specific? Primary results from a comparison of related psychiatric disorders and healthy controls. Psychiatry Clin Neurosci 2013; 67(4): 228-36.
9.     Freudenreich O, Brockman MA, Henderson DC, Evins AE, Fan X, Walsh JP, et al. Analysis of peripheral immune activation in schizophrenia using quantitative reverse-transcription polymerase chain reaction (RT-PCR). Psychiatry Res 2010; 176(2-3): 99-102.
10.  Schwarz M, Müller N, Riedel M, Ackenheil M. The Th2-hypothesis of schizophrenia: a strategy to identify a subgroup of schizophrenia caused by immune mechanisms. Med Hypotheses 2001; 56(4): 483-6.
11.  Zhang T, Zeng J, Wei Y, Ye J, Tang X, Xu L, et al. Changes in inflammatory balance correlates with conversion to psychosis among individuals at clinical high-risk: A prospective cohort study. Psychiatry Res 2022; 318: 114938.
12.  Rezaee D, Saadatpour F, Akbari N, Zoghi A, Najafi S, Beyranvand P, et al. The role of microRNAs in the pathophysiology of human central nervous system: a focus on neurodegenerative diseases. Ageing Research Reviews 2023; 92: 102090.
13.  Li K, Zhu L, Lv H, Bai Y, Guo C, He K. The role of microRNA in schizophrenia: a scoping review. Int J Mol Sci 2024; 25(14): 7673.
14.  Xu S-J, Chen J-H, Chang S, Li H-L. The role of miRNAs in T helper cell development, activation, fate decisions and tumor immunity. Front Immunol 2024; 14: 1320305.
15.  Yu T, Wang P, Wu Y, Zhong J, Chen Q, Wang D, et al. MiR-26a reduces inflammatory responses via inhibition of PGE2 production by targeting COX-2. Inflammation 2022; 45(4): 1484-95.
16.  Shafiee-Kandjani AR, Nezhadettehad N, Farhang S, Bruggeman R, Shanebandi D, Hassanzadeh M, et al. MicroRNAs and pro-inflammatory cytokines as candidate biomarkers for recent-onset psychosis. BMC Psychiatry 2023; 23: 631.
17.  Jeffries C, Perkins D, Chandler S, Stark T, Yeo E, Addington J, et al. Insights into psychosis risk from leukocyte microRNA expression. Transl Psychiatry 2016; 6(12): e981-e.
18.  Sethupathy P, Collins FS. MicroRNA target site polymorphisms and human disease. Trends Genet 2008; 24(10): 489-97.
19.  Liu C, Zhang F, Li T, Lu M, Wang L, Yue W, et al. MirSNP, a database of polymorphisms altering miRNA target sites, identifies miRNA-related SNPs in GWAS SNPs and eQTLs. BMC Genomics 2012; 13: 661.
20.  Genome-wide association study identifies five new schizophrenia loci. Nat Genet 2011; 43(10): 969-76.
21.  Oliveros JC. (2007-2015) Venny. An Interactive Tool for Comparing Lists with Venn’s Diagrams. Available from: https://www.scirp.org/reference/referencespapers?referenceid=2904043 .
22.  Cao W, He J, Feng J, Wu X, Wu T, Wang D, et al. miRNASNP-v4: a comprehensive database for miRNA-related SNPs across 17 species. Nucleic Acids Res 2025; 53(D1): D1066-D74.
23.  Kumar S, Ambrosini G, Bucher P. SNP2TFBS–a database of regulatory SNPs affecting predicted transcription factor binding site affinity. Nucleic Acids Res 2017; 45(D1): D139-D44.
24.  He E, Lozano MAG, Stringer S, Watanabe K, Sakamoto K, den Oudsten F, et al. MIR137 schizophrenia-associated locus controls synaptic function by regulating synaptogenesis, synapse maturation and synaptic transmission. Hum Mol Genet 2018; 27(11): 1879-91.
25.  Miyano T, Hirouchi M, Yoshimura N, Hattori K, Mikkaichi T, Kiyosawa N. Plasma microRNAs Associate Positive, Negative, and Cognitive Symptoms with Inflammation in Schizophrenia. Int J Mol Sci 2024; 25(24): 13522.
26.  Martinez B, Peplow PV. MicroRNAs as potential biomarkers for diagnosis of schizophrenia and influence of antipsychotic treatment. Neural Regen Res 2024; 19(7): 1523-31.
27.  Starega-Roslan J, Witkos TM, Galka-Marciniak P, Krzyzosiak WJ. Sequence features of Drosha and Dicer cleavage sites affect the complexity of isomiRs. Int J Mol Sci 2015; 16(4): 8110-27.
28.  Sun G, Yan J, Noltner K, Feng J, Li H, Sarkis DA, et al. SNPs in human miRNA genes affect biogenesis and function. RNA 2009; 15(9): 1640-51.
29.  Hansen T, Olsen L, Lindow M, Jakobsen KD, Ullum H, Jonsson E, et al. Brain expressed microRNAs implicated in schizophrenia etiology. PloS One 2007; 2(9): e873.
30.  Xu Y, Li F, Zhang B, Zhang K, Zhang F, Huang X, et al. MicroRNAs and target site screening reveals a pre-microRNA-30e variant associated with schizophrenia. S Schizophr Res 2010; 119(1-3): 219-27.
31.  Shi S, Leites C, He D, Schwartz D, Moy W, Shi J, et al. MicroRNA-9 and microRNA-326 regulate human dopamine D2 receptor expression, and the microRNA-mediated expression regulation is altered by a genetic variant. J Biol Chem 2014; 289(19): 13434-44.
32.  Chen X, Zhang Z, Zhang Q, Zhao W, Zhai J, Chen M, et al. Effect of rs1344706 in the ZNF804A gene on the brain network. Neuroimage Clinl 2018; 17: 1000-5.
33.  Guella I, Sequeira A, Rollins B, Morgan L, Torri F, van Erp TG, et al. Analysis of miR-137 expression and rs1625579 in dorsolateral prefrontal cortex. J Psychiatr Res 2013; 47(9): 1215-21.
34.  Wang Z, Li X-N, Yang S-N, Wang Y, Gao K-J, Han B, et al. Exosomal miR-320e through wnt2targeted inhibition of the Wnt/β-catenin pathway allevisate cerebral small vessel disease and cognitive impairment. World J Psychiatr 2023; 13(9): 630-44.
35.  De V. Ferrari G, E. Avila M, A. Medina M, Pérez-Palma E, I. Bustos B, A. Alarcon M. Wnt/β-catenin signaling in Alzheimer’s disease. CNS Neurol Disord Drug Targets 2014; 13(5): 745-54.
36.  Nusse R, Clevers H. Wnt/β-catenin signaling, disease, and emerging therapeutic modalities. Cell 2017; 169(6): 985-99.
37.  Al-Dujaili AH, Mousa RF, Al-Hakeim HK, Maes M. High mobility group protein 1 and dickkopf-related protein 1 in schizophrenia and treatment-resistant schizophrenia: Associations with interleukin-6, symptom domains, and neurocognitive impairments. Schizophr Bull 2021; 47(2): 530-41.
38.  Vallée A. Neuroinflammation in schizophrenia: the key role of the WNT/β-catenin pathway. Int J Mol Sci 2022; 23(5): 2810.
39.  Vachev T, Popov N, Stoyanova V, Ivanov H, Minchev D. Alterations of miR-320 family members as a novel diagnostic biomarkers in peripheral blood of schizophrenia patients. Int J Curr Microbiol Appl Sci 2016;5(3): 865-75.
40.  Denk J, Boelmans K, Siegismund C, Lassner D, Arlt S, Jahn H. MicroRNA profiling of CSF reveals potential biomarkers to detect Alzheimers disease. PLoS One 2015; 10(5): e0126423.
41.  Jin M, Zhu X, Sun Y, Li Z, Li X, Ai L, et al. Identification of peripheral blood miRNA biomarkers in first-episode drug-free schizophrenia patients using bioinformatics strategy. Mol Neurobiol 2022; 59(8): 4730-46.
42.  Davarinejad O, Najafi S, Zhaleh H, Golmohammadi F, Radmehr F, Alikhani M, et al. MiR-574-5P, miR-1827, and miR-4429 as potential biomarkers for schizophrenia. J Mol Neurosci 2022; 72(2): 226-38.
43.  Zhu Y-M, Chen P, Shi L, Zhu T, Chen X. MiR-4429 suppresses the malignant development of ovarian cancer by targeting YOD1. Eur Rev Med Pharmacol Sci 2020; 24(17): 8722-30.
44.  Zhou S, Qian K, Yu S, Zhao Y, Shen Q, Li Y. MiR-4429 alleviates malignant behaviors of lung adenocarcioma through Wnt/β-catenin pathway. Cancer Biother Radiopharm 2024; 39(8): 562-72.
45.  Moghiseh E, Massoudifar A, Davoodian N, Mousavi P, Afsharpour S, Mahmoodi M. Aberrant Expression of TH2LCRR and GATA3 in Peripheral Blood Mononuclear Cells of Patients with Acute-Phase Schizophrenia: Integrative Bioinformatics Analysis and Experimental Study. Mol Neurobiol 2025; 62(10): 12413-25.
46.  Hauberg ME, Holm-Nielsen MH, Mattheisen M, Askou AL, Grove J, Børglum AD, et al. Schizophrenia risk variants affecting microRNA function and site-specific regulation of NT5C2 by miR-206. Eur Neuropsychopharmacol 2016; 26(9): 1522-6.
47.  Liu X, Dong L, Jiang Z, Song M, Yan P. Identifying the differentially expressed peripheral blood microRNAs in psychiatric disorders: A systematic review and meta-analysis. Front Psychiatry 2024; 15: 1390366.
48.  Zhang M, Du Y, Chen L, Tang Q, Liu C, Li N, et al. Genome-wide, integrative analysis implicates exosome-derived microRNA dysregulation in chronic insomnia. Sleep 2025; 48(6): zsaf051.
49.  Pandya CD, Kutiyanawalla A, Pillai A. BDNF–TrkB signaling and neuroprotection in schizophrenia. Asian J Psychiatr 2013; 6(1): 22-8.
Volume 44, Issue 875
2nd Week,October
September and October 2026
Pages 1543-1561

  • Receive Date 31 August 2025
  • Accept Date 25 July 2026