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Functional Variants of miR-143 Are Associated with Schizophrenia Susceptibility: A Preliminary Population-Based Study and Bioinformatics Analysis

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Abstract

Single nucleotide polymorphisms within genes encoding microRNAs may alter the expression of microRNAs and their target genes, contributing to the etiology of psychiatric disorders. We aimed to investigate the link between rs4705342T/C and rs4705343T/C polymorphisms in the promoter region of miR-143 and the risk of schizophrenia (SCZ) in a sample of an Iranian population. In this experimental study, a total of 398 subjects were recruited. Genotyping carried out using allele‐specific PCR (AS‐PCR) method. Different bioinformatics databases and Cytoscape V3.4.0 software were used for the analysis of the gene-miRNA interaction network. The genotypic analysis of rs4705342C/T showed that CC genotype in the co-dominant model significantly decreased the risk of SCZ (p < 0.001). Also, a significantly reduced risk of SCZ was observed under allelic (p < 0.001), dominant (p = 0.007), and recessive (p = 0.001) models of this variant. As regards rs4705343T/C, significantly enhanced risk of SCZ was found under the co-dominant CC (p = 0.01) and recessive (p = 0.007) contrasted genetic models. For this variant, the C allele conferred an increased risk of SCZ by 1.41 fold. Haplotype analysis showed that the Crs4705342 Trs4705343 haplotype significantly diminished SCZ susceptibility. The result of the bioinformatics analysis showed that miR-143, as a critical miRNA, targets ERK5, ERBB3, HK2, and PKCε, the four major genes involved in SCZ development. Our findings suggest that these two polymorphisms might affect SCZ susceptibility. Elucidating the precise regulatory mechanisms of gene expression in the development of SCZ will help researchers discover a novel target for therapeutic interventions.

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References

  • Abrial E, Lucas G, Scarna H, Haddjeri N, Lambás-Señas L (2011) A role for the PKC signaling system in the pathophysiology and treatment of mood disorders: involvement of a functional imbalance? Mol Neurobiol 44(3):407–419

    Article  CAS  PubMed  Google Scholar 

  • Allen NC, Bagade S, McQueen MB, Ioannidis JP, Kavvoura FK, Khoury MJ, Tanzi RE, Bertram L (2008) Systematic meta-analyses and field synopsis of genetic association studies in schizophrenia: the SzGene database. Nat Genet 40(7):827

    Article  CAS  PubMed  Google Scholar 

  • Anton E, Ghashghaei H, Weber JL, McCann C, Fischer TM, Cheung ID, Gassmann M, Messing A, Klein R, Schwab MH (2004) Receptor tyrosine kinase ErbB4 modulates neuroblast migration and placement in the adult forebrain. Nat Neurosci 7(12):1319–1328

    Article  CAS  PubMed  Google Scholar 

  • Bahmanpour Z, Sheervalilou R, Choupani J, Shekari Khaniani M, Montazeri V, Mansoori Derakhshan S (2019) A new insight on serum microRNA expression as novel biomarkers in breast cancer patients. J Cell Physiol 234(11):19199–19211

    Article  CAS  PubMed  Google Scholar 

  • Battaini F (2001) Protein kinase C isoforms as therapeutic targets in nervous system disease states. Pharmacol Res 44(5):353–361

    Article  CAS  PubMed  Google Scholar 

  • Black DW, Grant JE (2014) DSM-5® guidebook: the essential companion to the diagnostic and statistical manual of mental disorders. American Psychiatric Publication, Philadelphia

    Google Scholar 

  • Bradshaw G, Haupt LM, Aquino EM, Lea RA, Sutherland HG, Griffiths LR (2019) Single nucleotide polymorphisms in MIR143 contribute to protection against Non-Hodgkin Lymphoma (NHL) in Caucasian populations. Genes 10(3):185

    Article  CAS  PubMed Central  Google Scholar 

  • Chu H, Zhong D, Tang J, Li J, Xue Y, Tong N, Qin C, Yin C, Zhang Z, Wang M (2016) A functional variant in miR-143 promoter contributes to prostate cancer risk. Arch Toxicol 90(2):403–414

    Article  CAS  PubMed  Google Scholar 

  • Cundiff P, Liu L, Wang Y, Zou J, Pan Y-W, Abel G, Duan X, Ming G, Englund C, Hevner R (2009) ERK5 MAP kinase regulates neurogenin1 during cortical neurogenesis. PLoS ONE 4(4):e5204

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Esau C, Kang X, Peralta E, Hanson E, Marcusson EG, Ravichandran LV, Sun Y, Koo S, Perera RJ, Jain R (2004) MicroRNA-143 regulates adipocyte differentiation. J Biol Chem 279(50):52361–52365

    Article  CAS  PubMed  Google Scholar 

  • Fu X, Guo L, Jiang ZM, Zhao L-S, Xu A-G (2014) An variant associated with essential hypertension. Int J Clin Exp Med 7(7):1813

  • Gao F-B (2008) Posttranscriptional control of neuronal development by microRNA networks. Trends Neurosci 31(1):20–26

    Article  PubMed  CAS  Google Scholar 

  • Gaudet M, Fara A-G, Beritognolo I, Sabatti M (2009) Allele-specific PCR in SNP genotyping. In: Single nucleotide polymorphisms, pp 415–424. Springer, Berlin

  • Gearing RE, Alonzo D, Smolak A, McHugh K, Harmon S, Baldwin S (2011) Association of religion with delusions and hallucinations in the context of schizophrenia: Implications for engagement and adherence. Schizophr Res 126(1–3):150–163

    Article  PubMed  Google Scholar 

  • Ghasemvand F, Salehi Z, Fakour Y, Omidinia E (2013) Association of 757 C/T polymorphismin PRODH gene with Schizophrenia in Iranian population. J Paramed Sci 4:97–104

    Google Scholar 

  • Hahn C-G, Wang H-Y, Cho D-S, Talbot K, Gur RE, Berrettini WH, Bakshi K, Kamins J, Borgmann-Winter KE, Siegel SJ (2006) Altered neuregulin 1-erbB4 signaling contributes to NMDA> receptor hypofunction in schizophrenia. Nat Med 12(7):824–828

    Article  CAS  PubMed  Google Scholar 

  • Han K, Sun C, Jia N, Li R, Zhang Z, Zhong Y (2020) miR-143-3p inhibition promotes neuronal survival in an Alzheimer’s disease cell model by targeting neuregulin-1. Folia Neuropathol 58(1):10–21

    Article  PubMed  Google Scholar 

  • Heinz A, Schlagenhauf F (2010) Dopaminergic dysfunction in schizophrenia: salience attribution revisited. Schizophr Bull 36(3):472–485

    Article  PubMed  PubMed Central  Google Scholar 

  • Hernandez-Rapp J, Rainone S, Hebert SS (2017) MicroRNAs underlying memory deficits in neurodegenerative disorders. Prog Neuropsychopharmacol Biol Psychiatry 73:79–86

    Article  CAS  PubMed  Google Scholar 

  • Issler O, Chen A (2015) Determining the role of microRNAs in psychiatric disorders. Nat Rev Neurosci 16(4):201–212

    Article  CAS  PubMed  Google Scholar 

  • Kanazawa T, Glatt SJ, Tsutsumi A, Kikuyama H, Koh J, Yoneda H, Tsuang MT (2007) Schizophrenia is not associated with the functional candidate gene ERBB3: results from a case-control study. Am J Med Genet B Neuropsychiatr Genet 144(1):113–116

    Article  CAS  Google Scholar 

  • Kang S-G, Lee YJ, Park Y-M, Kim L, Lee H-J (2018) Haplotype association of the MAP2K5 gene with antipsychotics-induced symptoms of restless legs syndrome among patients with schizophrenia. Psychiatry Investig 15(1):84

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kim VN, Han J, Siomi MC (2009) Biogenesis of small RNAs in animals. Nat Rev Mol Cell Biol 10(2):126

    Article  CAS  PubMed  Google Scholar 

  • Li C, Zhang Y, Li Y, Ma Q, Liu S, Yao Y, Tan F, Shi L, Yao Y (2018) The association of polymorphisms in miRNAs with nonsmall cell lung cancer in a Han Chinese population. Cancer Manag Res 10:697

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Li D, Feng G, He L (2009) Case–control study of association between the functional candidate gene ERBB3 and schizophrenia in Caucasian population. World J Biol Psychiatry 10(4–2):595–598

    Article  PubMed  Google Scholar 

  • Liang Y, Sun R, Li L, Yuan F, Liang W, Wang L, Nie X, Chen P, Zhang L, Gao L (2015) A functional polymorphism in the promoter of MiR-143/145 is associated with the risk of cervical squamous cell carcinoma in Chinese women: a case–control study. Medicine 94(31):e1289

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lin G-M, Chen Y-J, Kuo D-J, Jaiteh LE, Wu Y-C, Lo T-S, Li Y-H (2013) Cancer incidence in patients with schizophrenia or bipolar disorder: a nationwide population-based study in Taiwan, 1997–2009. Schizophr Bull 39(2):407–416

    Article  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Moreau MP, Bruse SE, David-Rus R, Buyske S, Brzustowicz LM (2011) Altered microRNA expression profiles in postmortem brain samples from individuals with schizophrenia and bipolar disorder. Biol Psychiatry 69(2):188–193

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Moudi M, Sargazi S, Heidari Nia M, Saravani R, Shirvaliloo M, Shakiba M (2020) Polymorphism in the 3′-UTR of LIF but not in the ATF6B gene associates with schizophrenia susceptibility: a case–control study and in silico analyses. J Mol Neurosci 70:2093–2101

    Article  CAS  PubMed  Google Scholar 

  • Nelson PT, Wang WX, Rajeev BW (2008) MicroRNAs (miRNAs) in neurodegenerative diseases. Brain Pathol 18(1):130–138

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Omidinia E, Mazar FM, Shahamati P, Kianmehr A, Mohammadi HS (2014) Polymorphism of the CLDN5 gene and Schizophrenia in an Iranian Population. Iran J Public Health 43(1):79

    PubMed  PubMed Central  Google Scholar 

  • Preti A, Wilson DR (2011) Schizophrenia, cancer and obstetric complications in an evolutionary perspective-an empirically based hypothesis. Psychiatry Investig 8(2):77

    Article  PubMed  Google Scholar 

  • Purcell SM, Wray NR, Stone JL, Visscher PM, O’Donovan MC, Sullivan PF, Sklar P (2009) Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature 460(7256):748–752

    Article  CAS  PubMed  Google Scholar 

  • Qin J, Wang F, Jiang H, Xu J, Jiang Y, Wang Z (2015) MicroRNA-145 suppresses cell migration and invasion by targeting paxillin in human colorectal cancer cells. Int J Clin Exp Pathol 8(2):1328

    PubMed  PubMed Central  Google Scholar 

  • Reif A, Schmitt A, Fritzen S, Lesch K-P (2007) Neurogenesis and schizophrenia: dividing neurons in a divided mind? Eur Arch Psychiatry Clin Neurosci 257(5):290–299

    Article  PubMed  Google Scholar 

  • Rizos E, Siafakas N, Skourti E, Papageorgiou C, Tsoporis J, Parker T, Christodoulou D, Spandidos D, Katsantoni E, Zoumpourlis V (2016) miRNAs and their role in the correlation between schizophrenia and cancer. Mol Med Rep 14(6):4942–4946

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rozen S, Skaletsky H (2000) Primer3 on the WWW for general users and for biologist programmers. In: Bioinformatics methods and protocols. Springer, Berlin, pp 365–386

  • Shastry BS (2009) SNPs: impact on gene function and phenotype. In: Single nucleotide polymorphisms. Springer, Berlin, pp 3–22

  • Sheervalilou R, Shahraki O, Hasanifard L, Shirvaliloo M, Mehranfar S, Lotfi H, Pilehvar-Soltanahmadi Y, Bahmanpour Z, Zadeh SS, Nazarlou Z (2020) Electrochemical nano-biosensors as novel approach for the detection of lung cancer-related microRNAs. Curr Mol Med 20(1):13–35

    Article  CAS  Google Scholar 

  • Sima X, Sun H, Zhou P, You C (2015) A potential polymorphism in the promoter of let-7 is associated with an increased risk of intracranial aneurysm: a case–control study. Medicine 94(51):e2267

    Article  PubMed  PubMed Central  Google Scholar 

  • Sima X, Sun H, Zhou P, You C, Cai B (2017) Association between functional polymorphisms in the promoter of the miR-143/145 cluster and risk of intracranial aneurysm. Sci Rep 7:43633

    Article  PubMed  PubMed Central  Google Scholar 

  • Smalheiser NR, Lugli G, Zhang H, Rizavi H, Cook EH, Dwivedi Y (2014) Expression of microRNAs and other small RNAs in prefrontal cortex in schizophrenia, bipolar disorder and depressed subjects. PLoS ONE 9(1):e86469

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Stone WS, Faraone SV, Su J, Tarbox SI, Van Eerdewegh P, Tsuang MT (2004) Evidence for linkage between regulatory enzymes in glycolysis and schizophrenia in a multiplex sample. Am J Med Genet B Neuropsychiatr Genet 127(1):5–10

    Article  Google Scholar 

  • Su J, Liang H, Yao W, Wang N, Zhang S, Yan X, Feng H, Pang W, Wang Y, Wang X (2014) MiR-143 and MiR-145 regulate IGF1R to suppress cell proliferation in colorectal cancer. PLoS ONE 9(12):e114420

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Sun R, Chen P, Li L, Sun H, Nie X, Liang Y, Yuan F, Pu Y, Bai P, Zhang L (2016) A polymorphism rs4705341 in the flanking region of miR-143/145 predicts risk and prognosis of colorectal cancer. Oncotarget 7(38):62084

    Article  PubMed  PubMed Central  Google Scholar 

  • Wang P, Cao T, Chen J, Jiang Y, Wang C, Waddington JL, Zhen X (2019) D2 receptor-mediated miRNA-143 expression is associated with the effects of antipsychotic drugs on phencyclidine-induced schizophrenia-related locomotor hyperactivity and with neuregulin-1 expression in mice. Neuropharmacology 157:107675

    Article  CAS  PubMed  Google Scholar 

  • Watanabe Y, Fukui N, Nunokawa A, Muratake T, Kaneko N, Kitamura H, Someya T (2007) No association between the ERBB3 gene and schizophrenia in a Japanese population. Neurosci Res 57(4):574–578

    Article  CAS  PubMed  Google Scholar 

  • Waters F, Woodward T, Allen P, Aleman A, Sommer I (2010) Self-recognition deficits in schizophrenia patients with auditory hallucinations: a meta-analysis of the literature. Schizophr Bull 38(4):741–750

    Article  PubMed  PubMed Central  Google Scholar 

  • Wei Y-S, Xiang Y, Liao P-H, Wang J-L, Peng Y-F (2016a) An rs4705342 T> C polymorphism in the promoter of miR-143/145 is associated with a decreased risk of ischemic stroke. Sci Rep 6(1):1–6

    CAS  Google Scholar 

  • Wei Y-S, Xiang Y, Liao P-H, Wang J-L, Peng Y-F (2016b) An rs4705342 T > C polymorphism in the promoter of miR-143/145 is associated with a decreased risk of ischemic stroke. Sci Rep 6:34620

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yang M, Li Z, Jin M, Sun Y, He Y, Liu Y, Yu Q (2020) Associations between three microRNA gene polymorphisms and schizophrenia susceptibility in a Han Chinese population. Asian J Psychiatry 50:102035

    Article  Google Scholar 

  • Yang X, Li X, Quan X, Li H, Hao X, Jiang M, Zhou B (2019) Association between two polymorphisms in the promoter region of miR-143/miR-145 and the susceptibility of lung cancer in northeast chinese nonsmoking females. DNA Cell Biol 38(8):814–823

    Article  CAS  PubMed  Google Scholar 

  • Yuan F, Sun R, Li L, Jin B, Wang Y, Liang Y, Che G, Gao L, Zhang L (2016) A functional variant rs353292 in the flanking region of miR-143/145 contributes to the risk of colorectal cancer. Sci Rep 6:30195

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang XY, Chen D-C, Tan Y-L, An H-M, Zunta-Soares GB, Huang X-F, Soares JC (2015) Glucose disturbances in first-episode drug-naive schizophrenia: relationship to psychopathology. Psychoneuroendocrinology 62:376–380

    Article  CAS  PubMed  Google Scholar 

  • Zou J, Pan Y-W, Wang Z, Chang S-Y, Wang W, Wang X, Tournier C, Storm DR, Xia Z (2012) Targeted deletion of ERK5 MAP kinase in the developing nervous system impairs development of GABAergic interneurons in the main olfactory bulb and behavioral discrimination between structurally similar odorants. J Neurosci 32(12):4118–4132

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors wish to thank Dr. Azizollah Mojahed and the technical operators of the psychiatric clinic of Baharan Hospital (Zahedan, Iran).

Funding

This work was financially supported by Zahedan University of Medical Sciences, Zahedan, Iran (Grant No. 9357).

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Authors and Affiliations

  1. Cellular and Molecular Research Center, Research Institute of Cellular and Molecular Sciences in Infectious Diseases, Zahedan University of Medical Sciences, Zahedan, Iran

    Saman Sargazi, Fariba Mirani Sargazi, Milad Heidari Nia, Ramin Saravani & Shekoufeh Mirinejad

  2. Pharmacology Research Center, Zahedan University of Medical Sciences, Zahedan, Iran

    Roghayeh Sheervalilou

  3. Department of Clinical Biochemistry, School of Medicine, Zahedan University of Medical Sciences, Zahedan, Iran

    Ramin Saravani

  4. Department of Psychiatry, Zahedan University of Medical Sciences, Zahedan, Iran

    Mansoor Shakiba

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  1. Saman Sargazi
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Correspondence to Ramin Saravani.

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Sargazi, S., Mirani Sargazi, F., Heidari Nia, M. et al. Functional Variants of miR-143 Are Associated with Schizophrenia Susceptibility: A Preliminary Population-Based Study and Bioinformatics Analysis. Biochem Genet 60, 868–881 (2022). https://doi.org/10.1007/s10528-021-10133-z

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