Ukr.Biochem.J. 2021; Volume 93, Issue 1, Jan-Feb, pp. 82-87


MicroRNAs hsa-mir-34a and hsa-mir-124 as biomarkers for predicting and monitoring the lithium treatment in bipolar disorder: in silico analysis

Orcun Avsar

Hitit University, Department of Molecular Biology and Genetics, Corum, Turkey;

Received: 14 July 2020; Accepted: 17 December 2020

Lithium is known to be efficient in treatment for mental disorders in people with bipolar disorder. The aim of the study was to identify bipolar disorder-specific MicroRNAs (miRNAs) that are associated with genes targeted by lithium treatment and lead to variance in the clinical response.  miRNAs which are experimentally validated and shown to have differential expression pattern in bipolar disorder were selected from online public databases miRTarbase and HMDD v3.2. Target prediction was carried out for each miRNA, and experimentally validated miRNA-target mRNA pairs were obtained and analyzed by miRTarbase, HMDD v3.2, TargetScan, and DIANA databases. miRNA-target genes that are associated with lithium was determined by the use of DrugBank. According to the in silico analysis, it has been found that IMPA1 gene was targeted by hsa-mir-34a and GRIA3 gene was targeted by hsa-mir-124. The present study demonstrated that IMPA1, GRIA3, hsa-mir-34a, hsa-mir-124 may have the potential to be used as molecular biomarkers for estimating and monitoring the response to lithium treatment in bipolar disorder.

Keywords: , , , , ,


  1. Forstner AJ, Hofmann  A, Maaser  A, Sumer S, Khudayberdiev S, Mühleisen  TW, Leber M, Schulze TG, Strohmaier J, Degenhardt F, Treutlein J, Mattheisen M, Schumacher J. et al. Genome-wide analysis implicates microRNAs and their target genes in the development of bipolar disorder. Transl Psychiatry. 2015;5(11):e678.  PubMed, PubMedCentral, CrossRef
  2. McCormick U, Murray B, McNew B. Diagnosis and treatment of patients with bipolar disorder: A review for advanced practice nurses. J Am Assoc Nurse Pract. 2015;27(9):530-542. PubMed, PubMedCentral, CrossRef
  3. Rowland TA, Marwaha S. Epidemiology and risk factors for bipolar disorder. Ther Adv Psychopharmacol. 2018;8(9):251-269. PubMed, PubMedCentral, CrossRef
  4. Reinbold CS, Forstner AJ, Hecker J, Fullerton JM, Hoffmann P, Hou L, Heilbronner U, Degenhardt F, Adli M, Akiyama K. et al. Analysis of the Influence of microRNAs in Lithium Response in Bipolar Disorder. Front Psychiatry. 2018;9:207. PubMed, PubMedCentral, CrossRef
  5. Chiu CT, Wang Z, Hunsberger JG, Chuang DM. Therapeutic potential of mood stabilizers lithium and valproic acid: beyond bipolar disorder. Pharmacol Rev. 2013;65(1):105-142. PubMed, PubMedCentral, CrossRef
  6. Piedade D, Azevedo-Pereira JM. The Role of microRNAs in the Pathogenesis of Herpesvirus Infection. Viruses. 2016;8(6):156.  PubMed, PubMedCentral, CrossRef
  7. Alural B, Genc S, Haggarty SJ. Diagnostic and therapeutic potential of microRNAs in neuropsychiatric disorders: Past, present, and future. Prog Neuropsychopharmacol Biol Psychiatry. 2017;73:87-103. PubMed, PubMedCentral, CrossRef
  8. Huang HY, Lin YCD, Li J, Huang KY, Shrestha S, Hong HC, Tang Y, Chen YG, Jin CN, Yu Y, Xu JT, Li YM, Cai XX, Zhou ZY, Chen XH, Pei YY, Hu L, Su JJ, Cui SD, Wang F, Xie YY, Ding SY, Luo MF, Chou  CH, Chang NW, Chen KW, Cheng YH, Wan XH, Hsu WL, Lee TY, Wei FX, Huang HD. miRTarBase 2020: updates to the experimentally validated microRNA-target interaction database. Nucleic Acids Res. 2020;48(D1):D148-D154. PubMed, PubMedCentral, CrossRef
  9. Huang Z, Shi J, Gao Y, Cui C, Zhang S, Li J, Zhou Y, Cui Q. HMDD v3.0: a database for experimentally supported human microRNA-disease associations. Nucleic Acids Res. 2019;47(D1):D1013-D1017. PubMed, PubMedCentral, CrossRef
  10. Agarwal V, Bell GW, Nam JW, Bartel DP. Predicting effective microRNA target sites in mammalian mRNAs. Elife. 2015;4:e05005. PubMed, PubMedCentral, CrossRef
  11. Vlachos IS, Hatzigeorgiou AG. Functional analysis of miRNAs using the DIANA tools online suite. In: Schmidt M. (eds) Drug Target miRNA. Methods in Molecular Biology, 2017; vol. 1517. Humana Press, New York, NY.  CrossRef
  12. Wishart DS, Feunang YD, Guo AC, Lo J, Marcu A, Grant JR, Sajed T, Johnson D, Li C, Sayeeda Z, Assempour N, Iynkkaran I, Liu Y, Maciejewski A, Gale N, Wilson A, Chin L, Cummings R, Le D, Pon A, Knox C, Wilson M. DrugBank 5.0: a major update to the DrugBank database for 2018. Nucleic Acids Res. 2018;46(D1):D1074-D1082. PubMed, PubMedCentral, CrossRef
  13. López-Muñoz F, Shen WW, D’Ocon P, Romero A, Álamo C. A History of the Pharmacological Treatment of Bipolar Disorder. Int J Mol Sci. 2018;19(7):2143. PubMed, PubMedCentral, CrossRef
  14. Anand A, McClintick JN, Murrell J, Karne H, Nurnberger JI, Edenberg HJ. Effects of Lithium Monotherapy for Bipolar Disorder on Gene Expression in Peripheral Lymphocytes. Mol Neuropsychiatry. 2016;2(3):115-123. PubMed, PubMedCentral, CrossRef
  15. Oedegaard KJ, Alda M, Anand A, Andreassen OA, Balaraman Y, Berrettini WH, Bhattacharjee A, Brennand KJ, Burdick KE, Calabrese JR, Calkin CV, Claasen A, Coryell  WH, Craig D, DeModena A. et al.  The Pharmacogenomics of Bipolar Disorder study (PGBD): identification of genes for lithium response in a prospective sample. BMC Psychiatry. 2016;16:129. PubMed, PubMedCentral, CrossRef
  16. Kim Y, Zhang Y, Pang K, Kang H, Park H, Lee Y, Lee B, Lee HJ, Kim WK, Geum D, Han K. Bipolar Disorder Associated microRNA, miR-1908-5p, Regulates the Expression of Genes Functioning in Neuronal Glutamatergic Synapses. Exp Neurobiol. 2016;25(6):296-306. PubMed, PubMedCentral, CrossRef
  17. Cryns K, Shamir A, Acker NV, Levi I, Daneels G, Goris I, Bouwknecht JA, Andries L, Kass S, Agam G, Belmaker H, Bersudsky Y, Steckler T, Moechars D. IMPA1 is essential for embryonic development and lithium-like pilocarpine sensitivity. Neuropsychopharmacology. 2008;33(3):674-684.  PubMed, CrossRef
  18. Sjøholt G, Ebstein RP, Lie RT,  Berle JØ, Mallet J, Deleuze JF, Levinson DF, Laurent C, Mujahed M, Bannoura I, Murad I, Molven A, Steen VM. Examination of IMPA1 and IMPA2 genes in manic-depressive patients: association between IMPA2 promoter polymorphisms and bipolar disorder. Mol Psychiatry. 2004;9(6):621-629. PubMed, CrossRef
  19. Ohnishi T, Tanizawa Y, Watanabe A, Nakamura T, Ohba H, Hirata H, Kaneda C, Iwayama Y, Arimoto T, Watanabe K, Mori I, Yoshikawa T. Human myo-inositol monophosphatase 2 rescues the nematode thermotaxis mutant ttx-7 more efficiently than IMPA1: functional and evolutionary considerations of the two mammalian myo-inositol monophosphatase genes. J Neurochem. 2013;124(5):685-694. PubMed, CrossRef
  20. Fang J, An X, Chen S, Yu Z, Ma Q, Qu H. Case-control study of GRIA1 and GRIA3 gene variants in migraine. J Headache Pain. 2015;17:2. PubMed, PubMedCentral, CrossRef
  21. Ripka S, Riedel J, Neesse A, Griesmann H, Buchholz M, Ellenrieder V, Moeller F, Bart P, Gress TM, Michl P. Glutamate receptor GRIA3–target of CUX1 and mediator of tumor progression in pancreatic cancer. Neoplasia. 2010;12(8):659-667. PubMed, PubMedCentral, CrossRef
  22. Davies B, Brown LA, Cais O, Watson J, Clayton AJ, Chang VT, Biggs D, Preece C, Hernandez-Pliego P, Krohn J, Bhomra A, Twigg SRF, Rimmer A, Kanapin A. et al. A point mutation in the ion conduction pore of AMPA receptor GRIA3 causes dramatically perturbed sleep patterns as well as intellectual disability. Hum Mol Genet. 2017;26(20):3869-3882. PubMed, PubMedCentral, CrossRef

Creative CommonsThis work is licensed under a Creative Commons Attribution 4.0 International License.