A study of association of the VNTR MIR-137 rs58335419 with schizophrenia

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Abstract

The MIR137 gene encodes microRNA-137 (miR-137), which is a brain-enriched miR that is highly expressed in various brain regions. miR-137 has been identified as a modulator of processes involved in the pathogenesis of neuropsychiatric disorders. Functional polymorphism of variable number of tandem repeats (VNTR) rs58335419 was found in the regulatory region of the MIR137 gene. It is associated with a change in the expression of miR-137 and, as a result, with an increased risk of developing psychopathologies, including schizophrenia. In this study, we for the first time have analyzed the distribution of frequencies of alleles and genotypes of VNTR MIR137 in a large sample from the Russian population. The association of VNTR with the risk of schizophrenia has been studied. It was found that the presence of VNTR alleles with more than three repeats, as well as a genotype homozygous for such alleles, is associated with an increased risk of developing schizophrenia (OR = 1.4, 95% CI: 1.01-1.95).

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About the authors

G. I. Korovaitseva

Mental Health Research Centre

Author for correspondence.
Email: korovaitseva@mail.ru
Russian Federation, 115522 Moscow

I. V. Oleichik

Mental Health Research Centre

Email: korovaitseva@mail.ru
Russian Federation, 115522 Moscow

T. V. Lezheiko

Mental Health Research Centre

Email: korovaitseva@mail.ru
Russian Federation, 115522 Moscow

V. E. Golimbet

Mental Health Research Centre

Email: golimbet@mail.ru
Russian Federation, 115522 Moscow

References

  1. Stefansson H., Ophof R.A., Steinberg S. et al. Common variants conferring risk of schizophrenia // Nature. 2009. V. 460. № 7256. P. 744–747. https://doi.org/10.1038/nature08186
  2. Gejman P.V., Sanders A.R., Duan J. The role of genetics in the etiology of schizophrenia // Psychiatr. Clin. North Am. 2010. V. 33. № 1. P. 35–66. https://doi.org/10.1016/j.psc.2009.12.003
  3. Polderman T.J., Benyamin B., de Leeuw C.A. et al. Meta-analysis of the heritability of human traits based on fifty years of twin studies // Nat. Genet. 2015. V. 47. № 7. P. 702–709. https://doi.org/10.1038/ng.3285
  4. Trubetskoy V., Pardiña, A.F., Qi T. et al. Mapping genomic loci implicates genes and synaptic biology in schizophrenia // Nature. 2022. V.604. P. 502–508. https://doi.org/10.1038/s41586-022-04434-5
  5. Lam M., Chen C.Y., Li Z. et al. Comparative genetic architectures of schizophrenia in East Asian and European populations // Nat. Genet. 2019. V. 51. № 12. Р. 1670–1678. https://doi.org/10.1038/s41588-019-0512-x
  6. Schizophrenia Working Group of the Psychiatric Genomics Consortium, Ripke S., Walters J.T., O’Donovan M.C. Mapping genomic loci prioritises genes and implicates synaptic biology in schizophrenia // MedRxiv. 2020. https://doi.org/10.1101/2020.09.12.20192922
  7. Jaffe A.E., Straub R.E., Shin J.H. et al. Developmental and genetic regulation of the human cortex transcriptome illuminate schizophrenia pathogenesis // Nat. Neurosci. 2018. V. 21. № 8. Р. 1117–1125. https://doi.org/10.1038/s41593-018-0197-y
  8. Takata A., Matsumoto N., Kato T. Genome-wide identification of splicing QTLs in the human brain and their enrichment among schizophrenia-associated loci // Nat. Commun. 2017. V. 8. P. 14519–14529. https://doi.org/10.1038/ncomms14519
  9. Bakhtiari M., Park J., Ding Y.C. et al. Variable number tandem repeats mediate the expression of proximal genes // Nat. Commun. 2021. V. 12. № 1. P. 2075–2099. https://doi.org/10.1038/s41467-021-22206-z
  10. Eslami R.M., Hernández Y., Drinan S.D. et al. Genome-wide characterization of human minisatellite VNTRs: Population-specific alleles and gene expression differences // Nucleic Acids Res. 2021. V. 49. № 8. P. 4308–4324. https://doi.org/10.1093/nar/gkab224
  11. Mahmoudi E., Atkins J.R., Quidé Y. et al. The MIR137 VNTR rs58335419 is associated with cognitive impairment in schizophrenia and altered cortical morphology // Schizophr. Bull. 2021. V. 47. № 2. P. 495–504. https://doi.org/10.1093/schbul/sbaa123
  12. Warburton A., Breen G., Rujescu D. et al. Characterization of a REST-regulated internal promoter in the schizophrenia genome-wide associated gene MIR137 // Schizophr. Bull. 2015. V. 41. № 3. P. 698–707. ttps://doi.org/10.1093/schbul/sbu117
  13. Li M., Jaffe A.E., Straub R.E. et al. A human-specific AS3MT isoform and BORCS7 are molecular risk factors in the 10q24.32 schizophrenia-associated locus // Nature Med. 2016. V. 22. P. 649–656.https://doi.org/10.1038/nm.4096
  14. Mahmoudi E., Cairns M.J. MiR-137: An important player in neural development and neoplastic transformation // Mol. Psychiatry. 2017. V. 22. № 1. P. 44–55. https://doi.org/10.1038/mp.2016.150
  15. Warburton A., Breen G., Bubb V.J. et al. A GWAS SNP for schizophrenia is linked to the internal MIR137 promoter and supports differential allele-specific expression // Schizophr. Bull. 2016. V. 42. № 4. P. 1003–1008. https://doi.org/10.1093/schbul/sbv144
  16. Pacheco A., Berger R., Freedman R., Law A.J. A VNTR regulates miR-137 expression through novel alternative splicing and contributes to risk for schizophrenia // Sci. Rep. 2019. V. 9. № 1. P. 11793–11804. https://doi.org/10.1038/s41598-019-48141-0
  17. O’Connor R.M., Gururajan A., DinanT.G. et al. All Roads Lead to the miRNome: miRNAs have a central role in the molecular pathophysiology of psychiatric disorders // Trends in pharmacological sciences. 2016. V. 37. № 12. P. 1029–1044. https://doi.org/10.1016/j.tips.2016.10.004
  18. Arakawa Y., Yokoyama K., Tasaki S. et al. Transgenic mice overexpressing miR-137 in the brain show schizophrenia-associated behavioral deficits and transcriptome profiles // PLoS One. 2019. V. 14. № 7. https://doi.org/10.1371/journal.pone.0220389
  19. Forero D.A., van der Ven K., Callaerts P., Del-Favero J. miRNA genes and the brain: Implications for psychiatric disorders // Hum. Mutat. 2010. V. 31. № 11. P. 1195–1204. https://doi.org/10.1002/humu.21344
  20. He E., Lozano M.A.G., Stringer S. et al. MIR137 schizophrenia-associated locus controls synaptic function by regulating synaptogenesis, synapse maturation and synaptic transmission // Hum. Mol. Genet. 2018. V. 27. № 11. P. 1879–1891. https://doi.org/10.1093/hmg/ddy089
  21. Strazisar M., Cammaerts S., van der Ven K. et al. MIR137 variants identified in psychiatric patients affect synaptogenesis and neuronal transmission gene sets // Mol. Psychiatry. 2015. V. 20. № 4. P. 472–481. https://doi.org/10.1038/mp.2014.53
  22. Hill M.J., Donocik J.G., Nuamah R.A. et al. Transcriptional consequences of schizophrenia candidate miR-137 manipulation in human neural progenitor cells // Schizophr. Res. 2014. V. 153. № 1-3. P. 225–230. https://doi.org/10.1016/j.schres.2014.01.034
  23. Siegert S., Seo J., Kwon E.J. et al. The schizophrenia risk gene product miR-137 alters presynaptic plasticity // Nat. Neurosci. 2015. V. 18. № 7. P. 1008–1016.https://doi.org/10.1038/nn.4023
  24. He E., Lozano M.A.G., Stringer S. et al. MIR137 schizophrenia-associated locus controls synaptic function by regulating synaptogenesis, synapse maturation and synaptic transmission // Hum. Mol. Genet. 2018. V. 27. № 11. P. 1879–1891. https://doi.org/10.1093/hmg/ddy089
  25. Collins A.L., Kim Y., Bloom R.J. et al. Transcriptional targets of the schizophrenia risk gene MIR137 // Transl. Psychiatry. 2014. V. 4. № 7. e404. https://doi.org/10.1038/tp.2014.42
  26. Kwon E., Wang W., Tsai L.H. Validation of schizophrenia-associated genes CSMD1, C10orf26, CACNA1C and TCF4 as miR-137 targets // Mol. Psychiatry. 2013. V. 18. P. 11–12. https://doi.org/10.1038/mp.2011.170
  27. Kim A.H., Parker E.K., Williamson V. et al. Experimental validation of candidate schizophrenia gene ZNF804A as target for hsa-miR-137 // Schizophr. Res. 2012. V. 141. № 1. P. 60–64. https://doi.org/10.1016/j.schres.2012.06.038
  28. Agarwal V., Bell G.W., Nam J.-W., Bartel, D.P. Predicting effective microRNA target sites in mammalian mRNAs. // eLife. 2015. V. 4. e05005. https://doi.org/10.7554/eLife.05005
  29. Wright C., Gupta C.N., Chen J. et al. Polymorphisms in MIR137HG and microRNA-137-regulated genes influence gray matter structure in schizophrenia // Transl. Psychiatry. 2016. V. 6. № 2. e724. https://doi.org/10.1038/tp.2015.211
  30. Guella I., Sequeira A., Rollins B. et al. Analysis of miR-137 expression and rs1625579 in dorsolateral prefrontal cortex // J. Psychiatr. Res. 2013. V. 47. № 9. P. 1215–1221. https://doi.org/10.1016/j.jpsychires.2013.05.021
  31. Zhang Z., Yan T., Wang Y. et al. Polymorphism in schizophrenia risk gene MIR137 is associated with the posterior cingulate Cortex’s activation and functional and structural connectivity in healthy controls // Neuroimage Clin. 2018. V. 19. P. 160–166. https://doi.org/10.1016/j.nicl.2018.03.039
  32. Jafari P., Baghernia S., Moghanibashi M., Mohamadynejad P. Significant association of variable number tandem repeat polymorphism rs58335419 in the MIR137 gene with the risk of gastric and colon cancers // Br. J. Biomed. Sci. 2022. V. 79. P. 10095–10099. https://doi.org/10.3389/bjbs.2021.10095
  33. Egawa J., Nunokawa A., Shibuya M. et al. Resequencing and association analysis of MIR137 with schizophrenia in a Japanese population // Psychiatry Clin. Neurosci. 2013. V. 67. № 4. P. 277–279. https://doi.org/10.1111/pcn.12047
  34. Проект “1000 геномов”. http://www.internationalgenome.org
  35. Mamdani M., McMichael G.O., Gadepalli V. et al. Differential regulation of schizophrenia-associated microRNA gene function by variable number tandem repeats (VNTR) polymorphism // Schizophr. Res. 2013. V. 151. № 1–3. P. 284–286. https://doi.org/10.1016/j.schres.2013.10.024
  36. Bemis L.T., Chen R., Amato C.M, et al. MicroRNA-137 targets microphthalmia-associated transcription factor in melanoma cell lines // Cancer Res. 2008. V. 68. P. 1362–1368. https://doi.org/10.1158/0008-5472.CAN-07-2912
  37. González-Giraldo Y., González-Reyes R.E., Forero D.A. A functional variant in MIR137, a candidate gene for schizophrenia, affects Stroop test performance in young adults // Psychiatry. Res. 2016. V. 236. P. 202–205. https://doi.org/10.1016/j.psychres.2016.01.006

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