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MIR137 variants identified in psychiatric patients affect synaptogenesis and neuronal transmission gene sets

Abstract

Sequence analysis of 13 microRNA (miRNA) genes expressed in the human brain and located in genomic regions associated with schizophrenia and/or bipolar disorder, in a northern Swedish patient/control population, resulted in the discovery of two functional variants in the MIR137 gene. On the basis of their location and the allele frequency differences between patients and controls, we explored the hypothesis that the discovered variants impact the expression of the mature miRNA and consequently influence global mRNA expression affecting normal brain functioning. Using neuronal-like SH-SY5Y cells, we demonstrated significantly reduced mature miR-137 levels in the cells expressing the variant miRNA gene. Subsequent transcriptome analysis showed that the reduction in miR-137 expression led to the deregulation of gene sets involved in synaptogenesis and neuronal transmission, all implicated in psychiatric disorders. Our functional findings add to the growing data, which implicate that miR-137 has an important role in the etiology of psychiatric disorders and emphasizes its involvement in nervous system development and proper synaptic function.

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Acknowledgements

We are grateful to the patients and control individuals for their cooperation and participation in this research study. We acknowledge the contribution of the personnel of the VIB Genetic Service Facility (www.vibgeneticservicefacility.be) for the genetic analyses, Sofie Goethals and Vicky De Winter for their assistance and expertise in generation of stable cell lines, Bart Aelterman and Jenne Dierckx for their help with the prediction analyses and Professor Dr Kristel Sleegers for the assistance with statistical analysis. We also thank Professor Dr Michel Georges and Dr Haruko Takeda from the University of Liege, Faculty of Veterinary Sciences, for their helpful discussion. This research was funded by grants from the Fund for Scientific Research Flanders (FWO-F), the Institute for the Promotion of Innovation through Science and Technology in Flanders (IWT-F), VIB International PhD Program and Stanley Medical Research Institute. The work was also supported by the Swedish Research Council (grant numbers 2006-4472, 2009-5269, 2009-3413) and the County Councils of Västerbotten and Norrbotten, Sweden. The Betula Study, from which the controls were recruited, is supported by grants from the Swedish Research Council (grant numbers 345-2003-3883, 315-2004-6977) and the Bank of Sweden Tercentenary Foundation, the Swedish Council for Planning and Coordination of Research, the Swedish Council for Research in the Humanities and Social Sciences and the Swedish Council for Social Research.

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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 20, 472–481 (2015). https://doi.org/10.1038/mp.2014.53

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