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Whole Genome Expression Analyses of miRNAs and mRNAs Suggest the Involvement of miR-320a and miR-155-3p and their Targeted Genes in Lithium Response in Bipolar Disorder

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Department of Biomedical Science, Section of Neuroscience and Clinical Pharmacology, University of Cagliari, Monserrato, 09042 Cagliari, Italy
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Consiglio Nazionale delle Ricerche (C.N.R.), Istituto di Ricerca Genetica e Biomedica (I.R.G.B.), Monserrato, 09042 Cagliari, Italy
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Medical Genetics, R. Binaghi Hospital, ASSL Cagliari, ATS Sardegna, 09021 Cagliari, Italy
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Unit of Biostatistics and Bioinformatics, Department of Molecular and Translational Medicine, University of Brescia, 25121 Brescia, Italy
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Big & Open Data Innovation Laboratory, University of Brescia, 25121 Brescia, Italy
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Medical Genetics, Department of Medical Sciences and Public Health, University of Cagliari, 09042 Cagliari, Italy
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Unit of Clinical Pharmacology of the University Hospital of Cagliari, 09042 Cagliari, Italy
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2019, 20(23), 6040; https://doi.org/10.3390/ijms20236040
Received: 12 November 2019 / Revised: 25 November 2019 / Accepted: 27 November 2019 / Published: 30 November 2019
(This article belongs to the Special Issue Pharmacogenomics)
Lithium is the mainstay in the maintenance of bipolar disorder (BD) and the most efficacious pharmacological treatment in suicide prevention. Nevertheless, its use is hampered by a high interindividual variability and important side effects. Genetic and epigenetic factors have been suggested to modulate lithium response, but findings so far have not allowed identifying molecular targets with predictive value. In this study we used next generation sequencing to measure genome-wide miRNA expression in lymphoblastoid cell lines from BD patients excellent responders (ER, n = 12) and non-responders (NR, n = 12) to lithium. These data were integrated with microarray genome-wide expression data to identify pairs of miRNA/mRNA inversely and significantly correlated. Significant pairs were prioritized based on strength of association and in-silico miRNA target prediction analyses to select candidates for validation with qRT-PCR. Thirty-one miRNAs were differentially expressed in ER vs. NR and inversely correlated with 418 genes differentially expressed between the two groups. A total of 331 of these correlations were also predicted by in-silico algorithms. miR-320a and miR-155-3p, as well as three of their targeted genes (CAPNS1 (Calpain Small Subunit 1) and RGS16 (Regulator of G Protein Signaling 16) for miR-320, SP4 (Sp4 Transcription Factor) for miR-155-3p) were validated. These miRNAs and mRNAs were previously implicated in psychiatric disorders (miR-320a and SP4), key processes of the central nervous system (CAPNS1, RGS16, SP4) or pathways involved in mental illnesses (miR-155-3p). Using an integrated approach, we identified miRNAs and their targeted genes potentially involved in lithium response in BD. View Full-Text
Keywords: mood stabilizers; mood disorders; microRNA; miRNA; pharmacogenetics; epigenetics; next generation sequencing mood stabilizers; mood disorders; microRNA; miRNA; pharmacogenetics; epigenetics; next generation sequencing
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Pisanu, C.; Merkouri Papadima, E.; Melis, C.; Congiu, D.; Loizedda, A.; Orrù, N.; Calza, S.; Orrù, S.; Carcassi, C.; Severino, G.; Ardau, R.; Chillotti, C.; Del Zompo, M.; Squassina, A. Whole Genome Expression Analyses of miRNAs and mRNAs Suggest the Involvement of miR-320a and miR-155-3p and their Targeted Genes in Lithium Response in Bipolar Disorder. Int. J. Mol. Sci. 2019, 20, 6040.

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