Abstract
MicroRNAs are about 22 nucleotide long single-stranded RNA molecules, negatively regulating gene expression of a single gene or a gene network. In neural tissues, they have been implicated in developmental and neuroplasticity-related processes, such as neurogenesis, differentiation, apoptosis and long-term potentiation. Their molecular mode of action is reminiscent of findings of genome-wide association studies in mental disorders, unable to attribute the risk of disease to a specific gene, but rather to multiple genes, gene-networks and gene-environment interaction. As such, microRNAs are an attractive target for research. Here, we review clinical studies conducted in humans on microRNAs in mental disorders with a particular focus on schizophrenia, bipolar disorder, major depressive disorder and anxiety disorders. The majority of clinical studies have focused on schizophrenia. The most robust finding has been reported for rs1625579 located in MIR137HG, which was associated with schizophrenia on a genome-wide level. Concerning bipolar disorder, major depression and anxiety disorders, promising results have been published, but only a considerably smaller number of clinical studies is available and genome-wide association studies did not suggest a direct link to microRNAs so far. Expression of microRNAs as biomarkers of mental disorders and treatment response is currently emerging with preliminary results. Larger-scaled genetic and functional studies along with translational research are needed to enhance our understanding of microRNAs in mental disorders. These studies will aid in disentangling the complex genetic nature of these disorders and possibly contribute to the development of novel, individualized diagnostic and therapeutic approaches.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Abu-Elneel K, Liu T, Gazzaniga FS et al (2008) Heterogeneous dysregulation of microRNAs across the autism spectrum. Neurogenetics 9:153–161. doi:10.1007/s10048-008-0133-5
Ambros V (2004) The functions of animal microRNAs. Nature 431:350–355. doi:10.1038/nature02871
Ambros V, Bartel B, Bartel DP et al (2003) A uniform system for microRNA annotation. RNA 9:277–279. doi:10.1261/rna.2183803
Angelucci F, Croce N, Spalletta G et al (2011) Paroxetine rapidly modulates the expression of brain-derived neurotrophic factor mRNA and protein in a human glioblastoma-astrocytoma cell line. Pharmacology 87:5–10. doi:10.1159/000322528
Armengol L, Gratacòs M, Pujana MA et al (2002) 5′ UTR-region SNP in the NTRK3 gene is associated with panic disorder. Mol Psychiatry 7:928–930. doi:10.1038/sj.mp.4001134
Arnold M, Ellwanger DC, Hartsperger ML et al (2012) Cis-acting polymorphisms affect complex traits through modifications of microRNA regulation pathways. PLoS One 7:e36694. doi:10.1371/journal.pone.0036694
Banigan MG, Kao PF, Kozubek JA et al (2013) Differential expression of exosomal microRNAs in prefrontal cortices of schizophrenia and bipolar disorder patients. PLoS One 8:e48814. doi:10.1371/journal.pone.0048814
Barry G (2014) Integrating the roles of long and small non-coding RNA in brain function and disease. Mol Psychiatry 19:410–416. doi:10.1038/mp.2013.196
Bartel DP (2004) MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116:281–297. doi:10.1016/S0092-8674(04)00045-5
Bartel DP, Chen C-Z (2004) Micromanagers of gene expression: the potentially widespread influence of metazoan microRNAs. Nat Rev Genet 5:396–400. doi:10.1038/nrg1328
Baudry A, Mouillet-Richard S, Schneider B et al (2010) miR-16 targets the serotonin transporter: a new facet for adaptive responses to antidepressants. Science 329:1537–1541. doi:10.1126/science.1193692
Begemann M, Grube S, Papiol S et al (2010) Modification of cognitive performance in schizophrenia by complexin 2 gene polymorphisms. Arch Gen Psychiatry 67:879–888. doi:10.1001/archgenpsychiatry.2010.107
Belzeaux R, Bergon A, Jeanjean V et al (2012) Responder and nonresponder patients exhibit different peripheral transcriptional signatures during major depressive episode. Transl Psychiatry 2:e185. doi:10.1038/tp.2012.112
Beveridge NJ, Tooney PA, Carroll AP et al (2008) Dysregulation of miRNA 181b in the temporal cortex in schizophrenia. Hum Mol Genet 17:1156–1168. doi:10.1093/hmg/ddn005
Beveridge NJ, Gardiner E, Carroll AP et al (2010) Schizophrenia is associated with an increase in cortical microRNA biogenesis. Mol Psychiatry 15:1176–1189. doi:10.1038/mp.2009.84
Bhattacharya A, Ziebarth JD, Cui Y (2014) PolymiRTS Database 3.0: linking polymorphisms in microRNAs and their target sites with human diseases and biological pathways. Nucleic Acids Res 42:D86–D91. doi:10.1093/nar/gkt1028
Bocchio-Chiavetto L, Maffioletti E, Bettinsoli P et al (2013) Blood microRNA changes in depressed patients during antidepressant treatment. Eur Neuropsychopharmacol 23:602–611. doi:10.1016/j.euroneuro.2012.06.013
Boudreau RL, Jiang P, Gilmore BL et al (2014) Transcriptome-wide Discovery of microRNA Binding Sites in Human Brain. Neuron 81:294–305. doi:10.1016/j.neuron.2013.10.062
Bouwknecht JA, Hijzen TH, van der Gugten J et al (2001) Absence of 5-HT(1B) receptors is associated with impaired impulse control in male 5-HT(1B) knockout mice. Biol Psychiatry 49:557–568
Bowman FD (2014) Brain Imaging Analysis. Annu Rev Stat Appl 1:61–85. doi:10.1146/annurev-statistics-022513-115611
Burmistrova OA, Goltsov AY, Abramova LI et al (2007) MicroRNA in schizophrenia: genetic and expression analysis of miR-130b (22q11). Biochemistry Mosc 72:578–582. doi:10.1134/S0006297907050161
Cao G, Huang B, Liu Z et al (2010) Intronic miR-301 feedback regulates its host gene, ska2, in A549 cells by targeting MEOX2 to affect ERK/CREB pathways. Biochem Biophys Res Commun 396:978–982. doi:10.1016/j.bbrc.2010.05.037
Caputo V, Sinibaldi L, Fiorentino A et al (2011) Brain derived neurotrophic factor (BDNF) expression is regulated by microRNAs miR-26a and miR-26b allele-specific binding. PLoS One 6:e28656. doi:10.1371/journal.pone.0028656
Chen H, Wang N, Burmeister M, McInnis MG (2009) MicroRNA expression changes in lymphoblastoid cell lines in response to lithium treatment. Int J Neuropsychopharmacol 12:975–981. doi:10.1017/S1461145709000029
Cheng L-C, Pastrana E, Tavazoie M, Doetsch F (2009) miR-124 regulates adult neurogenesis in the subventricular zone stem cell niche. Nat Neurosci 12:399–408. doi:10.1038/nn.2294
Cimmino A, Calin GA, Fabbri M et al (2005) miR-15 and miR-16 induce apoptosis by targeting BCL2. PNAS 102:13944–13949. doi:10.1073/pnas.0506654102
Cogswell JP, Ward J, Taylor IA et al (2008) Identification of miRNA changes in Alzheimer’s disease brain and CSF yields putative biomarkers and insights into disease pathways. J Alzheimers Dis 14:27–41
Conner TS, Jensen KP, Tennen H et al (2010) Functional polymorphisms in the serotonin 1B receptor gene (HTR1B) predict self-reported anger and hostility among young men. Am J Med Genet B Neuropsychiatr Genet 153B:67–78. doi:10.1002/ajmg.b.30955
Cousijn H, Eissing M, Fernández G et al (2014) No effect of schizophrenia risk genes MIR137, TCF4, and ZNF804A on macroscopic brain structure. Schizophr Res. doi:10.1016/j.schres.2014.08.007 (ahead of print)
Cross-Disorder Group of the Psychiatric Genomics Consortium (2013a) Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis. Lancet 381:1371–1379. doi:10.1016/S0140-6736(12)62129-1
Cross-Disorder Group of the Psychiatric Genomics Consortium (2013b) Genetic relationship between five psychiatric disorders estimated from genome-wide SNPs. Nat Genet 45:984–994. doi:10.1038/ng.2711
Cummings E, Donohoe G, Hargreaves A et al (2013) Mood congruent psychotic symptoms and specific cognitive deficits in carriers of the novel schizophrenia risk variant at MIR-137. Neurosci Lett 532:33–38. doi:10.1016/j.neulet.2012.08.065
Davis MJ, Iancu OD, Acher FC et al (2013) Role of mGluR4 in acquisition of fear learning and memory. Neuropharmacology 66:365–372. doi:10.1016/j.neuropharm.2012.07.038
Decoster J, De Hert M, Viechtbauer W et al (2012) Genetic association study of the P300 endophenotype in schizophrenia. Schizophr Res 141:54–59. doi:10.1016/j.schres.2012.07.018
Devanna P, Vernes SC (2014) A direct molecular link between the autism candidate gene RORa and the schizophrenia candidate MIR137. Sci Rep 4:3994. doi:10.1038/srep03994
Domschke K, Dannlowski U (2010) Imaging genetics of anxiety disorders. Neuroimage 53:822–831. doi:10.1016/j.neuroimage.2009.11.042
Domschke K, Deckert J (2012) Genetics of anxiety disorders—status quo and quo vadis. Curr Pharm Des 18:5691–5698
Donner J, Pirkola S, Silander K et al (2008) An association analysis of murine anxiety genes in humans implicates novel candidate genes for anxiety disorders. Biol Psychiatry 64:672–680. doi:10.1016/j.biopsych.2008.06.002
Dwivedi Y (2014) Emerging role of microRNAs in major depressive disorder: diagnosis and therapeutic implications. Dialogues Clin Neurosci 16:43–61
Egawa J, Nunokawa A, Shibuya M et al (2013) Resequencing and association analysis of MIR137 with schizophrenia in a Japanese population. Psychiatry Clin Neurosci 67:277–279. doi:10.1111/pcn.12047
Feng J, Sun G, Yan J et al (2009) Evidence for X-chromosomal schizophrenia associated with microRNA alterations. PLoS One 4:e6121. doi:10.1371/journal.pone.0006121
Flint J, Kendler KS (2014) The genetics of major depression. Neuron 81:484–503. doi:10.1016/j.neuron.2014.01.027
Forstner AJ, Basmanav FB, Mattheisen M et al (2014) Investigation of the involvement of MIR185 and its target genes in the development of schizophrenia. J Psychiatry Neurosci 39:386–396. doi:10.1503/jpn.130189
Friedman RC, Farh KK-H, Burge CB, Bartel DP (2009) Most mammalian mRNAs are conserved targets of microRNAs. Genome Res 19:92–105. doi:10.1101/gr.082701.108
Garbett KA, Vereczkei A, Kálmán S et al (2014) Coordinated Messenger RNA/MicroRNA Changes in Fibroblasts of Patients with Major Depression. Biol Psychiatry. doi:10.1016/j.biopsych.2014.05.015 [Epub ahead of print]
Gardiner E, Beveridge NJ, Wu JQ et al (2012) Imprinted DLK1-DIO3 region of 14q32 defines a schizophrenia-associated miRNA signature in peripheral blood mononuclear cells. Mol Psychiatry 17:827–840. doi:10.1038/mp.2011.78
Girgenti MJ, LoTurco JJ, Maher BJ (2012) ZNF804a Regulates Expression of the Schizophrenia-Associated Genes PRSS16, COMT, PDE4B, and DRD2. PLoS One 7(2):e32404. doi:10.1371/journal.pone.0032404
Gong Y, Wu CN, Xu J et al (2013) Polymorphisms in microRNA target sites influence susceptibility to schizophrenia by altering the binding of miRNAs to their targets. Eur Neuropsychopharm 23:1182–1189. doi:10.1016/j.euroneuro.2012.12.002
Green MJ, Cairns MJ, Wu J et al (2013) Genome-wide supported variant MIR137 and severe negative symptoms predict membership of an impaired cognitive subtype of schizophrenia. Mol Psychiatry 18:774–780. doi:10.1038/mp.2012.84
Griffiths-Jones S, Grocock RJ, van Dongen S et al (2006) miRBase: microRNA sequences, targets and gene nomenclature. Nucleic Acids Res 24(suppl 1):D140–D144. doi:10.1093/nar/gkj112
Grimson A, Farh KK-H, Johnston WK et al (2007) MicroRNA targeting specificity in mammals: determinants beyond seed pairing. Mol Cell 27:91–105. doi:10.1016/j.molcel.2007.06.017
Guan F, Zhang B, Yan T et al (2014) MIR137 gene and target gene CACNA1C of miR-137 contribute to schizophrenia susceptibility in Han Chinese. Schizophr Res 152:97–104. doi:10.1016/j.schres.2013.11.004
Guella I, Sequeira A, Rollins B et al (2013) Analysis of miR-137 expression and rs1625579 in dorsolateral prefrontal cortex. J Psychiatr Res 47:1215–1221. doi:10.1016/j.jpsychires.2013.05.021
Guintivano J, Brown T, Newcomer A et al (2014) Identification and Replication of a Combined Epigenetic and Genetic Biomarker Predicting Suicide and Suicidal Behaviors. Am J Psychiatry. doi:10.1176/appi.ajp.2014.14010008 [Epub ahead of print]
Hall M-H, Levy DL, Salisbury DF et al (2014) Neurophysiologic effect of GWAS derived schizophrenia and bipolar risk variants. Am J Med Genet B Neuropsychiatr Genet 165B:9–18. doi:10.1002/ajmg.b.32212
Halmai Z, Dome P, Vereczkei A et al (2013) Associations between depression severity and purinergic receptor P2RX7 gene polymorphisms. J Affect Disord 150:104–109. doi:10.1016/j.jad.2013.02.033
Han M, Zheng Y (2013) Comprehensive analysis of single nucleotide polymorphisms in human microRNAs. PLoS One 8:e78028. doi:10.1371/journal.pone.0078028
Hanin G, Shenhar-Tsarfaty S, Yayon N et al (2014) Competing targets of microRNA-608 affect anxiety and hypertension. Hum Mol Genet 23:4569–4580. doi:10.1093/hmg/ddu170
Hansen KF, Obrietan K (2013) MicroRNA as therapeutic targets for treatment of depression. Neuropsychiatr Dis Treat 9:1011–1021. doi:10.2147/NDT.S34811
Hansen T, Olsen L, Lindow M et al (2007) Brain expressed microRNAs implicated in schizophrenia etiology. PLoS One 2:e873. doi:10.1371/journal.pone.0000873
He Y, Zhou Y, Xi Q et al (2012) Genetic variations in microRNA processing genes are associated with susceptibility in depression. DNA Cell Biol 31:1499–1506. doi:10.1089/dna.2012.1660
Honda M, Kuwano Y, Katsuura-Kamano S et al (2013) Chronic academic stress increases a group of microRNAs in peripheral blood. PLoS One 8:e75960. doi:10.1371/journal.pone.0075960
Hu HY, Guo S, Xi J et al (2011) MicroRNA expression and regulation in human, chimpanzee, and macaque brains. PLoS Genet 7:e1002327. doi:10.1371/journal.pgen.1002327
Im H-I, Kenny PJ (2012) MicroRNAs in neuronal function and dysfunction. Trends Neurosci 35:325–334. doi:10.1016/j.tins.2012.01.004
Ioannidis JPA (2005) Microarrays and molecular research: noise discovery? Lancet 365:454–455. doi:10.1016/S0140-6736(05)17878-7
Issler O, Haramati S, Paul ED et al (2014) MicroRNA 135 is essential for chronic stress resiliency, antidepressant efficacy, and intact serotonergic activity. Neuron 83:344–360. doi:10.1016/j.neuron.2014.05.042
Jensen KP, Covault J (2011) Human miR-1271 is a miR-96 paralog with distinct non-conserved brain expression pattern. Nucleic Acids Res 39:701–711. doi:10.1093/nar/gkq798
Jensen KP, Covault J, Conner TS et al (2009) A common polymorphism in serotonin receptor 1B mRNA moderates regulation by miR-96 and associates with aggressive human behaviors. Mol Psychiatry 14:381–389. doi:10.1038/mp.2008.15
Jensen KP, Kranzler HR, Stein MB, Gelernter J (2014) The effects of a MAP2K5 microRNA target site SNP on risk for anxiety and depressive disorders. Am J Med Genet B Neuropsychiatr Genet 165:175–183. doi:10.1002/ajmg.b.32219
Johnston RJ, Chang S, Etchberger JF et al (2005) MicroRNAs acting in a double-negative feedback loop to control a neuronal cell fate decision. Proc Natl Acad Sci USA 102:12449–12454. doi:10.1073/pnas.0505530102
Kandaswamy R, McQuillin A, Curtis D, Gurling H (2014) Allelic association, DNA resequencing and copy number variation at the metabotropic glutamate receptor GRM7 gene locus in bipolar disorder. Am J Med Genet B Neuropsychiatr Genet 165B:365–372. doi:10.1002/ajmg.b.32239
Katsuura S, Kuwano Y, Yamagishi N et al (2012) MicroRNAs miR-144/144* and miR-16 in peripheral blood are potential biomarkers for naturalistic stress in healthy Japanese medical students. Neurosci Lett 516:79–84. doi:10.1016/j.neulet.2012.03.062
Kelly S, Morris DW, Mothersill O et al (2014) Genome-wide schizophrenia variant at MIR137 does not impact white matter microstructure in healthy participants. Neurosci Lett 574:6–10. doi:10.1016/j.neulet.2014.05.002
Kendler KS (2013) What psychiatric genetics has taught us about the nature of psychiatric illness and what is left to learn. Mol Psychiatry 18:1058–1066. doi:10.1038/mp.2013.50
Kertesz M, Iovino N, Unnerstall U et al (2007) The role of site accessibility in microRNA target recognition. Nat Genet 39:1278–1284. doi:10.1038/ng2135
Kim J, Bartel DP (2009) Allelic imbalance sequencing reveals that single-nucleotide polymorphisms frequently alter microRNA-directed repression. Nat Biotechnol 27:472–477. doi:10.1038/nbt.1540
Kim VN, Nam J-W (2006) Genomics of microRNA. Trends Genet 22:165–173. doi:10.1016/j.tig.2006.01.003
Kim JW, Biederman J, Arbeitman L et al (2007) Investigation of variation in SNAP-25 and ADHD and relationship to co-morbid major depressive disorder. Am J Med Genet B Neuropsychiatr Genet 144B:781–790. doi:10.1002/ajmg.b.30522
Kim AH, Reimers M, Maher B et al (2010) MicroRNA expression profiling in the prefrontal cortex of individuals affected with schizophrenia and bipolar disorders. Schizophr Res 124:183–191. doi:10.1016/j.schres.2010.07.002
Kim AH, Parker EK, Williamson V et al (2012) Experimental validation of candidate schizophrenia gene ZNF804A as target for hsa-miR-137. Schizophr Res 141:60–64. doi:10.1016/j.schres.2012.06.038
Klein ME, Lioy DT, Ma L et al (2007) Homeostatic regulation of MeCP2 expression by a CREB-induced microRNA. Nat Neurosci 10:1513–1514. doi:10.1038/nn2010
Kocerha J, Faghihi MA, Lopez-Toledano MA et al (2009) MicroRNA-219 modulates NMDA receptor-mediated neurobehavioral dysfunction. Proc Natl Acad Sci USA 106:3507–3512. doi:10.1073/pnas.0805854106
Kohen R, Dobra A, Tracy JH, Haugen E (2014) Transcriptome profiling of human hippocampus dentate gyrus granule cells in mental illness. Transl Psychiatry 4:e366. doi:10.1038/tp.2014.9
Kolshus E, Dalton VS, Ryan KM, McLoughlin DM (2013) When less is more—microRNAs and psychiatric disorders. Acta Psychiatr Scand 129:241–256. doi:10.1111/acps.12191
Kosik KS (2006) The neuronal microRNA system. Nat Rev Neurosci 7:911–920. doi:10.1038/nrn2037
Kovacs-Nagy R, Elek Z, Szekely A et al (2013) Association of aggression with a novel microRNA binding site polymorphism in the wolframin gene. Am J Med Genet B Neuropsychiatr Genet 162B:404–412. doi:10.1002/ajmg.b.32157
Kozomara A, Griffiths-Jones S (2014) miRBase: annotating high confidence microRNAs using deep sequencing data. Nucleic Acids Res 42:D68–D73. doi:10.1093/nar/gkt1181
Kulshreshtha R, Ferracin M, Wojcik SE et al (2007) A microRNA signature of hypoxia. Mol Cell Biol 27:1859–1867. doi:10.1128/MCB.01395-06
Kwon E, Wang W, Tsai L-H (2013) Validation of schizophrenia-associated genes CSMD1, C10orf26, CACNA1C and TCF4 as miR-137 targets. Mol Psychiatry 18:11–12. doi:10.1038/mp.2011.170
Lai C-Y, Yu S-L, Hsieh MH et al (2011) MicroRNA expression aberration as potential peripheral blood biomarkers for schizophrenia. PLoS One 6:e21635. doi:10.1371/journal.pone.0021635
Landgraf P, Rusu M, Sheridan R et al (2007) A mammalian microRNA expression atlas based on small RNA library sequencing. Cell 129:1401–1414. doi:10.1016/j.cell.2007.04.040
Lee RC, Feinbaum RL, Ambros V (1993) The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell 75:843–854. doi:10.1016/0092-8674(93)90529-Y
Lett TA, Chakravarty MM, Chakavarty MM et al (2013) The genome-wide supported microRNA-137 variant predicts phenotypic heterogeneity within schizophrenia. Mol Psychiatry 18:443–450. doi:10.1038/mp.2013.17
Lewis MA, Quint E, Glazier AM et al (2009) An ENU-induced mutation of miR-96 associated with progressive hearing loss in mice. Nat Genet 41:614–618. doi:10.1038/ng.369
Li M, Su B (2013) Impact of the genome-wide schizophrenia risk single nucleotide polymorphism (rs1625579) in miR-137 on brain structures in healthy individuals. Psychiatr Genet 23:267. doi:10.1097/YPG.0000000000000011
Li M, Wang Y, Zheng X-B et al (2012) Meta-analysis and brain imaging data support the involvement of VRK2 (rs2312147) in schizophrenia susceptibility. Schizophr Res 142:200–205. doi:10.1016/j.schres.2012.10.008
Li J, Li J, Liu X et al (2013a) MicroRNA expression profile and functional analysis reveal that miR-382 is a critical novel gene of alcohol addiction. EMBO Mol Med 5:1402–1414. doi:10.1002/emmm.201201900
Li Y-J, Xu M, Gao Z-H et al (2013b) Alterations of serum levels of BDNF-related miRNAs in patients with depression. PLoS One 8:e63648. doi:10.1371/journal.pone.0063648
Liu S, Yuan Y-B, Guan L-L et al (2013) MiRNA-365 and miRNA-520c-3p respond to risperidone treatment in first-episode schizophrenia after a 1 year remission. Chin Med J 126:2676–2680
Liu B, Zhang X, Hou B et al (2014) The Impact of MIR137 on Dorsolateral Prefrontal-Hippocampal Functional Connectivity in Healthy Subjects. Neuropsychopharmacol 39:2153–2160. doi:10.1038/npp.2014.63
Lopez JP, Fiori LM, Gross JA et al (2014a) Regulatory role of miRNAs in polyamine gene expression in the prefrontal cortex of depressed suicide completers. Int J Neuropsychopharmacol 17:23–32. doi:10.1017/S1461145713000941
Lopez JP, Lim R, Cruceanu C et al (2014b) miR-1202 is a primate-specific and brain-enriched microRNA involved in major depression and antidepressant treatment. Nat Med 20:764–768. doi:10.1038/nm.3582
Lugli G, Larson J, Demars MP, Smalheiser NR (2012) Primary microRNA precursor transcripts are localized at post-synaptic densities in adult mouse forebrain. J Neurochem 123:459–466. doi:10.1111/j.1471-4159.2012.07921.x
Ma G, Yin J, Fu J et al (2014) Association of a miRNA-137 Polymorphism with Schizophrenia in a Southern Chinese Han Population. Biomed Res Int 2014:751267–751268. doi:10.1155/2014/751267
Maffioletti E, Tardito D, Gennarelli M, Bocchio-Chiavetto L (2014) Micro spies from the brain to the periphery: new clues from studies on microRNAs in neuropsychiatric disorders. Front Cell Neurosci 8:75. doi:10.3389/fncel.2014.00075
Major Depressive Disorder Working Group of the Psychiatric GWAS Consortium (2013) A mega-analysis of genome-wide association studies for major depressive disorder. Mol Psychiatry 18:497–511. doi:10.1038/mp.2012.2
Malan-Müller S, Hemmings SMJ, Seedat S (2013) Big effects of small RNAs: a review of microRNAs in anxiety. Mol Neurobiol 47:726–739. doi:10.1007/s12035-012-8374-6
Mamdani M, McMichael GO, Gadepalli V et al (2013) Differential regulation of schizophrenia-associated microRNA gene function by variable number tandem repeats (VNTR) polymorphism. Schizophr Res 151:284–286. doi:10.1016/j.schres.2013.10.024
Marmol F (2008) Lithium: bipolar disorder and neurodegenerative diseases Possible cellular mechanisms of the therapeutic effects of lithium. Prog Neuropsychopharmacol Biol Psychiatry 32:1761–1771. doi:10.1016/j.pnpbp.2008.08.012
McNeill E, Van Vactor D (2012) MicroRNAs shape the neuronal landscape. Neuron 75:363–379. doi:10.1016/j.neuron.2012.07.005
Mellios N, Huang H-S, Baker SP et al (2009) Molecular determinants of dysregulated GABAergic gene expression in the prefrontal cortex of subjects with schizophrenia. Biol Psychiatry 65:1006–1014. doi:10.1016/j.biopsych.2008.11.019
Mellios N, Galdzicka M, Ginns E et al (2012) Gender-specific reduction of estrogen-sensitive small RNA, miR-30b, in subjects With schizophrenia. Schizophr Bull 38:433–443. doi:10.1093/schbul/sbq091
Mencía A, Modamio-Høybjør S, Redshaw N et al (2009) Mutations in the seed region of human miR-96 are responsible for nonsyndromic progressive hearing loss. Nat Genet 41:609–613. doi:10.1038/ng.355
Meyer-Lindenberg A, Weinberger DR (2006) Intermediate phenotypes and genetic mechanisms of psychiatric disorders. Nat Rev Neurosci 7:818–827. doi:10.1038/nrn1993
Miller BH, Zeier Z, Xi L et al (2012) MicroRNA-132 dysregulation in schizophrenia has implications for both neurodevelopment and adult brain function. Proc Natl Acad Sci USA 109:3125–3130. doi:10.1073/pnas.1113793109
Mor E, Kano S-I, Colantuoni C et al (2013) MicroRNA-382 expression is elevated in the olfactory neuroepithelium of schizophrenia patients. Neurobiol Dis 55:1–10. doi:10.1016/j.nbd.2013.03.011
Moreau MP, Bruse SE, David-Rus R et al (2011) Altered microRNA expression profiles in postmortem brain samples from individuals with schizophrenia and bipolar disorder. Biol Psychiatry 69:188–193. doi:10.1016/j.biopsych.2010.09.039
Mothersill O, Morris DW, Kelly S et al (2014) Effects of MIR137 on fronto-amygdala functional connectivity. Neuroimage 90:189–195. doi:10.1016/j.neuroimage.2013.12.019
Mouillet-Richard S, Baudry A, Launay J-M, Kellermann O (2012) MicroRNAs and depression. Neurobiol Dis 46:272–278. doi:10.1016/j.nbd.2011.12.035
Moya PR, Wendland JR, Salemme J et al (2013) miR-15a and miR-16 regulate serotonin transporter expression in human placental and rat brain raphe cells. Int J Neuropsychopharmacol 16:621–629. doi:10.1017/S1461145712000454
Mu W, Zhang W (2012) Bioinformatic Resources of microRNA Sequences, Gene Targets, and Genetic Variation. Front Genet 3:31. doi:10.3389/fgene.2012.00031
Muiños-Gimeno M, Guidi M, Kagerbauer B et al (2009) Allele variants in functional MicroRNA target sites of the neurotrophin-3 receptor gene (NTRK3) as susceptibility factors for anxiety disorders. Hum Mutat 30:1062–1071. doi:10.1002/humu.21005
Muiños-Gimeno M, Espinosa-Parrilla Y, Guidi M et al (2011) Human microRNAs miR-22, miR-138-2, miR-148a, and miR-488 are associated with panic disorder and regulate several anxiety candidate genes and related pathways. Biol Psychiatry 69:526–533. doi:10.1016/j.biopsych.2010.10.010
Mundalil Vasu M, Anitha A, Thanseem I et al (2014) Serum microRNA profiles in children with autism. Mol Autism 5:40. doi:10.1186/2040-2392-5-40
Németh N, Kovacs-Nagy R, Szekely A et al (2013) Association of impulsivity and polymorphic microRNA-641 target sites in the SNAP-25 gene. PLoS One 8:e84207. doi:10.1371/journal.pone.0084207
Oved K, Morag A, Pasmanik-Chor M et al (2012) Genome-wide miRNA expression profiling of human lymphoblastoid cell lines identifies tentative SSRI antidepressant response biomarkers. Pharmacogenomics 13:1129–1139. doi:10.2217/pgs.12.93
Oved K, Morag A, Pasmanik-Chor M et al (2013) Genome-wide expression profiling of human lymphoblastoid cell lines implicates integrin beta-3 in the mode of action of antidepressants. Transl Psychiatry 3:e313. doi:10.1038/tp.2013.86
Peng G, Yuan Y, He Q et al (2011) MicroRNA let-7e regulates the expression of caspase-3 during apoptosis of PC12 cells following anoxia/reoxygenation injury. Brain Res Bull 86:272–276. doi:10.1016/j.brainresbull.2011.07.017
Perkins DO, Jeffries CD, Jarskog LF et al (2007) microRNA expression in the prefrontal cortex of individuals with schizophrenia and schizoaffective disorder. Genome Biol 8:R27. doi:10.1186/gb-2007-8-2-r27
Peterson SM, Thompson JA, Ufkin ML et al (2014) Common features of microRNA target prediction tools. Front Genet 5:23. doi:10.3389/fgene.2014.00023
Psychiatric GWAS Consortium Bipolar Disorder Working Group (2011) Large-scale genome-wide association analysis of bipolar disorder identifies a new susceptibility locus near ODZ4. Nat Genet 43:977–983. doi:10.1038/ng.943
Psychosis Endophenotypes International Consortium et al, Wellcome Trust Case Control Consortium 2, Bramon E et al (2014) A genome-wide association analysis of a broad psychosis phenotype identifies three loci for further investigation. Biol Psychiatry 75:386–397. doi:10.1016/j.biopsych.2013.03.033
Rahman OA, Sasvari-Szekely M, Szekely A et al (2010) Analysis of a polymorphic microRNA target site in the purinergic receptor P2RX7 gene. Electrophoresis 31:1790–1795. doi:10.1002/elps.200900664
Rajasethupathy P, Fiumara F, Sheridan R et al (2009) Characterization of small RNAs in Aplysia reveals a role for miR-124 in constraining synaptic plasticity through CREB. Neuron 63:803–817. doi:10.1016/j.neuron.2009.05.029
Ripke S, O’Dushlaine C, Chambert K et al (2013) Genome-wide association analysis identifies 13 new risk loci for schizophrenia. Nat Genet 45:1150–1159. doi:10.1038/ng.2742
Rong H, Liu TB, Yang KJ et al (2011) MicroRNA-134 plasma levels before and after treatment for bipolar mania. J Psychiatr Res 45:92–95. doi:10.1016/j.jpsychires.2010.04.028
Rose EJ, Morris DW, Fahey C et al (2014) The miR-137 schizophrenia susceptibility variant rs1625579 does not predict variability in brain volume in a sample of schizophrenic patients and healthy individuals. Am J Med Genet B Neuropsychiatr Genet 165B:467–471. doi:10.1002/ajmg.b.32249
Rossi M, Kilpinen H, Muona M et al (2014) Allele-specific regulation of DISC1 expression by miR-135b-5p. Eur J Hum Genet 22:840–843. doi:10.1038/ejhg.2013.246
Ryan BM, Robles AI, Harris CC (2010) Genetic variation in microRNA networks: the implications for cancer research. Nat Rev Cancer 10:389–402. doi:10.1038/nrc2867
Sánchez-Mora C, Ramos-Quiroga J-A, Garcia-Martínez I et al (2013) Evaluation of single nucleotide polymorphisms in the miR-183-96-182 cluster in adulthood attention-deficit and hyperactivity disorder (ADHD) and substance use disorders (SUDs). Eur Neuropsychopharmacol J Eur Coll Neuropsychopharmacol 23:1463–1473. doi:10.1016/j.euroneuro.2013.07.002
Sanders AR, Göring HHH, Duan J et al (2013) Transcriptome study of differential expression in schizophrenia. Hum Mol Genet 22:5001–5014. doi:10.1093/hmg/ddt350
Santarelli DM, Beveridge NJ, Tooney PA, Cairns MJ (2011) Upregulation of dicer and microRNA expression in the dorsolateral prefrontal cortex Brodmann area 46 in schizophrenia. Biol Psychiatry 69:180–187. doi:10.1016/j.biopsych.2010.09.030
Saudou F, Amara DA, Dierich A et al (1994) Enhanced aggressive behavior in mice lacking 5-HT1B receptor. Science 265:1875–1878
Saus E, Soria V, Escaramís G et al (2010) Genetic variants and abnormal processing of pre-miR-182, a circadian clock modulator, in major depression patients with late insomnia. Hum Mol Genet 19:4017–4025. doi:10.1093/hmg/ddq316
Sayed D, Abdellatif M (2011) MicroRNAs in development and disease. Physiol Rev 91:827–887. doi:10.1152/physrev.00006.2010
Scarr E, Craig JM, Cairns MJ et al (2013) Decreased cortical muscarinic M1 receptors in schizophrenia are associated with changes in gene promoter methylation, mRNA and gene targeting microRNA. Transl Psychiatry 3:e230–e239. doi:10.1038/tp.2013.3
Schratt GM (2009a) Fine-tuning neural gene expression with microRNAs. Curr Opin Neurobiol 19:213–219. doi:10.1016/j.conb.2009.05.015
Schratt GM (2009b) microRNAs at the synapse. Nat Rev Neurosci 10:842–849. doi:10.1038/nrn2763
Schratt GM, Tuebing F, Nigh EA et al (2006) A brain-specific microRNA regulates dendritic spine development. Nature 439:283–289. doi:10.1038/nature04367
Schröder J, Ansaloni S, Schilling M et al (2014) MicroRNA-138 is a potential regulator of memory performance in humans. Front Hum Neurosci 8:501. doi:10.3389/fnhum.2014.00501
Serafini G, Pompili M, Innamorati M et al (2012) The role of microRNAs in synaptic plasticity, major affective disorders and suicidal behavior. Neurosci Res 73:179–190. doi:10.1016/j.neures.2012.04.001
Sethupathy P, Collins FS (2008) MicroRNA target site polymorphisms and human disease. Trends Genet 24:489–497. doi:10.1016/j.tig.2008.07.004
Sethupathy P, Megraw M, Hatzigeorgiou AG (2006) A guide through present computational approaches for the identification of mammalian microRNA targets. Nat Methods 3:881–886. doi:10.1038/nmeth954
Shao N-Y, Hu HY, Yan Z et al (2010) Comprehensive survey of human brain microRNA by deep sequencing. BMC Genom 11:409. doi:10.1186/1471-2164-11-409
Shi W, Du J, Qi Y et al (2012) Aberrant expression of serum miRNAs in schizophrenia. J Psychiatr Res 46:198–204. doi:10.1016/j.jpsychires.2011.09.010
Shi S, Leites C, He D et al (2014) MicroRNA-9 and microrna-326 regulate human dopamine D2 receptor expression, and the microRNA-mediated expression regulation is altered by a genetic variant. J Biol Chem 289:13434–13444. doi:10.1074/jbc.M113.535203
Siegel G, Obernosterer G, Fiore R et al (2009) A functional screen implicates microRNA-138-dependent regulation of the depalmitoylation enzyme APT1 in dendritic spine morphogenesis. Nat Cell Biol 11:705–716. doi:10.1038/ncb1876
Smalheiser NR, Lugli G, Rizavi HS et al (2011) MicroRNA expression in rat brain exposed to repeated inescapable shock: differential alterations in learned helplessness vs. non-learned helplessness. Int J Neuropsychopharmacol 14:1315–1325. doi:10.1017/S1461145710001628
Smalheiser NR, Lugli G, Rizavi HS et al (2012) MicroRNA Expression Is Down-Regulated and Reorganized in Prefrontal Cortex of Depressed Suicide Subjects. PLoS One 7:e33201. doi:10.1371/journal.pone.0033201
Smalheiser NR, Lugli G, Zhang H et al (2014) Expression of microRNAs and Other Small RNAs in prefrontal cortex in schizophrenia, bipolar disorder and depressed subjects. PLoS One 9:e86469. doi:10.1371/journal.pone.0086469
Smrt RD, Szulwach KE, Pfeiffer RL et al (2010) MicroRNA miR-137 regulates neuronal maturation by targeting ubiquitin ligase mind bomb-1. Stem Cells 28:1060–1070. doi:10.1002/stem.431
Song H-T, Sun X-Y, Zhang L et al (2014) A preliminary analysis of association between the down-regulation of microRNA-181b expression and symptomatology improvement in schizophrenia patients before and after antipsychotic treatment. J Psychiatr Res 54:134–140. doi:10.1016/j.jpsychires.2014.03.008
Stein JL, Medland SE, Vasquez AA et al (2012) Identification of common variants associated with human hippocampal and intracranial volumes. Nat Genet 44:552–561. doi:10.1038/ng.2250
Strazisar M, Cammaerts S, van der Ven K et al (2014) MIR137 variants identified in psychiatric patients affect synaptogenesis and neuronal transmission gene sets. Mol Psychiatry. doi:10.1038/mp.2014.53
Sun G, Ye P, Murai K et al (2011) miR-137 forms a regulatory loop with nuclear receptor TLX and LSD1 in neural stem cells. Nat Commun 2:529. doi:10.1038/ncomms1532
Sun AX, Crabtree GR, Yoo AS (2013) MicroRNAs: regulators of neuronal fate. Curr Opin Cell Biol 25:215–221. doi:10.1016/j.ceb.2012.12.007
Szulwach KE, Li X, Smrt RD et al (2010) Cross talk between microRNA and epigenetic regulation in adult neurogenesis. J Cell Biol 189:127–141. doi:10.1083/jcb.200908151
The Schizophrenia Psychiatric Genome-Wide Association Study (GWAS) Consortium (2011) Genome-wide association study identifies five new schizophrenia loci. Nat Genet 43:969–976. doi:10.1038/ng.940
Thum T, Galuppo P, Wolf C et al (2007) MicroRNAs in the human heart: a clue to fetal gene reprogramming in heart failure. Circulation 116:258–267. doi:10.1161/CIRCULATIONAHA.107.687947
Urdinguio RG, Fernandez AF, Lopez-Nieva P et al (2010) Disrupted microRNA expression caused by Mecp2 loss in a mouse model of Rett syndrome. Epigenetics 5:656–663. doi:10.4161/epi.5.7.13055
Van den Hove DL, Kompotis K, Lardenoije R et al (2014) Epigenetically regulated microRNAs in Alzheimer’s disease. Neurobiol Aging 35:731–745. doi:10.1016/j.neurobiolaging.2013.10.082
van Erp TGM, Guella I, Vawter MP et al (2014) Schizophrenia miR-137 locus risk genotype is associated with dorsolateral prefrontal cortex hyperactivation. Biol Psychiatry 75:398–405. doi:10.1016/j.biopsych.2013.06.016
Varga G, Szekely A, Antal P et al (2012) Additive effects of serotonergic and dopaminergic polymorphisms on trait impulsivity. Am J Med Genet B Neuropsychiatr Genet 159B:281–288. doi:10.1002/ajmg.b.32025
Wang S, Li W, Zhang H et al (2014a) Association of microRNA137 gene polymorphisms with age at onset and positive symptoms of schizophrenia in a Han Chinese population. Int J Psychiatry Med 47:153–168. doi:10.2190/PM.47.2.f
Wang Z, Zhang C, Huang J et al (2014b) MiRNA-206 and BDNF genes interacted in bipolar I disorder. J Affect Disorders 162:116–119. doi:10.1016/j.jad.2014.03.047
Warnica W, Merico D, Costain G et al (2014) Copy Number Variable MicroRNAs in Schizophrenia and Their Neurodevelopmental Gene Targets. Biol Psychiatry. doi:10.1016/j.biopsych.2014.05.011
Watanabe Y, Iijima Y, Egawa J et al (2013) Replication in a Japanese population that a MIR30E gene variation is associated with schizophrenia. Schizophr Res 150:596–597. doi:10.1016/j.schres.2013.08.028
Weigelt K, Bergink V, Burgerhout KM et al (2013) Down-regulation of inflammation-protective microRNAs 146a and 212 in monocytes of patients with postpartum psychosis. Brain Behav Immun 29:147–155. doi:10.1016/j.bbi.2012.12.018
Whalley HC, Papmeyer M, Romaniuk L et al (2012) Impact of a microRNA MIR137 susceptibility variant on brain function in people at high genetic risk of schizophrenia or bipolar disorder. Neuropsychopharmacology 37:2720–2729. doi:10.1038/npp.2012.137
Wong J, Duncan CE, Beveridge NJ et al (2013) Expression of NPAS3 in the human cortex and evidence of its posttranscriptional regulation by miR-17 during development, with implications for schizophrenia. Schizophr Bull 39:396–406. doi:10.1093/schbul/sbr177
Wright C, Turner JA, Calhoun VD, Perrone-Bizzozero N (2013) Potential Impact of miR-137 and Its Targets in Schizophrenia. Front Genet 4:58. doi:10.3389/fgene.2013.00058
Xu Y, Li F, Zhang B et al (2010a) MicroRNAs and target site screening reveals a pre-microRNA-30e variant associated with schizophrenia. Schizophr Res 119:219–227. doi:10.1016/j.schres.2010.02.1070
Xu Y, Liu H, Li F et al (2010b) A polymorphism in the microRNA-30e precursor associated with major depressive disorder risk and P300 waveform. J Affect Disord 127:332–336. doi:10.1016/j.jad.2010.05.019
Yin J, Lin J, Luo X et al (2014) miR-137: a new player in schizophrenia. Int J Mol Sci 15:3262–3271. doi:10.3390/ijms15023262
Yoo AS, Staahl BT, Chen L, Crabtree GR (2009) MicroRNA-mediated switching of chromatin-remodelling complexes in neural development. Nature 460:642–646. doi:10.1038/nature08139
Yuan J, Cheng Z, Zhang F et al (2014) Lack of association between microRNA-137 SNP rs1625579 and schizophrenia in a replication study of Han Chinese. Mol Genet Genomics 1–5. doi: 10.1007/s00438-014-0924-3
Zhang F, Chen Y, Liu C et al (2012) Systematic association analysis of microRNA machinery genes with schizophrenia informs further study. Neurosci Lett 520:47–50. doi:10.1016/j.neulet.2012.05.028
Zhou R, Yuan P, Wang Y et al (2009) Evidence for selective microRNAs and their effectors as common long-term targets for the actions of mood stabilizers. Neuropsychopharmacology 34:1395–1405. doi:10.1038/npp.2008.131
Zhou Y, Wang J, Lu X et al (2013) Evaluation of six SNPs of MicroRNA machinery genes and risk of schizophrenia. J Mol Neurosci 49:594–599. doi:10.1007/s12031-012-9887-1
Zhu Y, Kalbfleisch T, Brennan MD, Li Y (2009) A MicroRNA gene is hosted in an intron of a schizophrenia-susceptibility gene. Schizophr Res 109:86–89. doi:10.1016/j.schres.2009.01.022
Ziats MN, Rennert OM (2014) Identification of differentially expressed microRNAs across the developing human brain. Mol Psychiatry 19:848–852. doi:10.1038/mp.2013.93
Zou M, Li D, Lv R et al (2012) Association between two single nucleotide polymorphisms at corresponding microRNA and schizophrenia in a Chinese population. Mol Biol Rep 39:3385–3391. doi:10.1007/s11033-011-1109-3
Acknowledgments
This work was supported by the Interdisciplinary Center for Clinical Research (IZKF), University of Würzburg, project N-258 to LH, and the German Research Foundation (Deutsche Forschungsgemeinschaft, DFG), SFB-TRR-58, projects C02 (KD, JD) and Z02 (JD).
Conflict of interest
The authors declare to have no conflict of interest.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Hommers, L.G., Domschke, K. & Deckert, J. Heterogeneity and Individuality: microRNAs in Mental Disorders. J Neural Transm 122, 79–97 (2015). https://doi.org/10.1007/s00702-014-1338-4
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00702-014-1338-4