Bipolar disorder (BD) is a severe and highly heritable neuropsychiatric disorder with a lifetime prevalence of 1%. Molecular genetic studies have identified the first BD susceptibility genes. However, the disease pathways remain largely unknown. Accumulating evidence suggests that microRNAs, a class of small noncoding RNAs, contribute to basic mechanisms underlying brain development and plasticity, suggesting their possible involvement in the pathogenesis of several psychiatric disorders, including BD. In the present study, gene-based analyses were performed for all known autosomal microRNAs using the largest genome-wide association data set of BD to date (9747 patients and 14 278 controls). Associated and brain-expressed microRNAs were then investigated in target gene and pathway analyses. Functional analyses of miR-499 and miR-708 were performed in rat hippocampal neurons. Ninety-eight of the six hundred nine investigated microRNAs showed nominally significant P-values, suggesting that BD-associated microRNAs might be enriched within known microRNA loci. After correction for multiple testing, nine microRNAs showed a significant association with BD. The most promising were miR-499, miR-708 and miR-1908. Target gene and pathway analyses revealed 18 significant canonical pathways, including brain development and neuron projection. For miR-499, four Bonferroni-corrected significant target genes were identified, including the genome-wide risk gene for psychiatric disorder CACNB2. First results of functional analyses in rat hippocampal neurons neither revealed nor excluded a major contribution of miR-499 or miR-708 to dendritic spine morphogenesis. The present results suggest that research is warranted to elucidate the precise involvement of microRNAs and their downstream pathways in BD.

Biometric Psychiatric Genetics Research Unit Alexandru Obregia Clinical Psychiatric Hospital Bucharest Romania

Black Dog Institute Prince of Wales Hospital Randwick NSW Australia

Center for Research in Environmental Epidemiology Barcelona Spain

Center of Psychiatry Weinsberg Weinsberg Germany

Cologne Center for Genomics University of Cologne Cologne Germany

Département des sciences fondamentales Université du Québec à Chicoutimi Chicoutimi QC Canada

Department of Biology Medical Genetics and Ecology Kursk State Medical University Kursk Russian Federation

Department of Biomedicine Aarhus University Aarhus Denmark

Department of Cancer Epidemiology and Prevention Maria Sklodowska Curie Memorial Cancer Centre and Institute of Oncology Warsaw Warsaw Poland

Department of Epidemiology Nofer Institute of Occupational Medicine Lodz Poland

Department of Genetic Epidemiology in Psychiatry Central Institute of Mental Health Medical Faculty Mannheim University of Heidelberg Heidelberg Germany

Department of Genetics and Fundamental Medicine Bashkir State University Ufa Russian Federation

Department of Genomics Life and Brain Center University of Bonn Bonn Germany

Department of Human Genetics McGill University Montreal QC Canada

Department of Psychiatry and Psychotherapy University Hospital Carl Gustav Carus TU Dresden Dresden Germany

Department of Psychiatry Dalhousie University Halifax NS Canada

Department of Psychiatry Hospital Regional Universitario Biomedical Institute of Malaga Malaga Spain

Department of Psychiatry Laboratory of Psychiatric Genetics Poznan University of Medical Sciences Poznan Poland

Department of Psychiatry McGill University Montreal QC Canada

Department of Psychiatry Psychosomatic Medicine and Psychotherapy University Hospital Frankfurt am Main Frankfurt Germany

Department of Psychiatry University of Bonn Bonn Germany

Department of Psychology Clinical Psychology and Psychotherapy Eberhard Karls University Tübingen Tübingen Germany

Division of Medical Genetics Department of Biomedicine University of Basel Basel Switzerland

Genetic Cancer Susceptibility Group International Agency for Research on Cancer Lyon France

Genetic Epidemiology Group International Agency for Research on Cancer Lyon France

German Center for Neurodegenerative Diseases Bonn Germany

Institute for Genomics Mathematics University of Bonn Bonn Germany

Institute for Medical Biometry Informatics and Epidemiology University of Bonn Bonn Germany

Institute of Biochemistry and Genetics Ufa Scientific Center of Russian Academy of Sciences Ufa Russian Federation

Institute of Human Genetics University of Bonn Bonn Germany

Institute of Medical Informatics Biometry and Epidemiology University Duisburg Essen Essen Germany

Institute of Neuroscience and Medicine Research Center Juelich Juelich Germany

Institute of Physiological Chemistry Philipps University Marburg Marburg Germany

Institute of Psychiatric Phenomics and Genomics Ludwig Maximilians University Munich Munich Germany

Institute of Pulmonology Russian State Medical University Moscow Russian Federation

Max Planck Institute of Psychiatry Munich Germany

McGill Group for Suicide Studies and Douglas Research Institute Montreal QC Canada

Montreal Neurological Institute McGill University Montreal QC Canada

Moscow Research Institute of Psychiatry Moscow Russian Federation

Munich Cluster for Systems Neurology Munich Germany

National Center Register Based Research Aarhus University Aarhus Denmark

National Institute of Mental Health Klecany Czech Republic

Neuroscience Research Australia Sydney NSW Australia

Psychiatric Center Nordbaden Wiesloch Germany

Queensland Institute of Medical Research Brisbane QLD Australia

Russian Academy of Medical Sciences Mental Health Research Center Moscow Russian Federation

School of Medical Sciences Faculty of Medicine University of New South Wales Sydney NSW Australia

School of Psychiatry University of New South Wales Randwick NSW Australia

University of Liverpool Institute of Translational Medicine Liverpool UK

Zobrazit více v PubMed

Craddock N, Sklar P. Genetics of bipolar disorder. Lancet 2013; 381: 1654–1662. PubMed

Nothen MM, Nieratschker V, Cichon S, Rietschel M. New findings in the genetics of major psychoses. Dialogues Clin Neurosci 2010; 12: 85–93. PubMed PMC

Psychiatric GWAS Consortium Bipolar Disorder Working Group. Large-scale genome-wide association analysis of bipolar disorder identifies a new susceptibility locus near ODZ4. Nat Genet 2011; 43: 977–983. PubMed PMC

Baum AE, Akula N, Cabanero M, Cardona I, Corona W, Klemens B et al. A genome-wide association study implicates diacylglycerol kinase eta (DGKH) and several other genes in the etiology of bipolar disorder. Mol Psychiatry 2008; 13: 197–207. PubMed PMC

Ferreira MA, O'Donovan MC, Meng YA, Jones IR, Ruderfer DM, Jones L et al. Collaborative genome-wide association analysis supports a role for ANK3 and CACNA1C in bipolar disorder. Nat Genet 2008; 40: 1056–1058. PubMed PMC

Muhleisen TW, Leber M, Schulze TG, Strohmaier J, Degenhardt F, Treutlein J et al. Genome-wide association study reveals two new risk loci for bipolar disorder. Nat Commun 2014; 5: 3339. PubMed

Sullivan PF, Daly MJ, O'Donovan M. Genetic architectures of psychiatric disorders: the emerging picture and its implications. Nat Rev Genet 2012; 13: 537–551. PubMed PMC

Nurnberger JI Jr., Koller DL, Jung J, Edenberg HJ, Foroud T, Guella I et al. Identification of pathways for bipolar disorder: a meta-analysis. JAMA Psychiatry 2014; 71: 657–664. PubMed PMC

Fineberg SK, Kosik KS, Davidson BL. MicroRNAs potentiate neural development. Neuron 2009; 64: 303–309. PubMed

Schratt G. MicroRNAs at the synapse. Nat Rev Neurosci 2009; 10: 842–849. PubMed

Forstner AJ, Degenhardt F, Schratt G, Nöthen MM. MicroRNAs as the cause of schizophrenia in 22q11.2 deletion carriers, and possible implications for idiopathic disease: a mini-review. Front Mol Neurosci 2013; 6: 47. PubMed PMC

Xu B, Karayiorgou M, Gogos JA. MicroRNAs in psychiatric and neurodevelopmental disorders. Brain Res 2010; 1338: 78–88. PubMed PMC

Kim AH, Reimers M, Maher B, Williamson V, McMichael O, McClay JL et al. MicroRNA expression profiling in the prefrontal cortex of individuals affected with schizophrenia and bipolar disorders. Schizophr Res 2010; 124: 183–191. PubMed PMC

Moreau MP, Bruse SE, David-Rus R, Buyske S, Brzustowicz LM. Altered microRNA expression profiles in postmortem brain samples from individuals with schizophrenia and bipolar disorder. Biol Psychiatry 2011; 69: 188–193. PubMed PMC

Godnic I, Zorc M, Jevsinek Skok D, Calin GA, Horvat S, Dovc P et al. Genome-wide and species-wide in silico screening for intragenic MicroRNAs in human, mouse and chicken. PLoS One 2013; 8: e65165. PubMed PMC

Maffioletti E, Tardito D, Gennarelli M, Bocchio-Chiavetto L. Micro spies from the brain to the periphery: new clues from studies on microRNAs in neuropsychiatric disorders. Front Cell Neurosci 2014; 8: 75. PubMed PMC

Rodriguez A, Griffiths-Jones S, Ashurst JL, Bradley A. Identification of mammalian microRNA host genes and transcription units. Genome Res 2004; 14: 1902–1910. PubMed PMC

Han J, Lee Y, Yeom KH, Kim YK, Jin H, Kim VN. The Drosha-DGCR8 complex in primary microRNA processing. Genes Dev 2004; 18: 3016–3027. PubMed PMC

Lee Y, Ahn C, Han J, Choi H, Kim J, Yim J et al. The nuclear RNase III Drosha initiates microRNA processing. Nature 2003; 425: 415–419. PubMed

Krol J, Loedige I, Filipowicz W. The widespread regulation of microRNA biogenesis, function and decay. Nat Rev Genet 2010; 11: 597–610. PubMed

Gregory RI, Chendrimada TP, Cooch N, Shiekhattar R. Human RISC couples microRNA biogenesis and posttranscriptional gene silencing. Cell 2005; 123: 631–640. PubMed

He L, Hannon GJ. MicroRNAs: small RNAs with a big role in gene regulation. Nat Rev Genet 2004; 5: 522–531. PubMed

Meola N, Gennarino VA, Banfi S. microRNAs and genetic diseases. Pathogenetics 2009; 2: 7. PubMed PMC

Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 2004; 116: 281–297. PubMed

Didiano D, Hobert O. Molecular architecture of a miRNA-regulated 3' UTR. RNA 2008; 14: 1297–1317. PubMed PMC

Sathyan P, Golden HB, Miranda RC. Competing interactions between micro-RNAs determine neural progenitor survival and proliferation after ethanol exposure: evidence from an PubMed PMC

Choi WY, Giraldez AJ, Schier AF. Target protectors reveal dampening and balancing of Nodal agonist and antagonist by miR-430. Science 2007; 318: 271–274. PubMed

Johnston RJ, Hobert O. A microRNA controlling left/right neuronal asymmetry in PubMed

Geeleher P, Huang SR, Gamazon ER, Golden A, Seoighe C. The regulatory effect of miRNAs is a heritable genetic trait in humans. BMC Genomics 2012; 13: 383. PubMed PMC

Forstner AJ, Basmanav FB, Mattheisen M, Bohmer AC, Hollegaard MV, Janson E et al. Investigation of the involvement of MIR185 and its target genes in the development of schizophrenia. J Psychiatry Neurosci 2014; 39: 386–396. PubMed PMC

Lopez JP, Lim R, Cruceanu C, Crapper L, Fasano C, Labonte B et al. miR-1202 is a primate-specific and brain-enriched microRNA involved in major depression and antidepressant treatment. Nat Med 2014; 20: 764–768. PubMed PMC

Strazisar M, Cammaerts S, van der Ven K, Forero DA, Lenaerts AS, Nordin A et al. MIR137 variants identified in psychiatric patients affect synaptogenesis and neuronal transmission gene sets. Mol Psychiatry 2015; 20: 472–481. PubMed

Wang Z, Zhang C, Huang J, Yuan C, Hong W, Chen J et al. MiRNA-206 and BDNF genes interacted in bipolar I disorder. J Affect Disord 2014; 162: 116–119. PubMed

Liu JZ, McRae AF, Nyholt DR, Medland SE, Wray NR, Brown KM et al. A versatile gene-based test for genome-wide association studies. Am J Hum Genet 2010; 87: 139–145. PubMed PMC

Kozomara A, Griffiths-Jones S. miRBase: annotating high confidence microRNAs using deep sequencing data. Nucleic Acids Res 2014; 42: D68–D73. PubMed PMC

Pruim RJ, Welch RP, Sanna S, Teslovich TM, Chines PS, Gliedt TP et al. LocusZoom: regional visualization of genome-wide association scan results. Bioinformatics 2010; 26: 2336–2337. PubMed PMC

Ziats MN, Rennert OM. Identification of differentially expressed microRNAs across the developing human brain. Mol Psychiatry 2014; 19: 848–852. PubMed PMC

Siegel G, Obernosterer G, Fiore R, Oehmen M, Bicker S, Christensen M et al. A functional screen implicates microRNA-138-dependent regulation of the depalmitoylation enzyme APT1 in dendritic spine morphogenesis. Nat Cell Biol 2009; 11: 705–716. PubMed PMC

Hackenberg M, Rodriguez-Ezpeleta N, Aransay AM. miRanalyzer: an update on the detection and analysis of microRNAs in high-throughput sequencing experiments. Nucleic Acids Res 2011; 39: W132–W138. PubMed PMC

Lewis BP, Burge CB, Bartel DP. Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell 2005; 120: 15–20. PubMed

Hawrylycz MJ, Lein ES, Guillozet-Bongaarts AL, Shen EH, Ng L, Miller JA et al. An anatomically comprehensive atlas of the adult human brain transcriptome. Nature 2012; 489: 391–399. PubMed PMC

Baskerville S, Bartel DP. Microarray profiling of microRNAs reveals frequent coexpression with neighboring miRNAs and host genes. RNA 2005; 11: 241–247. PubMed PMC

Lutter D, Marr C, Krumsiek J, Lang EW, Theis FJ. Intronic microRNAs support their host genes by mediating synergistic and antagonistic regulatory effects. BMC Genomics 2010; 11: 224. PubMed PMC

Rearick D, Prakash A, McSweeny A, Shepard SS, Fedorova L, Fedorov A. Critical association of ncRNA with introns. Nucleic Acids Res 2011; 39: 2357–2366. PubMed PMC

Green EK, Hamshere M, Forty L, Gordon-Smith K, Fraser C, Russell E et al. Replication of bipolar disorder susceptibility alleles and identification of two novel genome-wide significant associations in a new bipolar disorder case-control sample. Mol Psychiatry 2013; 18: 1302–1307. PubMed PMC

Wang JX, Jiao JQ, Li Q, Long B, Wang K, Liu JP et al. miR-499 regulates mitochondrial dynamics by targeting calcineurin and dynamin-related protein-1. Nat Med 2011; 17: 71–78. PubMed

Smalheiser NR, Lugli G, Zhang H, Rizavi H, Cook EH, Dwivedi Y. Expression of microRNAs and other small RNAs in prefrontal cortex in schizophrenia, bipolar disorder and depressed subjects. PLoS One 2014; 9: e86469. PubMed PMC

Banigan MG, Kao PF, Kozubek JA, Winslow AR, Medina J, Costa J et al. Differential expression of exosomal microRNAs in prefrontal cortices of schizophrenia and bipolar disorder patients. PLoS One 2013; 8: e48814. PubMed PMC

Gong J, Tong Y, Zhang HM, Wang K, Hu T, Shan G et al. Genome-wide identification of SNPs in microRNA genes and the SNP effects on microRNA target binding and biogenesis. Hum Mutat 2012; 33: 254–263. PubMed

Zou M, Li D, Lv R, Zhou Y, Wang T, Liu J et al. Association between two single nucleotide polymorphisms at corresponding microRNA and schizophrenia in a Chinese population. Mol Biol Rep 2012; 39: 3385–3391. PubMed

Cross-Disorder Group of the Psychiatric Genomics Consortium. Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis. Lancet 2013; 381: 1371–1379. PubMed PMC

Zhao Z, Xu J, Chen J, Kim S, Reimers M, Bacanu SA et al. Transcriptome sequencing and genome-wide association analyses reveal lysosomal function and actin cytoskeleton remodeling in schizophrenia and bipolar disorder. Mol Psychiatry 2015; 20: 563–572. PubMed PMC

Auer M, Hausott B, Klimaschewski L. Rho GTPases as regulators of morphological neuroplasticity. Ann Anat 2011; 193: 259–266. PubMed PMC

Bellenchi GC, Gurniak CB, Perlas E, Middei S, Ammassari-Teule M, Witke W. N-cofilin is associated with neuronal migration disorders and cell cycle control in the cerebral cortex. Genes Dev 2007; 21: 2347–2357. PubMed PMC

de Curtis I. Functions of Rac GTPases during neuronal development. Dev Neurosci 2008; 30: 47–58. PubMed

Kreis P, Barnier JV. PAK signalling in neuronal physiology. Cell Signal 2009; 21: 384–393. PubMed

Jones I, Craddock N. Familiality of the puerperal trigger in bipolar disorder: results of a family study. Am J Psychiatry 2001; 158: 913–917. PubMed

Weigelt K, Bergink V, Burgerhout KM, Pescatori M, Wijkhuijs A, Drexhage HA. Down-regulation of inflammation-protective microRNAs 146a and 212 in monocytes of patients with postpartum psychosis. Brain Behav Immun 2013; 29: 147–155. PubMed

Xu S, Zhang R, Niu J, Cui D, Xie B, Zhang B et al. Oxidative stress mediated-alterations of the microRNA expression profile in mouse hippocampal neurons. Int J Mol Sci 2012; 13: 16945–16960. PubMed PMC

Ryu S, McDonnell K, Choi H, Gao D, Hahn M, Joshi N et al. Suppression of miRNA-708 by polycomb group promotes metastases by calcium-induced cell migration. Cancer Cell 2013; 23: 63–76. PubMed

Carlezon WA Jr., Duman RS, Nestler EJ. The many faces of CREB. Trends Neurosci 2005; 28: 436–445. PubMed

Maher BS, Hughes HB 3rd, Zubenko WN, Zubenko GS. Genetic linkage of region containing the CREB1 gene to depressive disorders in families with recurrent, early-onset, major depression: a re-analysis and confirmation of sex-specific effect. Am J Med Genet B Neuropsychiatr Genet 2010; 153B: 10–16. PubMed PMC

Wallace TL, Stellitano KE, Neve RL, Duman RS. Effects of cyclic adenosine monophosphate response element binding protein overexpression in the basolateral amygdala on behavioral models of depression and anxiety. Biol Psychiatry 2004; 56: 151–160. PubMed

Li M, Luo XJ, Rietschel M, Lewis CM, Mattheisen M, Muller-Myhsok B et al. Allelic differences between Europeans and Chinese for CREB1 SNPs and their implications in gene expression regulation, hippocampal structure and function, and bipolar disorder susceptibility. Mol Psychiatry 2014; 19: 452–461. PubMed PMC

Rawlings-Goss RA, Campbell MC, Tishkoff SA. Global population-specific variation in miRNA associated with cancer risk and clinical biomarkers. BMC Med Genomics 2014; 7: 53. PubMed PMC

Ye SB, Li ZL, Luo DH, Huang BJ, Chen YS, Zhang XS et al. Tumor-derived exosomes promote tumor progression and T-cell dysfunction through the regulation of enriched exosomal microRNAs in human nasopharyngeal carcinoma. Oncotarget 2014; 5: 5439–5452. PubMed PMC

Gamazon ER, Ziliak D, Im HK, LaCroix B, Park DS, Cox NJ et al. Genetic architecture of microRNA expression: implications for the transcriptome and complex traits. Am J Hum Genet 2012; 90: 1046–1063. PubMed PMC

Borel C, Deutsch S, Letourneau A, Migliavacca E, Montgomery SB, Dimas AS et al. Identification of cis- and trans-regulatory variation modulating microRNA expression levels in human fibroblasts. Genome Res 2011; 21: 68–73. PubMed PMC

Analysis of the Influence of microRNAs in Lithium Response in Bipolar Disorder