Forstner, A JHofmann, AMaaser, ASumer, SKhudayberdiev, SMühleisen, T WLeber, MSchulze, T GStrohmaier, JDegenhardt, FTreutlein, JMattheisen, MSchumacher, JBreuer, RMeier, SHerms, SHoffmann, PLacour, AWitt, S HReif, AMüller-Myhsok, BLucae, SMaier, WSchwarz, MVedder, HKammerer-Ciernioch, JPfennig, ABauer, MHautzinger, MMoebus, SPriebe, LSivalingam, SVerhaert, ASchulz, HCzerski, P MHauser, JLissowska, JSzeszenia-Dabrowska, NBrennan, PMcKay, J DWright, AMitchell, P BFullerton, J MSchofield, P RMontgomery, G WMedland, S EGordon, S DMartin, N GKrasnov, VChuchalin, ABabadjanova, GPantelejeva, GAbramova, L ITiganov, A SPolonikov, AKhusnutdinova, EAlda, MCruceanu, CRouleau, G ATurecki, GLaprise, CRivas, FMayoral, FKogevinas, MGrigoroiu-Serbanescu, MPropping, PBecker, TRietschel, MCichon, SSchratt, GNöthen, M M2016-06-282016-06-282015-10-10Forstner AJ, Hofmann A, Maaser A, Sumer S, Khudayberdiev S, Mühleisen TW, et al. Genome-wide analysis implicates microRNAs and their target genes in the development of bipolar disorder. Transl Psychiatry. 2015; 5:e678http://hdl.handle.net/10668/2226Journal Article; Research Support, Non-U.S. Gov't;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.enTrastorno bipolarPrevalenciaMicroARNPlasticidad neuronalPredisposición genética a la enfermedadHipocampoRatasMedical Subject Headings::Psychiatry and Psychology::Mental Disorders::Mood Disorders::Affective Disorders, Psychotic::Bipolar DisorderMedical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Data Collection::Vital Statistics::Morbidity::PrevalenceMedical Subject Headings::Chemicals and Drugs::Nucleic Acids, Nucleotides, and Nucleosides::Nucleic Acids::RNA::RNA, Untranslated::RNA, Small Untranslated::MicroRNAsMedical Subject Headings::Phenomena and Processes::Musculoskeletal and Neural Physiological Phenomena::Nervous System Physiological Phenomena::Nervous System Physiological Processes::Neuronal PlasticityMedical Subject Headings::Phenomena and Processes::Genetic Phenomena::Genotype::Genetic Predisposition to DiseaseMedical Subject Headings::Anatomy::Nervous System::Central Nervous System::Brain::Prosencephalon::Telencephalon::Cerebrum::Cerebral Cortex::HippocampusMedical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Rodentia::Muridae::Murinae::Ratsresearch article26556287open access10.1038/tp.2015.1592158-3188