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00925njm 22002777a 4500 dc Forstner, A J author Hofmann, A author Maaser, A author Sumer, S author Khudayberdiev, S author Mühleisen, T W author Leber, M author Schulze, T G author Strohmaier, J author Degenhardt, F author Treutlein, J author Mattheisen, M author Schumacher, J author Breuer, R author Meier, S author Herms, S author Hoffmann, P author Lacour, A author Witt, S H author Reif, A author Müller-Myhsok, B author Lucae, S author Maier, W author Schwarz, M author Vedder, H author Kammerer-Ciernioch, J author Pfennig, A author Bauer, M author Hautzinger, M author Moebus, S author Priebe, L author Sivalingam, S author Verhaert, A author Schulz, H author Czerski, P M author Hauser, J author Lissowska, J author Szeszenia-Dabrowska, N author Brennan, P author McKay, J D author Wright, A author Mitchell, P B author Fullerton, J M author Schofield, P R author Montgomery, G W author Medland, S E author Gordon, S D author Martin, N G author Krasnov, V author Chuchalin, A author Babadjanova, G author Pantelejeva, G author Abramova, L I author Tiganov, A S author Polonikov, A author Khusnutdinova, E author Alda, M author Cruceanu, C author Rouleau, G A author Turecki, G author Laprise, C author Rivas, F author Mayoral, F author Kogevinas, M author Grigoroiu-Serbanescu, M author Propping, P author Becker, T author Rietschel, M author Cichon, S author Schratt, G author Nöthen, M M author 2015-10-10 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. http://hdl.handle.net/10668/2226 http://hdl.handle.net/20.500.12105/18876 26556287 10.1038/tp.2015.159 2158-3188 Translational Psychiatry Trastorno bipolar Prevalencia MicroARN Plasticidad neuronal Predisposición genética a la enfermedad Hipocampo Ratas Genome-wide analysis implicates microRNAs and their target genes in the development of bipolar disorder