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Genome-wide analysis implicates microRNAs and their target genes in the development of bipolar disorder

2015; Springer Nature; Volume: 5; Issue: 11 Linguagem: Inglês

10.1038/tp.2015.159

2158-3188

Andreas J. Forstner, Andrea Hofmann, Anna Maaser, Simon Sumer, Sharof Khudayberdiev, Thomas W. Mühleisen, Markus Leber, Thomas G. Schulze, Jana Strohmaier, Franziska Degenhardt, Jens Treutlein, Manuel Mattheisen, Johannes Schumacher, René Breuer, S Meier, Stefan Herms, Per Hoffmann, André Lacour, Stephanie H. Witt, Andreas Reif, Bertram Müller‐Myhsok, Susanne Lucae, Wolfgang Maier, Markus Schwarz, Helmut Vedder, Jutta Kammerer-Ciernioch, Andrea Pfennig, Michael Bauer, Martin Hautzinger, Susanne Moebus, Lutz Priebe, Sugirthan Sivalingam, A. Verhaert, Herbert Schulz, Piotr M. Czerski, Joanna Hauser, Jolanta Lissowska, Neonila Szeszenia‐Dąbrowska, Paul Brennan, James D. McKay, A. Jordan Wright, Philip B. Mitchell, Janice M. Fullerton, Peter R. Schofield, Grant W. Montgomery, Sarah E. Medland, Scott D. Gordon, Nicholas G. Martin, В. Краснов, А. Г. Чучалин, Gulja Babadjanova, Galina Pantelejeva, Л. И. Абрамова, Tiganov As, Alexey Polonikov, Э. К. Хуснутдинова, Martin Alda, Cristiana Cruceanu, Guy A. Rouleau, Gustavo Turecki, Catherine Laprise, Fatima Rivas, Fermín Mayoral, Manolis Kogevinas, Maria Grigoroiu‐Serbânescu, Peter Propping, Tim Becker, Marcella Rietschel, Sven Cichon, Gerhard Schratt, Markus M. Nöthen,

Circular RNAs in diseases

Abstract 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.