AUTHOR=Reinbold Céline S. , Forstner Andreas J. , Hecker Julian , Fullerton Janice M. , Hoffmann Per , Hou Liping , Heilbronner Urs , Degenhardt Franziska , Adli Mazda , Akiyama Kazufumi , Akula Nirmala , Ardau Raffaella , Arias Bárbara , Backlund Lena , Benabarre Antonio , Bengesser Susanne , Bhattacharjee Abesh K. , Biernacka Joanna M. , Birner Armin , Marie-Claire Cynthia , Cervantes Pablo , Chen Guo-Bo , Chen Hsi-Chung , Chillotti Caterina , Clark Scott R. , Colom Francesc , Cousins David A. , Cruceanu Cristiana , Czerski Piotr M. , Dayer Alexandre , Étain Bruno , Falkai Peter , Frisén Louise , Gard Sébastien , Garnham Julie S. , Goes Fernando S. , Grof Paul , Gruber Oliver , Hashimoto Ryota , Hauser Joanna , Herms Stefan , Jamain Stéphane , Jiménez Esther , Kahn Jean-Pierre , Kassem Layla , Kittel-Schneider Sarah , Kliwicki Sebastian , König Barbara , Kusumi Ichiro , Lackner Nina , Laje Gonzalo , Landén Mikael , Lavebratt Catharina , Leboyer Marion , Leckband Susan G. , López Jaramillo Carlos A. , MacQueen Glenda , Manchia Mirko , Martinsson Lina , Mattheisen Manuel , McCarthy Michael J. , McElroy Susan L. , Mitjans Marina , Mondimore Francis M. , Monteleone Palmiero , Nievergelt Caroline M. , Ösby Urban , Ozaki Norio , Perlis Roy H. , Pfennig Andrea , Reich-Erkelenz Daniela , Rouleau Guy A. , Schofield Peter R. , Schubert K. Oliver , Schweizer Barbara W. , Seemüller Florian , Severino Giovanni , Shekhtman Tatyana , Shilling Paul D. , Shimoda Kazutaka , Simhandl Christian , Slaney Claire M. , Smoller Jordan W. , Squassina Alessio , Stamm Thomas J. , Stopkova Pavla , Tighe Sarah K. , Tortorella Alfonso , Turecki Gustavo , Volkert Julia , Witt Stephanie H. , Wright Adam J. , Young L. Trevor , Zandi Peter P. , Potash James B. , DePaulo J. Raymond , Bauer Michael , Reininghaus Eva , Novák Tomáš , Aubry Jean-Michel , Maj Mario , Baune Bernhard T. , Mitchell Philip B. , Vieta Eduard , Frye Mark A. , Rybakowski Janusz K. , Kuo Po-Hsiu , Kato Tadafumi , Grigoroiu-Serbanescu Maria , Reif Andreas , Del Zompo Maria , Bellivier Frank , Schalling Martin , Wray Naomi R. , Kelsoe John R. , Alda Martin , McMahon Francis J. , Schulze Thomas G. , Rietschel Marcella , Nöthen Markus M. , Cichon Sven TITLE=Analysis of the Influence of microRNAs in Lithium Response in Bipolar Disorder JOURNAL=Frontiers in Psychiatry VOLUME=9 YEAR=2018 URL=https://www.frontiersin.org/journals/psychiatry/articles/10.3389/fpsyt.2018.00207 DOI=10.3389/fpsyt.2018.00207 ISSN=1664-0640 ABSTRACT=

Bipolar disorder (BD) is a common, highly heritable neuropsychiatric disease characterized by recurrent episodes of mania and depression. Lithium is the best-established long-term treatment for BD, even though individual response is highly variable. Evidence suggests that some of this variability has a genetic basis. This is supported by the largest genome-wide association study (GWAS) of lithium response to date conducted by the International Consortium on Lithium Genetics (ConLiGen). Recently, we performed the first genome-wide analysis of the involvement of miRNAs in BD and identified nine BD-associated miRNAs. However, it is unknown whether these miRNAs are also associated with lithium response in BD. In the present study, we therefore tested whether common variants at these nine candidate miRNAs contribute to the variance in lithium response in BD. Furthermore, we systematically analyzed whether any other miRNA in the genome is implicated in the response to lithium. For this purpose, we performed gene-based tests for all known miRNA coding genes in the ConLiGen GWAS dataset (n = 2,563 patients) using a set-based testing approach adapted from the versatile gene-based test for GWAS (VEGAS2). In the candidate approach, miR-499a showed a nominally significant association with lithium response, providing some evidence for involvement in both development and treatment of BD. In the genome-wide miRNA analysis, 71 miRNAs showed nominally significant associations with the dichotomous phenotype and 106 with the continuous trait for treatment response. A total of 15 miRNAs revealed nominal significance in both phenotypes with miR-633 showing the strongest association with the continuous trait (p = 9.80E-04) and miR-607 with the dichotomous phenotype (p = 5.79E-04). No association between miRNAs and treatment response to lithium in BD in either of the tested conditions withstood multiple testing correction. Given the limited power of our study, the investigation of miRNAs in larger GWAS samples of BD and lithium response is warranted.