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Analysis of the influence of microRNAs in lithium response in bipolar disorder

Lookup NU author(s): Dr David Cousins



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


© 2018 Reinbold and et al. 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.

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Author(s): Reinbold CS, Forstner AJ, Hecker J, Fullerton JM, Hoffmann P, Hou L, Heilbronner U, Degenhardt F, Adli M, Akiyama K, Akula N, Ardau R, Arias B, Backlund L, Benabarre A, Bengesser S, Bhattacharjee AK, Biernacka JM, Birner A, Marie-Claire C, Cervantes P, Chen G-B, Chen H-C, Chillotti C, Clark SR, Colom F, Cousins DA, Cruceanu C, Czerski PM, Dayer A, Etain B, Falkai P, Frisen L, Gard S, Garnham JS, Goes FS, Grof P, Gruber O, Hashimoto R, Hauser J, Herms S, Jamain S, Jimenez E, Kahn J-P, Kassem L, Kittel-Schneider S, Kliwicki S, Konig B, Kusumi I, Lackner N, Laje G, Landen M, Lavebratt C, Leboyer M, Leckband SG, Jaramillo CAL, MacQueen G, Manchia M, Martinsson L, Mattheisen M, McCarthy MJ, McElroy SL, Mitjans M, Mondimore FM, Monteleone P, Nievergelt CM, Osby U, Ozaki N, Perlis RH, Pfennig A, Reich-Erkelenz D, Rouleau GA, Schofield PR, Schubert KO, Schweizer BW, Seemuller F, Severino G, Shekhtman T, Shilling PD, Shimoda K, Simhandl C, Slaney CM, Smoller JW, Squassina A, Stamm TJ, Stopkova P, Tighe SK, Tortorella A, Turecki G, Volkert J, Witt SH, Wright AJ, Trevor Young L, Zandi PP, Potash JB, DePaulo JR, Bauer M, Reininghaus E, Novak T, Aubry J-M, Maj M, Baune BT, Mitchell PB, Vieta E, Frye MA, Rybakowski JK, Kuo P-H, Kato T, Grigoroiu-Serbanescu M, Reif A, Zompo MD, Bellivier F, Schalling M, Wray NR, Kelsoe JR, Alda M, McMahon FJ, Schulze TG, Rietschel M, Nothen MM, Cichon S

Publication type: Article

Publication status: Published

Journal: Frontiers in Psychiatry

Year: 2018

Volume: 9

Online publication date: 31/05/2018

Acceptance date: 03/05/2018

ISSN (electronic): 1664-0640

Publisher: Frontiers Research Foundation


DOI: 10.3389/fpsyt.2018.00207


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