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

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 GB, Chen HC, Chillotti C, Clark SR, Colom F, Cousins DA, Cruceanu C, Czerski PM, Dayer A, Étain B, Falkai P, Frisén L, Gard S, Garnham JS, Goes FS, Grof P, Gruber O, Hashimoto R, Hauser J, Herms S, Jamain S, Jiménez E, Kahn JP, Kassem L, Kittel-Schneider S, Kliwicki S, König B, Kusumi I, Lackner N, Laje G, Landén M, Lavebratt C, Leboyer M, Leckband SG, Jaramillo CA, MacQueen G, Manchia M, Martinsson L, Mattheisen M, McCarthy MJ, McElroy SL, Mitjans M, Mondimore FM, Monteleone P, Nievergelt CM, Ösby U, Ozaki N, Perlis RH, Pfennig A, Reich-Erkelenz D, Rouleau GA, Schofield PR, Schubert KO, Schweizer BW, Seemüller 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, Novák T, Aubry JM, Maj M, Baune BT, Mitchell PB, Vieta E, Frye MA, Rybakowski JK, Kuo PH, 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, Nöthen MM, Cichon S (2018)

Publication Type: Journal article

Publication year: 2018

Journal

Book Volume: 9

Article Number: 207

Journal Issue: MAY

DOI: 10.3389/fpsyt.2018.00207

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.

Involved external institutions

Geneva University Hospitals / Hôpitaux universitaires de Genève (HUG) Switzerland (CH) Università degli studi della Campania Luigi Vanvitelli Italy (IT) Institut Mondor de Recherche Biomédicale France (FR) Massachusetts General Hospital United States (USA) (US) Charité - Universitätsmedizin Berlin Germany (DE) Dokkyo Medical University Japan (JP) Universitätsklinikum Carl Gustav Carus Dresden Germany (DE) Klinikum der Universität München (LMU Klinikum) Germany (DE) National Institute of Mental Health Information Resource Center United States (USA) (US) National Institute of Mental Health (NIMH) / Národní ústav duševního zdraví (NUDZ) Czech Republic (CZ) Universität Basel Switzerland (CH) Harvard T.H. Chan School of Public Health United States (USA) (US) Neuroscience Research Australia NeuRA Australia (AU) Università degli Studi di Salerno Italy (IT) Mayo Clinic United States (USA) (US) Karolinska University Hospital / Karolinska Universitetssjukhuset Sweden (SE) Nagoya University / 名古屋大学 Japan (JP) Rheinische Friedrich-Wilhelms-Universität Bonn Germany (DE) Universitat de Barcelona (UB) / University of Barcelona Spain (ES) University of New South Wales (UNSW) Australia (AU) University of Adelaide Australia (AU) Johns Hopkins University (JHU) United States (USA) (US) Medizinische Universität Graz Austria (AT) Università degli Studi di Cagliari Italy (IT) Université Sorbonne Paris Cité France (FR) McGill University Health Centre (MUHC) / Centre universitaire de santé McGill Canada (CA) Sigmund-Freud-Privatuniversität Wien (SFU) / Sigmund Freud University Austria (AT) Dalhousie University Canada (CA) University of Queensland Australia (AU) National Taiwan University Hospital (NTUH) / 國立台灣大學醫學院附設醫院 Taiwan (TW) Azienda Ospedaliera Universitaria di Cagliari Italy (IT) Hospital del Mar Spain (ES) Newcastle University United Kingdom (GB) Ruprecht-Karls-Universität Heidelberg Germany (DE) VA San Diego Healthcare System United States (USA) (US) University of Cincinnati United States (USA) (US) Montreal Neurological Institute and Hospital (MNI, The Neuro) Canada (CA) University of Iowa United States (USA) (US) Douglas Mental Health University Institute Canada (CA) Poznan University of Medical Sciences / Uniwersytet Medyczny im. Karola Marcinkowskiego w Poznaniu Poland (PL) Universitätsklinikum Frankfurt am Main (KGU) Germany (DE) University of British Columbia Canada (CA) Centre Hospitalier Charles Perrens (CHCP) France (FR) Mood Disorders Ottawa Canada (CA) Georg-August-Universität Göttingen Germany (DE) Osaka University / 大阪大学 Japan (JP) Université de Lorraine France (FR) National Institute for Health and Medical Research / Institut national de la santé et de la recherche médicale (INSERM) France (FR) National Taiwan University (NTU) Taiwan (TW) RIKEN Center for Brain Science (CBS) Japan (JP) Sahlgrenska University Hospital / Sahlgrenska Universitetssjukhuset Sweden (SE) Hospital Albert Chenevier Ap-Hp / Hôpital Albert Chenevier AP-HP Paris France (FR) Universidad de Antioquía (UDEA) Colombia (CO) University of Calgary Canada (CA) Karolinska Institute Sweden (SE) Aarhus University Denmark (DK)

How to cite

APA:

Reinbold, C.S., Forstner, A.J., Hecker, J., Fullerton, J.M., Hoffmann, P., Hou, L.,... Cichon, S. (2018). Analysis of the influence of microRNAs in lithium response in bipolar disorder. Frontiers in Psychiatry, 9(MAY). https://doi.org/10.3389/fpsyt.2018.00207

MLA:

Reinbold, Céline S., et al. "Analysis of the influence of microRNAs in lithium response in bipolar disorder." Frontiers in Psychiatry 9.MAY (2018).

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