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Analysis of the Influence of microRNAs in Lithium Response in Bipolar Disorder
CS. Reinbold, AJ. Forstner, J. Hecker, JM. Fullerton, P. Hoffmann, L. Hou, U. Heilbronner, F. Degenhardt, M. Adli, K. Akiyama, N. Akula, R. Ardau, B. Arias, L. Backlund, A. Benabarre, S. Bengesser, AK. Bhattacharjee, JM. Biernacka, A. Birner, C....
Language English Country Switzerland
Document type Journal Article
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- Journal Article MeSH
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.
Campus for Ageing and Vitality Newcastle University Newcastle upon Tyne United Kingdom
Department of Adult Psychiatry Poznan University of Medical Sciences Poznan Poland
Department of Biomedical Sciences University of Cagliari Cagliari Italy
Department of Biomedicine Aarhus University Aarhus Denmark
Department of Biostatistics Harvard T H Chan School of Public Health Boston MA United States
Department of Clinical Neurosciences Karolinska Institutet Stockholm Sweden
Department of Pharmacy VA San Diego Healthcare System San Diego CA United States
Department of Psychiatry and Behavioral Sciences Johns Hopkins University Baltimore MD United States
Department of Psychiatry and Psychotherapy Charité Universitätsmedizin Berlin Germany
Department of Psychiatry and Psychotherapy Ludwig Maximilians University Munich Munich Germany
Department of Psychiatry Dalhousie University Halifax NS Canada
Department of Psychiatry Dokkyo Medical University School of Medicine Mibu Japan
Department of Psychiatry Hokkaido University Graduate School of Medicine Sapporo Japan
Department of Psychiatry Lindner Center of Hope University of Cincinnati Mason OH United States
Department of Psychiatry Nagoya University Graduate School of Medicine Nagoya Japan
Department of Psychiatry National Institute of Mental Health Klecany Czechia
Department of Psychiatry University of Antioquia Medellín Medellín Colombia
Department of Psychiatry University of British Columbia Vancouver BC Canada
Department of Psychiatry University of Calgary Calgary AB Canada
Department of Psychiatry University of Campania Luigi Vanvitelli Naples Italy
Department of Psychiatry University of Iowa Iowa IA United States
Department of Psychiatry VA San Diego Healthcare System San Diego CA United States
Discipline of Psychiatry University of Adelaide Adelaide SA Australia
Douglas Mental Health University Institute McGill University Montreal QC Canada
Health Sciences Research Mayo Clinic Rochester MN United States
Institut National de la Santé et de la Recherche Médicale U1144 Paris France
Laboratory for Molecular Dynamics of Mental Disorders RIKEN Brain Science Institute Saitama Japan
Medical school Sigmund Freud University Vienna Austria Bipolar Center Wiener Neustadt Vienna Austria
Mental Health Research Group IMIM Hospital del Mar Barcelona Spain
Mood Disorders Center of Ottawa Ottawa ON Canada
Mood Disorders Unit HUG Geneva University Hospitals Geneva Switzerland
Psychiatric Genetic Unit Poznan University of Medical Sciences Poznan Poland
Queensland Brain Institute The University of Queensland Brisbane QLD Australia
School of Psychiatry University of New South Wales and Black Dog Institute Sydney NSW Australia
Service de Psychiatrie Hôpital Charles Perrens Bordeaux France
Special Outpatient Center for Bipolar Affective Disorder Medical University of Graz Graz Austria
The Neuromodulation Unit McGill University Health Centre Montreal QC Canada
Unit of Clinical Pharmacology University Hospital of Cagliari Cagliari Italy
References provided by Crossref.org
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- $a Reinbold, Céline S $u Human Genomics Research Group, Department of Biomedicine, University of Basel, Basel, Switzerland. Institute of Medical Genetics and Pathology, University Hospital Basel, Basel, Switzerland.
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- $a Analysis of the Influence of microRNAs in Lithium Response in Bipolar Disorder / $c CS. Reinbold, AJ. Forstner, J. Hecker, JM. Fullerton, P. Hoffmann, L. Hou, U. Heilbronner, F. Degenhardt, M. Adli, K. Akiyama, N. Akula, R. Ardau, B. Arias, L. Backlund, A. Benabarre, S. Bengesser, AK. Bhattacharjee, JM. Biernacka, A. Birner, C. Marie-Claire, P. Cervantes, GB. Chen, HC. Chen, C. Chillotti, SR. Clark, F. Colom, DA. Cousins, C. Cruceanu, PM. Czerski, A. Dayer, B. Étain, P. Falkai, L. Frisén, S. Gard, JS. Garnham, FS. Goes, P. Grof, O. Gruber, R. Hashimoto, J. Hauser, S. Herms, S. Jamain, E. Jiménez, JP. Kahn, L. Kassem, S. Kittel-Schneider, S. Kliwicki, B. König, I. Kusumi, N. Lackner, G. Laje, M. Landén, C. Lavebratt, M. Leboyer, SG. Leckband, CA. López Jaramillo, G. MacQueen, M. Manchia, L. Martinsson, M. Mattheisen, MJ. McCarthy, SL. McElroy, M. Mitjans, FM. Mondimore, P. Monteleone, CM. Nievergelt, U. Ösby, N. Ozaki, RH. Perlis, A. Pfennig, D. Reich-Erkelenz, GA. Rouleau, PR. Schofield, KO. Schubert, BW. Schweizer, F. Seemüller, G. Severino, T. Shekhtman, PD. Shilling, K. Shimoda, C. Simhandl, CM. Slaney, JW. Smoller, A. Squassina, TJ. Stamm, P. Stopkova, SK. Tighe, A. Tortorella, G. Turecki, J. Volkert, SH. Witt, AJ. Wright, LT. Young, PP. Zandi, JB. Potash, JR. DePaulo, M. Bauer, E. Reininghaus, T. Novák, JM. Aubry, M. Maj, BT. Baune, PB. Mitchell, E. Vieta, MA. Frye, JK. Rybakowski, PH. Kuo, T. Kato, M. Grigoroiu-Serbanescu, A. Reif, M. Del Zompo, F. Bellivier, M. Schalling, NR. Wray, JR. Kelsoe, M. Alda, FJ. McMahon, TG. Schulze, M. Rietschel, MM. Nöthen, S. Cichon,
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- $a 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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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
- $a Backlund, Lena $u Department of Molecular Medicine and Surgery, Karolinska Institutet and Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden.
- 700 1_
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- 700 1_
- $a Bengesser, Susanne $u Special Outpatient Center for Bipolar Affective Disorder, Medical University of Graz, Graz, Austria.
- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
- $a Cousins, David A $u Campus for Ageing and Vitality, Newcastle University, Newcastle upon Tyne, United Kingdom.
- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
- $a Étain, Bruno $u Université Paris Diderot, Sorbonne Paris Cité, UMR-S 1144, Paris, France. Department of Psychiatry, University of California, San Diego, San Diego, CA, United States. AP-HP, GH Saint-Louis - Lariboisière - F. Widal, Département de Psychiatrie et de Médecine Addictologique, Paris, France.
- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
- $a Herms, Stefan $u Human Genomics Research Group, Department of Biomedicine, University of Basel, Basel, Switzerland. Institute of Medical Genetics and Pathology, University Hospital Basel, Basel, Switzerland. Institute of Human Genetics, University of Bonn, Bonn, Germany. Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany.
- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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