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.

AP HP GH Saint Louis Lariboisière F Widal Département de Psychiatrie et de Médecine Addictologique Paris France

Assistance Publique Hôpitaux de Paris Hôpital Albert Chenevier Henri Mondor Pôle de Psychiatrie Créteil France

Biometric Psychiatric Genetics Research Unit Alexandru Obregia Clinical Psychiatric Hospital Bucharest Romania

Bipolar Center Wiener Neustadt Vienna Austria

Bipolar Disorder Program Institute of Neuroscience Hospital Clinic CIBERSAM IDIBAPS University of Barcelona Barcelona Spain

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 Biological Psychiatry and Neuroscience Dokkyo Medical University School of Medicine Mibu Japan

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 Genetic Epidemiology in Psychiatry Medical Faculty Mannheim Central Institute of Mental Health University of Heidelberg Mannheim Germany

Department of Genomics Life and Brain Center University of Bonn Bonn Germany

Department of Medical Epidemiology and Biostatistics Karolinska Institutet Stockholm Sweden

Department of Mental Health Johns Hopkins Bloomberg School of Public Health Baltimore MD United States

Department of Molecular Medicine and Surgery Karolinska Institutet and Center for Molecular Medicine Karolinska University Hospital Stockholm Sweden

Department of Neurobiology Care Sciences and Society Karolinska Institutet and Center for Molecular Medicine Karolinska University Hospital Stockholm Sweden

Department of Neurology and Neurosurgery Montreal Neurological Institute and Hospital McGill University Montreal QC Canada

Department of Pharmacology Dalhousie University Halifax NS Canada

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 Center of Sleep Disorders National Taiwan University Hospital Taipei Taiwan

Department of Psychiatry and Psychology Mayo Clinic Rochester MN United States

Department of Psychiatry and Psychotherapeuthic Medicine Landesklinikum Neunkirchen Neunkirchen Austria

Department of Psychiatry and Psychotherapy Charité Universitätsmedizin Berlin Germany

Department of Psychiatry and Psychotherapy Ludwig Maximilians University Munich Munich Germany

Department of Psychiatry and Psychotherapy Medical Faculty University Hospital Carl Gustav Carus Technische Universität Dresden Dresden Germany

Department of Psychiatry and Psychotherapy University Medical Center Georg August University Göttingen Göttingen 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 Massachusetts General Hospital and Harvard Medical School Boston MA 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 Psychosomatic Medicine and Psychotherapy University Hospital Frankfurt Frankfurt Germany

Department of Psychiatry Psychotherapy and Psychosomatics Medical School Brandenburg Neuruppin Germany

Department of Psychiatry University of Antioquia Medellín Medellín Colombia

Department of Psychiatry University of Basel Basel Switzerland

Department of Psychiatry University of British Columbia Vancouver BC Canada

Department of Psychiatry University of Calgary Calgary AB Canada

Department of Psychiatry University of California San Diego San Diego CA United States

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

Department of Public Health and Institute of Epidemiology and Preventive Medicine National Taiwan University Taipei Taiwan

Department Psychiatry and Psychotherapy Institute of Psychiatric Phenomics and Genomics University Hospital LMU Munich Munich Germany

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

Human Genomics Research Group Department of Biomedicine University of Basel Basel Switzerland

Institut National de la Santé et de la Recherche Médicale U1144 Paris France

Institut National de la Santé et de la Recherche Médicale U955 Psychiatrie Translationnelle Créteil France

Institute of Human Genetics University of Bonn Bonn Germany

Institute of Medical Genetics and Pathology University Hospital Basel Basel Switzerland

Institute of Neuroscience and Physiology The Sahlgrenska Academy at the Gothenburg University Gothenburg Sweden

Intramural Research Program US Department of Health and Human Services National Institute of Mental Health National Institutes of Health Bethesda MD United States

Laboratory for Molecular Dynamics of Mental Disorders RIKEN Brain Science Institute Saitama Japan

Medical school Sigmund Freud University Vienna Austria

Mental Health Research Group IMIM Hospital del Mar Barcelona Spain

Mental Illness Neuroscience Research Australia Sydney NSW Australia

Molecular Research Center for Children's Mental Development United Graduate School of Child Development Osaka University Osaka Japan

Mood Disorders Center of Ottawa Ottawa ON Canada

Mood Disorders Unit HUG Geneva University Hospitals Geneva Switzerland

Neuroscience Research Australia Sydney NSW Australia

Neurosciences Section Department of Medicine and Surgery University of Salerno Salerno Italy

Psychiatric Genetic Unit Poznan University of Medical Sciences Poznan Poland

Queensland Brain Institute The University of Queensland Brisbane QLD Australia

Research Centre Jülich Institute of Neuroscience and Medicine Jülich Germany

School of Medical Sciences University of New South Wales Sydney NSW Australia

School of Psychiatry University of New South Wales and Black Dog Institute Sydney NSW Australia

Section of Psychiatry Department of Medical Sciences and Public Health University of Cagliari Cagliari Italy

Service de Psychiatrie et Psychologie Clinique Centre Psychothérapique de Nancy Université de Lorraine Nancy France

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

Université Paris Diderot Sorbonne Paris Cité UMR S 1144 Paris France

Zoology and Biological Anthropology Section Facultat de Biologia and Institut de Biomedicina CIBERSAM Universitat de Barcelona Barcelona Spain

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Exemplar scoring identifies genetically separable phenotypes of lithium responsive bipolar disorder