BACKGROUND: Lithium is a first-line treatment in bipolar disorder, but individual response is variable. Previous studies have suggested that lithium response is a heritable trait. However, no genetic markers of treatment response have been reproducibly identified. METHODS: Here, we report the results of a genome-wide association study of lithium response in 2563 patients collected by 22 participating sites from the International Consortium on Lithium Genetics (ConLiGen). Data from common single nucleotide polymorphisms (SNPs) were tested for association with categorical and continuous ratings of lithium response. Lithium response was measured using a well established scale (Alda scale). Genotyped SNPs were used to generate data at more than 6 million sites, using standard genomic imputation methods. Traits were regressed against genotype dosage. Results were combined across two batches by meta-analysis. FINDINGS: A single locus of four linked SNPs on chromosome 21 met genome-wide significance criteria for association with lithium response (rs79663003, p=1·37 × 10(-8); rs78015114, p=1·31 × 10(-8); rs74795342, p=3·31 × 10(-9); and rs75222709, p=3·50 × 10(-9)). In an independent, prospective study of 73 patients treated with lithium monotherapy for a period of up to 2 years, carriers of the response-associated alleles had a significantly lower rate of relapse than carriers of the alternate alleles (p=0·03268, hazard ratio 3·8, 95% CI 1·1-13·0). INTERPRETATION: The response-associated region contains two genes for long, non-coding RNAs (lncRNAs), AL157359.3 and AL157359.4. LncRNAs are increasingly appreciated as important regulators of gene expression, particularly in the CNS. Confirmed biomarkers of lithium response would constitute an important step forward in the clinical management of bipolar disorder. Further studies are needed to establish the biological context and potential clinical utility of these findings. FUNDING: Deutsche Forschungsgemeinschaft, National Institute of Mental Health Intramural Research Program.

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

Biometric Psychiatric Genetics Research Unit Alexandru Obregia Psychiatric Hospital Bucharest Romania

Bipolar Center Wiener Neustadt Wiener Neustadt Austria

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

Campus for Ageing and Vitality Newcastle University Newcastle upon Tyne UK

Department of Adult Psychiatry Poznan University of Medical Sciences Poznan Poland

Department of Biologia Animal Unitat d'Antropologia Universitat de Barcelona CIBERSAM Barcelona Catalonia Spain

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 Biomedical Sciences University of Cagliari Cagliari Italy; Department of Pharmacology Dalhousie University Halifax NS Canada

Department of Biomedicine Aarhus University Aarhus Denmark

Department of Clinical Neurosciences Karolinska Institutet Stockholm Sweden

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

Department of Health Sciences Research Mayo Clinic Rochester MN USA; Department of Psychiatry and Psychology Mayo Clinic Rochester MN USA

Department of Mental Health and Psychiatry Mood Disorders Unit Geneva University Hospitals Geneva Switzerland

Department of Mental Health Johns Hopkins Bloomberg School of Public Health Baltimore MD USA

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

Department of Molecular Medicine and Surgery Karolinska Institutet and Center for Molecular Medicine Karolinska University Hospital Stockholm Sweden; Department of Clinical Neuroscience Karolinska Institutet and Center for Molecular Medicine Karolinska University Hospital Stockholm Sweden; Child and Adolescent Psychiatry Research Center Stockholm Sweden

Department of Molecular Medicine and Surgery Karolinska Institutet and Center for Molecular Medicine Karolinska University Hospital Stockholm Sweden; Department of Pharmacy VA San Diego Healthcare System San Diego CA USA

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

Department of Psychiatry and Behavioral Sciences Johns Hopkins University Baltimore MD USA

Department of Psychiatry and Center of Sleep Disorders National Taiwan University Hospital Taipei Taiwan

Department of Psychiatry and Psychology Mayo Clinic Rochester MN USA

Department of Psychiatry and Psychotherapeutic Medicine Landesklinikum Neunkirchen Neunkirchen Austria

Department of Psychiatry and Psychotherapy Charité Universitätsmedizin Berlin Campus Charité Mitte Berlin Germany

Department of Psychiatry and Psychotherapy Charité Universitätsmedizin Berlin Campus Charité Mitte Berlin Germany; Fliedner Klinik Berlin Center for Psychiatry Psychotherapy and Psychosomatic Medicine Berlin Germany

Department of Psychiatry and Psychotherapy Ludwig Maximilians University Munich Munich Germany

Department of Psychiatry and Psychotherapy University Hospital Carl Gustav Carus Medical Faculty 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 Nova Scotia NS Canada

Department of Psychiatry Dalhousie University Halifax Nova Scotia NS Canada; National Institute of Mental Health Klecany Czech Republic

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 USA

Department of Psychiatry Massachusetts General Hospital and Harvard Medical School Boston MA USA

Department of Psychiatry Nagoya University Graduate School of Medicine Nagoya Japan

Department of Psychiatry Psychosomatic Medicine and Psychotherapy University Hospital Frankfurt Frankfurt Germany

Department of Psychiatry University of Antioquia Medellín Medellín Colombia

Department of Psychiatry University of Calgary Calgary AB Canada

Department of Psychiatry University of California San Diego San Diego CA USA

Department of Psychiatry University of Campinas Campinas Brazil

Department of Psychiatry University of Iowa Iowa City IA USA

Department of Psychiatry University of Iowa Iowa City IA USA; University of Iowa Carver College of Medicine and University of Iowa College of Public Health VA Quality Scholars Program Iowa City VA Hospital Iowa City IA USA

Department of Psychiatry University of Naples SUN Naples Italy

Department of Psychiatry University of Toronto Toronto ON Canada

Department of Psychiatry VA San Diego Healthcare System San Diego CA USA

Discipline of Psychiatry University of Adelaide Adelaide SA Australia

Douglas Mental Health University Institute McGill University Montreal QC Canada

Inserm U955 Psychiatrie Translationnelle Créteil France

INSERM UMR S 1144 Université Paris Diderot Pôle de Psychiatrie AP HP Groupe Hospitalier Lariboisière F Widal Paris France

Institute of Epidemiology and Preventive Medicine National Taiwan University Taipei Taiwan

Institute of Human Genetics University of Bonn and Department of Genomics Life and Brain Center Bonn Germany

Institute of Human Genetics University of Bonn and Department of Genomics Life and Brain Center Bonn Germany; Human Genomics Research Group Department of Biomedicine University Hospital Basel Basel Switzerland

Institute of Neuroscience and Physiology The Sahlgrenska Academy at the Gothenburg University Gothenburg Sweden; Department of Medical Epidemiology and Biostatistics Karolinska Institutet Stockholm Sweden

Institute of Psychiatric Phenomics and Genomics Ludwig Maximilians University Munich Munich Germany

Institute of Psychiatric Phenomics and Genomics Ludwig Maximilians University Munich Munich Germany; Department of Psychiatry and Psychotherapy University Medical Center Georg August University Göttingen Göttingen Germany

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

Intramural Research Program National Institute of Mental Health National Institutes of Health US Department of Health and Human Services Bethesda MD USA; Institute of Psychiatric Phenomics and Genomics Ludwig Maximilians University Munich Munich Germany; Department of Psychiatry and Psychotherapy University Medical Center Georg August University Göttingen Göttingen Germany; Department of Psychiatry and Behavioral Sciences Johns Hopkins University Baltimore MD USA; Department of Genetic Epidemiology in Psychiatry Central Institute of Mental Health Medical Faculty Mannheim University of Heidelberg Mannheim Germany

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

Mental Illness Research Theme Neuroscience Research Australia Sydney NSW Australia; School of Medical Sciences University of New South Wales Sydney NSW Australia

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

Montreal Neurological Institute and Hospital McGill University Montreal QC Canada

Mood Disorders Center of Ottawa Ottawa ON Canada

National Institute of Mental Health Klecany Czech Republic

Neurobiological Background and Anthropometrics in Bipolar Affective Disorder Department of Psychiatry Medical University of Graz Graz Austria

Neurosciences Section Department of Medicine and Surgery University of Salerno Salerno Italy; Department of Psychiatry University of Naples SUN Naples Italy

Pôle de Psychiatrie Générale Universitaire Centre Hospitalier Charles Perrens Bordeaux France

Psychiatric Genetic Unit Poznan University of Medical Sciences Poznan Poland

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

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

The Neuromodulation Unit McGill University Health Centre Montreal QC Canada

The University of Queensland Queensland Brain Institute Brisbane Queensland QLD Australia

Unit of Clinical Pharmacology Hospital University Agency of Cagliari Cagliari Italy

Unit of Clinical Pharmacology Hospital University Agency of Cagliari Cagliari Italy; Department of Biomedical Sciences University of Cagliari Cagliari Italy

Veterans Administration San Diego Healthcare System San Diego CA USA; Department of Psychiatry University of California San Diego San Diego CA USA

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Lancet. 2016 Mar 12;387(10023):1034-1036. doi: 10.1016/S0140-6736(16)00147-1. PubMed

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