Lithium is regarded as the first-line treatment for bipolar disorder (BD), a severe and disabling mental health disorder that affects about 1% of the population worldwide. Nevertheless, lithium is not consistently effective, with only 30% of patients showing a favorable response to treatment. To provide personalized treatment options for bipolar patients, it is essential to identify prediction biomarkers such as polygenic scores. In this study, we developed a polygenic score for lithium treatment response (Li+PGS) in patients with BD. To gain further insights into lithium's possible molecular mechanism of action, we performed a genome-wide gene-based analysis. Using polygenic score modeling, via methods incorporating Bayesian regression and continuous shrinkage priors, Li+PGS was developed in the International Consortium of Lithium Genetics cohort (ConLi+Gen: N = 2367) and replicated in the combined PsyCourse (N = 89) and BipoLife (N = 102) studies. The associations of Li+PGS and lithium treatment response - defined in a continuous ALDA scale and a categorical outcome (good response vs. poor response) were tested using regression models, each adjusted for the covariates: age, sex, and the first four genetic principal components. Statistical significance was determined at P < 0.05. Li+PGS was positively associated with lithium treatment response in the ConLi+Gen cohort, in both the categorical (P = 9.8 × 10-12, R2 = 1.9%) and continuous (P = 6.4 × 10-9, R2 = 2.6%) outcomes. Compared to bipolar patients in the 1st decile of the risk distribution, individuals in the 10th decile had 3.47-fold (95%CI: 2.22-5.47) higher odds of responding favorably to lithium. The results were replicated in the independent cohorts for the categorical treatment outcome (P = 3.9 × 10-4, R2 = 0.9%), but not for the continuous outcome (P = 0.13). Gene-based analyses revealed 36 candidate genes that are enriched in biological pathways controlled by glutamate and acetylcholine. Li+PGS may be useful in the development of pharmacogenomic testing strategies by enabling a classification of bipolar patients according to their response to treatment.

AMEOS Clinical Center Hildesheim Hildesheim Germany

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

Bipolar and Depressive Disorders Program Institute of Neuroscience Hospital Clinic University of Barcelona IDIBAPS CIBERSAM Barcelona Catalonia Spain

Bipolar Center Wiener Neustadt Sigmund Freud University Medical Faculty Vienna Austria

Center for Molecular Medicine Karolinska University Hospital Stockholm Sweden

Center for Systems Neuroscience Hannover Germany

Centre for Healthy Brain Ageing Discipline of Psychiatry and Mental Health UNSW Medicine and Health University of New South Wales Sydney Australia

Centro de Investigación Biomédica en Salud Mental Instituto de Salud Carlos 3 Madrid Spain

Clinic for Psychiatry and Psychotherapy Clinical Center Werra Meißner Eschwege Germany

Department of Adult Psychiatry Poznan University of Medical Sciences Poznan Poland

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

Department of Biomedical Resonance University of Tuebingen Tuebingen Germany

Department of Biomedical Sciences University of Cagliari Cagliari Italy

Department of Biomedicine University Hospital Basel Basel Switzerland

Department of Child and Adolescent Psychiatry Psychosomatics and Psychotherapy LVR Klinikum Essen University of Duisburg Essen Rheinische Kliniken Essen Germany

Department of Clinical Neurosciences Karolinska Institutet Stockholm Sweden

Department of Clinical Psychiatry and Psychotherapy Brandenburg Medical School Brandenburg Germany

Department of General Psychiatry University of Tuebingen Tuebingen Germany

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

Department of Genetics Microbiology and Statistics Faculty of Biology University of Barcelona Barcelona Spain

Department of Immunology Faculty of Medicine Ahvaz Jundishapur University of Medical Sciences Ahvaz Iran

Department of Medical Epidemiology and Biostatistics Karolinska Institutet Stockholm Sweden

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

Department of Molecular Medicine and Surgery Karolinska Institute Stockholm Sweden

Department of Neurology University Hospital rechts der Isar School of Medicine Technical University of Munich Munich Germany

Department of Pathology of Mental Diseases National Institute of Mental Health National Center of Neurology and Psychiatry 4 1 1 Ogawahigashi Kodaira Tokyo 187 8553 Japan

Department of Pharmacology Dalhousie University Halifax NS Canada

Department of Psychiatry 2 Ulm University Bezirkskrankenhaus Günzburg Günzburg Germany

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

Department of Psychiatry and Behavioral Sciences SUNY Upstate Medical University Norton College of Medicine Syracuse NY USA

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

Department of Psychiatry and Department of Child and Adolescent Psychiatry Nagoya University Graduate School of Medicine Nagoya Japan

Department of Psychiatry and Psychology Mayo Clinic Rochester MN USA

Department of Psychiatry and Psychotherapeutic Medicine Landesklinikum Neunkirchen Neunkirchen Austria

Department of Psychiatry and Psychotherapeutic Medicine Research Unit for bipolar affective disorder Medical University of Graz Graz Austria

Department of Psychiatry and Psychotherapy Agaplesion Diakonieklinikum Rotenburg Germany

Department of Psychiatry and Psychotherapy Bezirkskrankenhaus Augsburg Augsburg Germany

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

Department of Psychiatry and Psychotherapy Medical University of Vienna Vienna Austria

Department of Psychiatry and Psychotherapy Mental Health Institute Berlin Berlin Germany

Department of Psychiatry and Psychotherapy Philipps University Marburg Marburg Germany

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

Department of Psychiatry and Psychotherapy University Hospital Ludwig Maximilian University Munich Munich Germany

Department of Psychiatry and Psychotherapy University Medical Center Göttingen Göttingen Germany

Department of Psychiatry and Psychotherapy University Medical Center Hamburg Eppendorf Hamburg Germany

Department of Psychiatry and Psychotherapy University of Münster Münster Germany

Department of Psychiatry Dalhousie University Halifax Nova Scotia Canada

Department of Psychiatry Dokkyo Medical University School of Medicine Mibu Tochigi Japan

Department of Psychiatry Health North Hospital Group Bremen Germany

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 Melbourne Medical School University of Melbourne Parkville VIC Australia

Department of Psychiatry Mood Disorders Unit HUG Geneva University Hospitals Geneva Switzerland

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

Department of Psychiatry Psychotherapy and Psychosomatic Medicine University Hospital of Würzburg Wurzburg Germany

Department of Psychiatry Psychotherapy and Psychosomatics University Hospital of Frankfurt Goethe University Frankfurt Germany

Department of Psychiatry Ruhr University Bochum LWL University Hospital Bochum Germany

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

Department of Psychiatry University of Campania Luigi Vanvitelli Naples Italy

Department of Psychiatry University of Perugia Perugia Italy

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

Department of Psychosomatic Medicine and Psychotherapy University Medical Center Rostock Rostock Germany

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

Department of Quantitative Health Sciences Mayo Clinic Rochester MN USA

Discipline of Psychiatry School of Medicine University of Adelaide Adelaide SA Australia

Douglas Mental Health University Institute McGill University Montreal Canada

Epidemiology Branch Division of Population Health Research Division of Intramural Research Eunice Kennedy Shriver National Institute of Child Health and Human Development National Institutes of Health Bethesda MD USA

German Center for Neurodegenerative Diseases Göttingen Germany

HSL Institute for Aging Research Harvard Medical School Boston MA USA

Inserm U955 Translational Psychiatry laboratory Fondation FondaMental Créteil France

Inserm U955 Translational Psychiatry laboratory Université Paris Est Créteil Department of Psychiatry and Addictology of Mondor University Hospital AP HP Fondation FondaMental Créteil France

INSERM UMR S 1144 Université Paris Cité Département de Psychiatrie et de Médecine Addictologique AP HP Groupe Hospitalier Saint Louis Lariboisière F Widal Paris France

Institut de Biomedicina de la Universitat de Barcelona Barcelona Spain

Institute for Medical Informatics University Medical Center Göttingen Göttingen Germany

Institute for Translational Psychiatry University of Münster Münster Germany

Institute of Human Genetics University of Bonn School of Medicine and University Hospital Bonn Bonn Germany

Institute of Neuroscience and Medicine Research Center Jülich Jülich Germany

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

Institute of Psychiatric Phenomics and Genomics University Hospital LMU Munich Munich Germany

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

Karl Jaspers Clinic European Medical School Oldenburg Groningen Oldenburg 26160 Germany

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

Laboratory of Neuroscience Institute of Psychiatry University of Sao Paulo São Paulo Brazil

Max Planck Institute of Psychiatry Munich Germany

Mental Health Research Group IMIM Hospital del Mar Barcelona Catalonia Spain

Montreal Neurological Institute and Hospital McGill University Montreal Canada

Mood Disorders Center of Ottawa Ontario Canada

National Institute of Mental Health Klecany Czech Republic

Neuroscience Research Australia Sydney NSW Australia

Neurosciences Section Department of Medicine Surgery and Dentistry Scuola Medica Salernitana University of Salerno Salerno Italy

Northern Adelaide Local Health Network Mental Health Services Adelaide SA Australia

Office of Mental Health VA San Diego Healthcare System San Diego CA USA

Pôle de Psychiatrie Générale Universitaire Hôpital Charles Perrens Bordeaux France

Program for Quantitative Genomics Harvard School of Public Health Boston MA USA

Psychiatric Genetic Unit Poznan University of Medical Sciences Poznan Poland

Psychiatrieverbund Oldenburger Land gGmbH Karl Jaspers Klinik Bad Zwischenahn 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 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

The Florey Institute of Neuroscience and Mental Health The University of Melbourne Parkville VIC Australia

The Neuromodulation Unit McGill University Health Centre Montreal Canada

Unit of Clinical Pharmacology Hospital University Agency of Cagliari Cagliari Italy

Unitat de Zoologia i Antropologia Biològica University of Barcelona CIBERSAM Barcelona Spain

Université Paris Cité Inserm Optimisation Thérapeutique en Neuropsychopharmacologie F 75006 Paris France

University Department of Psychiatry and Psychotherapy Tuebingen University of Tübingen Tuebingen Germany

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Exploring the genetics of lithium response in bipolar disorders

Lithium response in bipolar disorder is associated with focal adhesion and PI3K-Akt networks: a multi-omics replication study