Lithium is the gold standard treatment for bipolar disorder (BD). However, its mechanism of action is incompletely understood, and prediction of treatment outcomes is limited. In our previous multi-omics study of the Pharmacogenomics of Bipolar Disorder (PGBD) sample combining transcriptomic and genomic data, we found that focal adhesion, the extracellular matrix (ECM), and PI3K-Akt signaling networks were associated with response to lithium. In this study, we replicated the results of our previous study using network propagation methods in a genome-wide association study of an independent sample of 2039 patients from the International Consortium on Lithium Genetics (ConLiGen) study. We identified functional enrichment in focal adhesion and PI3K-Akt pathways, but we did not find an association with the ECM pathway. Our results suggest that deficits in the neuronal growth cone and PI3K-Akt signaling, but not in ECM proteins, may influence response to lithium in BD.

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 and Depressive Disorders Unit Institute of Neuroscience Hospital Clinic University of Barcelona IDIBAPS CIBERSAM ISCIII Barcelona Catalonia Spain

Bipolar Center Wiener Neustadt Austria

Campus for Ageing and Vitality Newcastle University Newcastle upon Tyne UK

Center for Computational Biology and Bioinformatics Department of Medicine University of California San Diego La Jolla CA USA

Child and Adolescent Psychiatry Research Center Stockholm Sweden

CIBER de Salud Mental ISCIII Madrid Barcelona Catalonia Spain

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 Clinical Neuroscience Karolinska Institutet and Center for Molecular Medicine Karolinska University Hospital Stockholm Sweden

Department of Clinical Neurosciences Karolinska Institutet Stockholm Sweden

Department of Evolutive Biology Ecology and Environmental Sciences Facultat de Biologia and Institut de Biomedicina Universitat de Barcelona Barcelona Spain

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 and Institut de Biomedicina Universitat de Barcelona Barcelona CIBER de Salud Mental ISCIII Madrid Spain

Department of Health Sciences Research Mayo Clinic Rochester MN USA

Department of Medical Epidemiology and Biostatistics Karolinska Institutet Stockholm Sweden

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

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

Department of Pathology of Mental Diseases National Institute of Mental Health National Center of Neurology and Psychiatry Tokyo Japan

Department of Pharmacology Dalhousie University Halifax NS Canada

Department of Pharmacy VA San Diego Healthcare System La Jolla CA USA

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 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 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 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 Goethe University Frankfurt am Main 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 La Jolla 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 Münster Münster Germany

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 La Jolla CA USA

Discipline of Psychiatry University of Adelaide Adelaide SA Australia

Douglas Mental Health University Institute McGill University Montreal QC Canada

Fliedner Klinik Berlin Center for Psychiatry Psychotherapy and Psychosomatic Medicine Berlin Germany

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

Inserm U955 Psychiatrie Translationnelle Créteil France

INSERM UMR S 1144 Université Paris Cité Département de Psychiatrie et de Médecine Addictologique 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 Neuroscience and Physiology The Sahlgrenska Academy at the Gothenburg University Gothenburg Sweden

Institute of Psychiatric Phenomics and Genomics and Department of Psychiatry and Psychotherapy Ludwig Maximilians University of 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

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

Ludwig Maximilians University of Munich Munich Germany

Mental Illness Research Theme Neuroscience Research Australia Sydney NSW Australia

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 Division of Psychiatry and Psychotherapeutic Medicine Medical University of Graz Graz Austria

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

Pôle de Psychiatrie Générale Universitaire Centre Hospitalier Charles Perrens Bordeaux France

Psychiatric Genetic Unit Poznan University of Medical Sciences Poznan Poland

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

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 QLD Australia

Unit of Clinical Pharmacology Hospital University Agency of Cagliari Cagliari Italy

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

Veterans Administration San Diego Healthcare System San Diego CA USA

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Pathway-Specific Polygenic Scores for Predicting Clinical Lithium Treatment Response in Patients With Bipolar Disorder