IMPORTANCE: Lithium is a first-line mood stabilizer for the treatment of bipolar affective disorder (BPAD). However, the efficacy of lithium varies widely, with a nonresponse rate of up to 30%. Biological response markers are lacking. Genetic factors are thought to mediate treatment response to lithium, and there is a previously reported genetic overlap between BPAD and schizophrenia (SCZ). OBJECTIVES: To test whether a polygenic score for SCZ is associated with treatment response to lithium in BPAD and to explore the potential molecular underpinnings of this association. DESIGN, SETTING, AND PARTICIPANTS: A total of 2586 patients with BPAD who had undergone lithium treatment were genotyped and assessed for long-term response to treatment between 2008 and 2013. Weighted SCZ polygenic scores were computed at different P value thresholds using summary statistics from an international multicenter genome-wide association study (GWAS) of 36 989 individuals with SCZ and genotype data from patients with BPAD from the Consortium on Lithium Genetics. For functional exploration, a cross-trait meta-GWAS and pathway analysis was performed, combining GWAS summary statistics on SCZ and response to treatment with lithium. Data analysis was performed from September 2016 to February 2017. MAIN OUTCOMES AND MEASURES: Treatment response to lithium was defined on both the categorical and continuous scales using the Retrospective Criteria of Long-Term Treatment Response in Research Subjects with Bipolar Disorder score. The effect measures include odds ratios and the proportion of variance explained. RESULTS: Of the 2586 patients in the study (mean [SD] age, 47.2 [13.9] years), 1478 were women and 1108 were men. The polygenic score for SCZ was inversely associated with lithium treatment response in the categorical outcome, at a threshold P < 5 × 10-2. Patients with BPAD who had a low polygenic load for SCZ responded better to lithium, with odds ratios for lithium response ranging from 3.46 (95% CI, 1.42-8.41) at the first decile to 2.03 (95% CI, 0.86-4.81) at the ninth decile, compared with the patients in the 10th decile of SCZ risk. In the cross-trait meta-GWAS, 15 genetic loci that may have overlapping effects on lithium treatment response and susceptibility to SCZ were identified. Functional pathway and network analysis of these loci point to the HLA antigen complex and inflammatory cytokines. CONCLUSIONS AND RELEVANCE: This study provides evidence for a negative association between high genetic loading for SCZ and poor response to lithium in patients with BPAD. These results suggest the potential for translational research aimed at personalized prescribing of lithium.

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

Bipolar Center Wiener Neustadt Sigmund Freud University Medical Faculty Vienna Austria

Bipolar Disorder Program Institute of Neuroscience Hospital Clinic University of Barcelona Institut d'Investigacions Biomèdiques August Pi i Sunyer Centro de Investigación Biomédica en Red Salud Mental Barcelona Catalonia Spain

Broad Institute of Massachusetts Institute of Technology and Harvard Cambridge Massachusetts

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

Clinical Neuroscience Max Planck Institute of Experimental Medicine Göttingen 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 Sciences University of Cagliari Cagliari Italy

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 Minnesota

Department of Medical Epidemiology and Biostatistics Karolinska Institutet Stockholm Sweden

Department of Mental Health Johns Hopkins Bloomberg School of Public Health Baltimore Maryland

Department of Molecular Medicine and Surgery Karolinska Institutet Stockholm Sweden 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 Pharmacology Dalhousie University Halifax Nova Scotia Canada

Department of Pharmacy Veterans Affairs San Diego Healthcare System San Diego California

Department of Psychiatry 2nd University of Naples Naples Italy

Department of Psychiatry and Behavioral Sciences Johns Hopkins University Baltimore Maryland

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

Department of Psychiatry and Psychology Mayo Clinic Rochester Minnesota

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 Charité Universitätsmedizin Berlin Campus Charité Mitte Berlin Germany

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

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

Department of Psychiatry and Psychotherapy University Medical Center Georg August University Göttingen Göttingen Germany

Department of Psychiatry Dalhousie University Halifax Nova Scotia Canada

Department of Psychiatry Dokkyo University School of Medicine Mibu Tochigi Japan

Department of Psychiatry Hokkaido University Graduate School of Medicine Sapporo Japan

Department of Psychiatry Lindner Center of Hope and University of Cincinnati Mason Ohio

Department of Psychiatry Mood Disorders Unit Geneva University Hospitals Geneva Switzerland

Department of Psychiatry Nagoya University Graduate School of Medicine Nagoya Aichi Japan

Department of Psychiatry Osaka University Graduate School of Medicine Osaka Japan

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

Department of Psychiatry University of Basel Basel Switzerland

Department of Psychiatry University of California San Diego

Department of Psychiatry University of Perugia Perugia Italy

Department of Psychiatry Veterans Affairs San Diego Healthcare System San Diego California

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

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

Douglas Mental Health University Institute McGill University Montreal Canada

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

Hebrew SeniorLife Institute for Aging Research Harvard Medical School Boston Massachusetts

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

Inserm U955 Translational Psychiatry Laboratory Université Paris Est Créteil Department of Psychiatry and Addictology of Mondor University Hospital Assistance Publique Hôpitaux de Paris Hôpital Albert Chenevier Henri Mondor Pôle de Psychiatrie Créteil France

Institut National de la Santé et de la Recherche Médicale Unité 955 Psychiatrie Translationnelle Créteil France

Institut National de la Santé et de la Recherche Médicale Unité Mixte de Recherche Scientifique 1144 Université Paris Diderot Département de Psychiatrie et de Médecine Addictologique Assistance Publique Hôpitaux de Paris Groupe Hospitalier Saint Louis Lariboisière F Widal Paris France

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

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

Institute of Psychiatric Phenomics and Genomics University Hospital Ludwig Maximilian 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 Maryland

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

Mental Health Research Group IMIM Hospital del Mar Barcelona Catalonia Spain

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 Canada

Mood Disorders Center of Ottawa Ontario Canada

National Institute of Mental Health Klecany Czech Republic

Neuroscience Research Australia Sydney New South Wales Australia

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

Northern Adelaide Local Health Network Mental Health Services Adelaide South Australia Australia

Program for Quantitative Genomics Harvard School of Public Health Boston Massachusetts

Psychiatric Genetic Unit Poznan University of Medical Sciences Poznan Poland

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

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

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 Facultat de Biologia and Institut de Biomedicina University of Barcelona Centro de Investigación Biomédica en Red de Salud Mental Barcelona Spain

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

Exploring the genetics of lithium response in bipolar disorders

Association of polygenic score and the involvement of cholinergic and glutamatergic pathways with lithium treatment response in patients with bipolar disorder

Association of Attention-Deficit/Hyperactivity Disorder and Depression Polygenic Scores with Lithium Response: A Consortium for Lithium Genetics Study

Combining schizophrenia and depression polygenic risk scores improves the genetic prediction of lithium response in bipolar disorder patients

HLA-DRB1 and HLA-DQB1 genetic diversity modulates response to lithium in bipolar affective disorders

Association of polygenic score for major depression with response to lithium in patients with bipolar disorder

Exemplar scoring identifies genetically separable phenotypes of lithium responsive bipolar disorder

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