Lithium is the gold standard therapy for Bipolar Disorder (BD) but its effectiveness differs widely between individuals. The molecular mechanisms underlying treatment response heterogeneity are not well understood, and personalized treatment in BD remains elusive. Genetic analyses of the lithium treatment response phenotype may generate novel molecular insights into lithium's therapeutic mechanisms and lead to testable hypotheses to improve BD management and outcomes. We used fixed effect meta-analysis techniques to develop meta-analytic polygenic risk scores (MET-PRS) from combinations of highly correlated psychiatric traits, namely schizophrenia (SCZ), major depression (MD) and bipolar disorder (BD). We compared the effects of cross-disorder MET-PRS and single genetic trait PRS on lithium response. For the PRS analyses, we included clinical data on lithium treatment response and genetic information for n = 2283 BD cases from the International Consortium on Lithium Genetics (ConLi+Gen; www.ConLiGen.org ). Higher SCZ and MD PRSs were associated with poorer lithium treatment response whereas BD-PRS had no association with treatment outcome. The combined MET2-PRS comprising of SCZ and MD variants (MET2-PRS) and a model using SCZ and MD-PRS sequentially improved response prediction, compared to single-disorder PRS or to a combined score using all three traits (MET3-PRS). Patients in the highest decile for MET2-PRS loading had 2.5 times higher odds of being classified as poor responders than patients with the lowest decile MET2-PRS scores. An exploratory functional pathway analysis of top MET2-PRS variants was conducted. Findings may inform the development of future testing strategies for personalized lithium prescribing in BD.

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 IDIBAPS CIBERSAM Barcelona Catalonia Spain

Centre for Healthy Brain Ageing School of Psychiatry University of New South Wales Sydney NSW Australia

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

Centro de Investigación Biomédica en Salud Mental Madrid Spain

Departament de Genètica Microbiologia i Estadística Facultat de Biologia Universitat de Barcelona Barcelona 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 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 Medical Epidemiology and Biostatistics Karolinska Institutet Stockholm Sweden

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

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

Department of Molecular Medicine and Surgery Karolinska Institute 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 NS Canada

Department of Psychiatry and Behavioral Science Juntendo University Graduate School of Medicine Tokyo Japan

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 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 Charité Universitätsmedizin Berlin Campus Charité Mitte Berlin Germany

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

Department of Psychiatry Dalhousie University Halifax NS Canada

Department of Psychiatry Dokkyo Medical 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 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 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 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 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 SA Australia

Douglas Mental Health University Institute McGill University Montreal QC 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 MD USA

HSL Institute for Aging Research Harvard Medical School Boston MA USA

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

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

INSERM UMR S 1144 Université Paris Diderot 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 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 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

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 QC Canada

Mood Disorders Center of Ottawa Ottawa ON Canada

National Institute of Mental Health Klecany Czech Republic

Neuroscience Research Australia Sydney NSW Australia

Northern Adelaide Local Health Network Mental Health Services Adelaide SA Australia

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

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

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 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

Service de psychiatrie Hôpital Charles Perrens Bordeaux France

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

The Neuromodulation Unit McGill University Health Centre Montreal QC Canada

Unit of Clinical Pharmacology Hospital University Agency of Cagliari Cagliari Italy

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

Univ Paris Est Créteil INSERM IMRB Translational Neuropsychiatry Fondation FondaMental Créteil France

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Transl Psychiatry. 2022 Jul 11;12(1):278. doi: 10.1038/s41398-022-02037-2. PubMed

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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