BACKGROUND: Polygenic scores (PGSs) hold the potential to identify patients who respond favorably to specific psychiatric treatments. However, their biological interpretation remains unclear. In this study, we developed pathway-specific PGSs (PSPGSs) for lithium response and assessed their association with clinical lithium response in patients with bipolar disorder. METHODS: Using sets of genes involved in pathways affected by lithium, we developed 9 PSPGSs and evaluated their associations with lithium response in the International Consortium on Lithium Genetics (ConLi+Gen) (N = 2367), with validation in combined PsyCourse (Pathomechanisms and Signatures in the Longitudinal Course of Psychosis) (N = 105) and BipoLife (N = 102) cohorts. The association between each PSPGS and lithium response-defined both as a continuous ALDA score and a categorical outcome (good vs. poor responses)-was evaluated using regression models, with adjustment for confounders. The cutoff for a significant association was p < .05 after multiple testing correction. RESULTS: The PGSs for acetylcholine, GABA (gamma-aminobutyric acid), and mitochondria were associated with response to lithium in both categorical and continuous outcomes. However, the PGSs for calcium channel, circadian rhythm, and GSK (glycogen synthase kinase) were associated only with the continuous outcome. Each score explained 0.29% to 1.91% of the variance in the categorical and 0.30% to 1.54% of the variance in the continuous outcomes. A multivariate model combining PSPGSs that showed significant associations in the univariate analysis (combined PSPGS) increased the percentage of variance explained (R 2) to 3.71% and 3.18% for the categorical and continuous outcomes, respectively. Associations for PGSs for GABA and circadian rhythm were replicated. Patients with the highest genetic loading (10th decile) for acetylcholine variants were 3.03 times more likely (95% CI, 1.95 to 4.69) to show a good lithium response (categorical outcome) than patients with the lowest genetic loading (1st decile). CONCLUSIONS: PSPGSs achieved predictive performance comparable to the conventional genome-wide PGSs, with the added advantage of biological interpretability using a smaller list of genetic variants.

Polygenic scores (PGSs) have the potential to identify patients likely to respond to specific psychiatric treatments, but their biological interpretation remains unclear. In this study, we developed 9 pathway-specific PGSs (PSPGSs) for lithium response by aggregating genetic variants involved in pathways affected by lithium. We assessed their associations with lithium response in the International Consortium on Lithium Genetics (ConLi+Gen) (N = 2367) cohort and validated the findings in the PsyCourse (N = 105) and BipoLife (N = 102) cohorts. Clinical response to lithium treatment was significantly associated with PSPGSs for acetylcholine, GABA (gamma-aminobutyric acid), calcium channel signaling, mitochondria, circadian rhythm, and GSK pathways, with explained variance (R 2) ranging from 0.29% to 1.91%. The combined PSPGS explained up to 3.71% of the variability. Associations for GABA and circadian rhythm PGSs were successfully replicated. In a decile-based analysis, patients with the highest genetic load (10th decile) for acetylcholine pathway variants were 3.03 times more likely to respond well to lithium compared with those in the lowest decile (1st decile). PSPGSs achieved predictive performance comparable to conventional genome-wide PGSs, with better biological interpretability and a more focused set of genetic variants.

AMEOS Clinical Center Hildesheim Hildesheim Germany

Asrat Woldeyes Health Science Campus Debre Berhan University Debre Berhan Ethiopia

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

Bipolar and Depressive Disorders Program Institute of Neuroscience Hospital Clínic University of Barcelona IDIBAPS CIBERSAM Barcelona 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 Psychiatry Research Department of Clinical Neuroscience Karolinska Institute Stockholm Sweden

CIBERSAM 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 Poznań Poland

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

Department of Biomedical Resonance University of Tübingen Tübingen Germany

Department of Biomedical Sciences University of Cagliari Cagliari Italy

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

Department of Clinical Neurosciences Karolinska Institute Stockholm Sweden

Department of Clinical Psychiatry and Psychotherapy Brandenburg Medical School Brandenburg Germany

Department of General Psychiatry University of Tübingen Tübingen 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 Maryland

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 Kodaira Tokyo Japan

Department of Pharmacology Dalhousie University Halifax Nova Scotia Canada

Department of Psychiatry 2 Ulm University Bezirkskrankenhaus Günzburg Günzburg Germany

Department of Psychiatry and Behavioral Sciences Johns Hopkins University Baltimore Maryland

Department of Psychiatry and Behavioral Sciences Norton College of Medicine SUNY Upstate Medical University Syracuse New York

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 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 Psychotherapie University of Bern Bern Switzerland

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 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 Georg August University Göttingen Göttingen 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 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 Ohio

Department of Psychiatry Melbourne Medical School University of Melbourne Parkville Victoria Australia

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

Department of Psychiatry National Institute of Mental Health and Neuroscience Bangalore India

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

Department of Psychiatry Psychotherapy and Psychosomatic Medicine University Hospital of Würzburg Würzburg 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 California

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 California

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 Minnesota

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

Douglas Mental Health University Institute McGill University Montreal Quebec Canada

Florey Institute of Neuroscience and Mental Health University of Melbourne Parkville Victoria Australia

German Center for Neurodegenerative Diseases University of Göttingen Göttingen Germany

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

Inserm U955 Fondation FondaMental Translational Psychiatry Laboratory 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

Institut de Biomedicina de la Universität de Barcelona Barcelona Spain

Institut de Recerca Sant Joan de Déu Esplugues de Llobregat Spain

Institut National de la Santé et de la Recherche Médicale UMR S 1144 Université Paris Cité Département de Psychiatrie et de Médecine Addictologique L'Assistance Publique Hôpitaux de Paris Groupe Hospitalier Saint Louis Lariboisière F Widal Paris France

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 Medical Genetics and Pathology University Hospital Basel Basel Switzerland

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 Ludwig Maximilian University of Munich Munich Germany

Intramural Research Program National Institute of Mental Health National Institutes of Health United States Department of Health and Human Services Bethesda Maryland

Karl Jaspers Clinic European Medical School Oldenburg Groningen Oldenburg Germany

Laboratory for Molecular Dynamics of Mental Disorders RIKEN Brain Science Institute Saitama 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 Hospital del Mar Medical Research Institute Barcelona Catalonia Spain

Montreal Neurological Institute and Hospital McGill University Montreal Quebec Canada

Mood Disorders Center of Ottawa Ottawa Ontario Canada

National Institute of Mental Health Klecany Czechia

Neuromodulation Unit McGill University Health Centre Montreal Quebec Canada

Neuroscience Research Australia Sydney New South Wales 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 South Australia Australia

Office of Mental Health VA San Diego Healthcare System San Diego California

Pôle de Psychiatrie Générale Universitaire Hôpital Charles Perrens Bordeaux France

Psychiatric Genetic Unit Poznan University of Medical Sciences Poznań Poland

Psychiatrieverbund Oldenburger Land GmbH Karl Jaspers Klinik Bad Zwischenahn Germany

School of Biomedical 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

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 CIBERSAM Barcelona Spain

Université Paris Cité Inserm Optimisation Thérapeutique en Neuropsychopharmacologie Paris France

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

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medRxiv. 2025 Mar 24:2025.03.20.25324216. doi: 10.1101/2025.03.20.25324216. PubMed

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