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

Nigussie T Sharew^{1

2}, Scott R Clark¹, Sergi Papiol^{3

4}, Urs Heilbronner³, Franziska Degenhardt^{5

6}, Janice M Fullerton^{7

8}, Liping Hou⁹, Tatyana Shekhtman¹⁰, Mazda Adli¹¹, Nirmala Akula⁹, Kazufumi Akiyama¹², Raffaella Ardau¹³, Bárbara Arias¹⁴, Roland Hasler¹⁵, Hélène Richard-Lepouriel¹⁵, Nader Perroud¹⁵, Lena Backlund^{16

17}, Abesh Kumar Bhattacharjee¹⁰, Frank Bellivier¹⁸, Antonio Benabarre¹⁹, Susanne Bengesser²⁰, Joanna M Biernacka^{21

22}, Armin Birner²⁰, Cynthia Marie-Claire^{18

23}, Pablo Cervantes²⁴, Hsi-Chung Chen²⁵, Caterina Chillotti¹³, Sven Cichon^{26

27

28}, Cristiana Cruceanu²⁹, Piotr M Czerski³⁰, Nina Dalkner²⁰, Maria Del Zompo³¹, J Raymond DePaulo³², Bruno Étain¹⁸, Stephane Jamain³³, Peter Falkai^{4

34}, Andreas J Forstner^{5

28}, Louise Frisen^{16

35}, Mark A Frye²², Sébastien Gard³⁶, Julie S Garnham³⁷, Fernando S Goes³², Maria Grigoroiu-Serbanescu³⁷, Andreas J Fallgatter³⁸, Sophia Stegmaier³⁹, Thomas Ethofer^{40

41}, Silvia Biere⁴², Kristiyana Petrova⁴², Ceylan Schuster⁴², Kristina Adorjan^{3

43}, Monika Budde³, Maria Heilbronner³, Janos L Kalman^{3

4}, Mojtaba Oraki Kohshour^{3

44}, Daniela Reich-Erkelenz³, Sabrina K Schaupp³, Eva C Schulte^{3

4}, Fanny Senner^{3

4}, Thomas Vogl³, Ion-George Anghelescu⁴⁵, Volker Arolt⁴⁶, Udo Dannlowski⁴⁶, Detlef E Dietrich^{47

48}, Christian Figge⁴⁹, Markus Jäger⁵⁰, Fabian U Lang⁵⁰, Georg Juckel⁵¹, Carsten Konrad⁵², Jens Reimer^{53

54}, Max Schmauß⁵⁵, Andrea Schmitt^{4

56}, Carsten Spitzer⁵⁷, Martin von Hagen⁵⁸, Jens Wiltfang^{59

60}, Jörg Zimmermann⁶¹, Till F M Andlauer⁶², Andre Fischer⁶⁰, Felix Bermpohl¹¹, Philipp Ritter⁶³, Silke Matura⁴², Anna Gryaznova³, Irina Falkenberg⁶⁴, Cüneyt Yildiz⁶⁴, Tilo Kircher⁶⁴, Julia Schmidt⁶⁵, Marius Koch⁶⁵, Kathrin Gade⁵⁹, Sarah Trost⁵⁹, Ida S Haussleiter⁵¹, Martin Lambert⁵³, Anja C Rohenkohl⁵³, Vivien Kraft⁵³, Paul Grof⁶⁶, Ryota Hashimoto⁶⁷, Joanna Hauser³⁰, Stefan Herms^{5

27}, Per Hoffmann^{5

27}, Esther Jiménez¹⁹, Jean-Pierre Kahn⁶⁸, Layla Kassem¹¹, Po-Hsiu Kuo⁶⁹, Tadafumi Kato⁷⁰, John Kelsoe¹⁰, Sarah Kittel-Schneider^{71

72}, Ewa Ferensztajn-Rochowiak⁷³, Barbara König⁷⁴, Ichiro Kusumi⁷⁵, Gonzalo Laje¹¹, Mikael Landén^{76

77}, Catharina Lavebratt^{16

17}, Marion Leboyer⁷⁸, Susan G Leckband⁷⁹, Alfonso Tortorella⁸⁰, Mirko Manchia^{81

82}, Lina Martinsson⁸³, Michael J McCarthy^{10

84}, Susan McElroy⁸⁵, Francesc Colom^{86

87}, Vincent Millischer^{16

17

88}, Marina Mitjans^{87

89

90

91}, Francis M Mondimore³², Palmiero Monteleone^{92

93}, Caroline M Nievergelt¹⁰, Markus M Nöthen⁵, Tomas Novák⁹⁴, Claire O'Donovan³⁷, Norio Ozaki⁹⁵, Andrea Pfennig⁶³, Claudia Pisanu³¹, James B Potash³², Andreas Reif⁷¹, Eva Reininghaus²⁰, Guy A Rouleau⁹⁶, Janusz K Rybakowski⁷³, Martin Schalling^{16

17}, Peter R Schofield^{7

8}, Barbara W Schweizer³², Giovanni Severino³¹, Paul D Shilling¹⁰, Katzutaka Shimoda⁹⁷, Christian Simhandl⁹⁸, Claire M Slaney³⁷, Alessio Squassina³¹, Thomas Stamm^{11

99}, Pavla Stopkova⁹⁴, Mario Maj⁹³, Gustavo Turecki²⁹, Eduard Vieta¹⁹, Julia Veeh⁷⁶, Biju Viswanath¹⁰⁰, Stephanie H Witt¹⁰¹, Adam Wright¹⁰², Peter P Zandi¹⁰³, Philip B Mitchell¹⁰², Michael Bauer⁶³, Martin Alda^{37

94}, Marcella Rietschel¹⁰¹, Francis J McMahon⁹, Thomas G Schulze^{3

9

32

101

104

105}, Bernhard T Baune^{106

107

108}, Klaus Oliver Schubert^{1

109}, Azmeraw T Amare¹

Affiliations

¹ Discipline of Psychiatry, School of Medicine, University of Adelaide, Adelaide, South Australia, Australia.
² Asrat Woldeyes Health Science Campus, Debre Berhan University, Debre Berhan, Ethiopia.
³ Institute of Psychiatric Phenomics and Genomics, University Hospital, Ludwig Maximilian University of Munich, Munich, Germany.
⁴ Department of Psychiatry and Psychotherapy, University Hospital, Ludwig-Maximilian-University Munich, Munich, Germany.
⁵ Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany.
⁶ Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University of Duisburg-Essen, Rheinische Kliniken, Essen, Germany.
⁷ Neuroscience Research Australia, Sydney, New South Wales, Australia.
⁸ School of Biomedical Sciences, University of New South Wales, Sydney, New South Wales, Australia.
⁹ Intramural Research Program, National Institute of Mental Health, National Institutes of Health, United States Department of Health and Human Services, Bethesda, Maryland.
¹⁰ Department of Psychiatry, University of California San Diego, San Diego, California.
¹¹ Department of Psychiatry and Psychotherapy, Charité Universitätsmedizin Berlin, Campus Charité Mitte, Berlin, Germany.
¹² Department of Biological Psychiatry and Neuroscience, Dokkyo Medical University School of Medicine, Tochigi, Japan.
¹³ Unit of Clinical Pharmacology, Hospital University Agency of Cagliari, Cagliari, Italy.
¹⁴ Unitat de Zoologia i Antropologia Biològica (Dpt. Biologia Evolutiva, Ecologia i Ciències Ambientals), Facultat de Biologia and Institut de Biomedicina, University of Barcelona, CIBERSAM, Barcelona, Spain.
¹⁵ Department of Psychiatry, Mood Disorders Unit, HUG - Geneva University Hospitals, Geneva, Switzerland.
¹⁶ Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden.
¹⁷ Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden.
¹⁸ Institut National de la Santé et de la Recherche Médicale (INSERM) 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.
¹⁹ Bipolar and Depressive Disorders Program, Institute of Neuroscience, Hospital Clínic, University of Barcelona, IDIBAPS, CIBERSAM, Barcelona, Spain.
²⁰ Department of Psychiatry and Psychotherapeutic Medicine, Research Unit for Bipolar Affective Disorder, Medical University of Graz, Graz, Austria.
²¹ Department of Quantitative Health Sciences, Mayo Clinic, Rochester, Minnesota.
²² Department of Psychiatry and Psychology, Mayo Clinic, Rochester, Minnesota.
²³ Université Paris Cité, Inserm, Optimisation Thérapeutique en Neuropsychopharmacologie, Paris, France.
²⁴ Neuromodulation Unit, McGill University Health Centre, Montreal, Quebec, Canada.
²⁵ Department of Psychiatry & Center of Sleep Disorders, National Taiwan University Hospital, Taipei, Taiwan.
²⁶ Human Genomics Research Group, Department of Biomedicine, University Hospital Basel, Basel, Switzerland.
²⁷ Institute of Medical Genetics and Pathology, University Hospital Basel, Basel, Switzerland.
²⁸ Institute of Neuroscience and Medicine, Research Center Jülich, Jülich, Germany.
²⁹ Douglas Mental Health University Institute, McGill University, Montreal, Quebec, Canada.
³⁰ Psychiatric Genetic Unit, Poznan University of Medical Sciences, Poznań, Poland.
³¹ Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy.
³² Department of Psychiatry and Behavioral Sciences, Johns Hopkins University, Baltimore, Maryland.
³³ Inserm U955, Fondation FondaMental, Translational Psychiatry Laboratory, Créteil, France.
³⁴ Max Planck Institute of Psychiatry, Munich, Germany.
³⁵ Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden.
³⁶ Pôle de Psychiatrie Générale Universitaire, Hôpital Charles Perrens, Bordeaux, France.
³⁷ Department of Psychiatry, Dalhousie University, Halifax, Nova Scotia, Canada.
³⁸ Biometric Psychiatric Genetics Research Unit, Alexandru Obregia Clinical Psychiatric Hospital, Bucharest, Romania.
³⁹ University Department of Psychiatry and Psychotherapy Tuebingen, University of Tübingen, Tübingen, Germany.
⁴⁰ Department of General Psychiatry, University of Tübingen, Tübingen, Germany.
⁴¹ Department of Biomedical Resonance, University of Tübingen, Tübingen, Germany.
⁴² Department of Psychiatry, Psychotherapy and Psychosomatics, University Hospital of Frankfurt, Goethe University, Frankfurt, Germany.
⁴³ Department of Psychiatry and Psychotherapie, University of Bern, Bern, Switzerland.
⁴⁴ Department of Immunology, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
⁴⁵ Department of Psychiatry and Psychotherapy, Mental Health Institute Berlin, Berlin, Germany.
⁴⁶ Institute for Translational Psychiatry, University of Münster, Münster, Germany.
⁴⁷ AMEOS Clinical Center Hildesheim, Hildesheim, Germany.
⁴⁸ Center for Systems Neuroscience, Hannover, Germany.
⁴⁹ Karl-Jaspers Clinic, European Medical School Oldenburg-Groningen, Oldenburg, Germany.
⁵⁰ Department of Psychiatry II, Ulm University, Bezirkskrankenhaus Günzburg, Günzburg, Germany.
⁵¹ Department of Psychiatry, Ruhr University Bochum, LWL University Hospital, Bochum, Germany.
⁵² Department of Psychiatry and Psychotherapy, Agaplesion Diakonieklinikum, Rotenburg, Germany.
⁵³ Department of Psychiatry and Psychotherapy, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
⁵⁴ Department of Psychiatry, Health North Hospital Group, Bremen, Germany.
⁵⁵ Department of Psychiatry and Psychotherapy, Bezirkskrankenhaus Augsburg, Augsburg, Germany.
⁵⁶ Laboratory of Neuroscience, Institute of Psychiatry, University of Sao Paulo, São Paulo, Brazil.
⁵⁷ Department of Psychosomatic Medicine and Psychotherapy, University Medical Center Rostock, Rostock, Germany.
⁵⁸ Clinic for Psychiatry and Psychotherapy, Clinical Center Werra-Meißner, Eschwege, Germany.
⁵⁹ Department of Psychiatry and Psychotherapy, University Medical Center Göttingen, Göttingen, Germany.
⁶⁰ German Center for Neurodegenerative Diseases, University of Göttingen, Göttingen, Germany.
⁶¹ Psychiatrieverbund Oldenburger Land GmbH, Karl-Jaspers-Klinik, Bad Zwischenahn, Germany.
⁶² Department of Neurology, University Hospital Rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany.
⁶³ Department of Psychiatry and Psychotherapy, University Hospital Carl Gustav Carus, Medical Faculty, Technische Universität Dresden, Dresden, Germany.
⁶⁴ Department of Psychiatry and Psychotherapy, Philipps-University, Marburg, Germany.
⁶⁵ Institute for Medical Informatics, University Medical Center Göttingen, Göttingen, Germany.
⁶⁶ Mood Disorders Center of Ottawa, Ottawa, Ontario, Canada.
⁶⁷ Department of Pathology of Mental Diseases, National Institute of Mental Health, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan.
⁶⁸ Service de Psychiatrie et Psychologie Clinique, Centre Psychothérapique de Nancy, Université de Lorraine, Nancy, France.
⁶⁹ Department of Public Health & Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan.
⁷⁰ Laboratory for Molecular Dynamics of Mental Disorders, RIKEN Brain Science Institute, Saitama, Saitama, Japan.
⁷¹ Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt, Frankfurt, Germany.
⁷² Department of Psychiatry, Psychotherapy and Psychosomatic Medicine, University Hospital of Würzburg, Würzburg, Germany.
⁷³ Department of Adult Psychiatry, Poznan University of Medical Sciences, Poznań, Poland.
⁷⁴ Department of Psychiatry and Psychotherapeutic Medicine, Landesklinikum Neunkirchen, Neunkirchen, Austria.
⁷⁵ Department of Psychiatry, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
⁷⁶ Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the Gothenburg University, Gothenburg, Sweden.
⁷⁷ Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
⁷⁸ Inserm U955, Translational Psychiatry Laboratory, Université Paris-Est-Créteil, Department of Psychiatry and Addictology of Mondor University Hospital, AP-HP, Fondation FondaMental, Créteil, France.
⁷⁹ Office of Mental Health, VA San Diego Healthcare System, San Diego, California.
⁸⁰ Department of Psychiatry, University of Perugia, Perugia, Italy.
⁸¹ Section of Psychiatry, Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy.
⁸² Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada.
⁸³ Department of Clinical Neurosciences, Karolinska Institute, Stockholm, Sweden.
⁸⁴ Department of Psychiatry, VA San Diego Healthcare System, San Diego, California.
⁸⁵ Department of Psychiatry, Lindner Center of Hope, University of Cincinnati, Mason, Ohio.
⁸⁶ Mental Health Research Group, Hospital del Mar Medical Research Institute, Barcelona, Catalonia, Spain.
⁸⁷ Department of Genetics, Microbiology and Statistics, Faculty of Biology, University of Barcelona, Barcelona, Spain.
⁸⁸ Department of Psychiatry and Psychotherapy, Medical University of Vienna, Vienna, Austria.
⁸⁹ CIBERSAM, Instituto de Salud Carlos III, Madrid, Spain.
⁹⁰ Institut de Biomedicina de la Universität de Barcelona, Barcelona, Spain.
⁹¹ Institut de Recerca Sant Joan de Déu, Esplugues de Llobregat, Spain.
⁹² Neurosciences Section, Department of Medicine, Surgery and Dentistry "Scuola Medica Salernitana", University of Salerno, Salerno, Italy.
⁹³ Department of Psychiatry, University of Campania "Luigi Vanvitelli", Naples, Italy.
⁹⁴ National Institute of Mental Health, Klecany, Czechia.
⁹⁵ Department of Psychiatry & Department of Child and Adolescent Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Japan.
⁹⁶ Montreal Neurological Institute and Hospital, McGill University, Montreal, Quebec, Canada.
⁹⁷ Department of Psychiatry, Dokkyo Medical University School of Medicine, Tochigi, Japan.
⁹⁸ Bipolar Center Wiener Neustadt, Sigmund Freud University, Medical Faculty, Vienna, Austria.
⁹⁹ Department of Clinical Psychiatry and Psychotherapy, Brandenburg Medical School, Brandenburg, Germany.
¹⁰⁰ Department of Psychiatry, National Institute of Mental Health and Neuroscience, Bangalore, India.
¹⁰¹ Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
¹⁰² School of Psychiatry, University of New South Wales and Black Dog Institute, Sydney, New South Wales, Australia.
¹⁰³ Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.
¹⁰⁴ Department of Psychiatry and Behavioral Sciences, Norton College of Medicine, SUNY Upstate Medical University, Syracuse, New York.
¹⁰⁵ Department of Psychiatry and Psychotherapy, University Medical Center, Georg-August University Göttingen, Göttingen, Germany.
¹⁰⁶ Department of Psychiatry and Psychotherapy, University of Münster, Münster, Germany.
¹⁰⁷ Department of Psychiatry, Melbourne Medical School, University of Melbourne, Parkville, Victoria, Australia.
¹⁰⁸ Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, Victoria, Australia.
¹⁰⁹ Northern Adelaide Local Health Network, Mental Health Services, Adelaide, South Australia, Australia.

PMID: 40821394
PMCID: PMC12357302
DOI: 10.1016/j.bpsgos.2025.100558

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

Nigussie T Sharew et al. Biol Psychiatry Glob Open Sci. 2025.

. 2025 Jun 25;5(5):100558.

doi: 10.1016/j.bpsgos.2025.100558. eCollection 2025 Sep.

Authors

Affiliations

¹ Discipline of Psychiatry, School of Medicine, University of Adelaide, Adelaide, South Australia, Australia.
² Asrat Woldeyes Health Science Campus, Debre Berhan University, Debre Berhan, Ethiopia.
³ Institute of Psychiatric Phenomics and Genomics, University Hospital, Ludwig Maximilian University of Munich, Munich, Germany.
⁴ Department of Psychiatry and Psychotherapy, University Hospital, Ludwig-Maximilian-University Munich, Munich, Germany.
⁵ Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany.
⁶ Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University of Duisburg-Essen, Rheinische Kliniken, Essen, Germany.
⁷ Neuroscience Research Australia, Sydney, New South Wales, Australia.
⁸ School of Biomedical Sciences, University of New South Wales, Sydney, New South Wales, Australia.
⁹ Intramural Research Program, National Institute of Mental Health, National Institutes of Health, United States Department of Health and Human Services, Bethesda, Maryland.
¹⁰ Department of Psychiatry, University of California San Diego, San Diego, California.
¹¹ Department of Psychiatry and Psychotherapy, Charité Universitätsmedizin Berlin, Campus Charité Mitte, Berlin, Germany.
¹² Department of Biological Psychiatry and Neuroscience, Dokkyo Medical University School of Medicine, Tochigi, Japan.
¹³ Unit of Clinical Pharmacology, Hospital University Agency of Cagliari, Cagliari, Italy.
¹⁴ Unitat de Zoologia i Antropologia Biològica (Dpt. Biologia Evolutiva, Ecologia i Ciències Ambientals), Facultat de Biologia and Institut de Biomedicina, University of Barcelona, CIBERSAM, Barcelona, Spain.
¹⁵ Department of Psychiatry, Mood Disorders Unit, HUG - Geneva University Hospitals, Geneva, Switzerland.
¹⁶ Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden.
¹⁷ Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden.
¹⁸ Institut National de la Santé et de la Recherche Médicale (INSERM) 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.
¹⁹ Bipolar and Depressive Disorders Program, Institute of Neuroscience, Hospital Clínic, University of Barcelona, IDIBAPS, CIBERSAM, Barcelona, Spain.
²⁰ Department of Psychiatry and Psychotherapeutic Medicine, Research Unit for Bipolar Affective Disorder, Medical University of Graz, Graz, Austria.
²¹ Department of Quantitative Health Sciences, Mayo Clinic, Rochester, Minnesota.
²² Department of Psychiatry and Psychology, Mayo Clinic, Rochester, Minnesota.
²³ Université Paris Cité, Inserm, Optimisation Thérapeutique en Neuropsychopharmacologie, Paris, France.
²⁴ Neuromodulation Unit, McGill University Health Centre, Montreal, Quebec, Canada.
²⁵ Department of Psychiatry & Center of Sleep Disorders, National Taiwan University Hospital, Taipei, Taiwan.
²⁶ Human Genomics Research Group, Department of Biomedicine, University Hospital Basel, Basel, Switzerland.
²⁷ Institute of Medical Genetics and Pathology, University Hospital Basel, Basel, Switzerland.
²⁸ Institute of Neuroscience and Medicine, Research Center Jülich, Jülich, Germany.
²⁹ Douglas Mental Health University Institute, McGill University, Montreal, Quebec, Canada.
³⁰ Psychiatric Genetic Unit, Poznan University of Medical Sciences, Poznań, Poland.
³¹ Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy.
³² Department of Psychiatry and Behavioral Sciences, Johns Hopkins University, Baltimore, Maryland.
³³ Inserm U955, Fondation FondaMental, Translational Psychiatry Laboratory, Créteil, France.
³⁴ Max Planck Institute of Psychiatry, Munich, Germany.
³⁵ Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden.
³⁶ Pôle de Psychiatrie Générale Universitaire, Hôpital Charles Perrens, Bordeaux, France.
³⁷ Department of Psychiatry, Dalhousie University, Halifax, Nova Scotia, Canada.
³⁸ Biometric Psychiatric Genetics Research Unit, Alexandru Obregia Clinical Psychiatric Hospital, Bucharest, Romania.
³⁹ University Department of Psychiatry and Psychotherapy Tuebingen, University of Tübingen, Tübingen, Germany.
⁴⁰ Department of General Psychiatry, University of Tübingen, Tübingen, Germany.
⁴¹ Department of Biomedical Resonance, University of Tübingen, Tübingen, Germany.
⁴² Department of Psychiatry, Psychotherapy and Psychosomatics, University Hospital of Frankfurt, Goethe University, Frankfurt, Germany.
⁴³ Department of Psychiatry and Psychotherapie, University of Bern, Bern, Switzerland.
⁴⁴ Department of Immunology, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
⁴⁵ Department of Psychiatry and Psychotherapy, Mental Health Institute Berlin, Berlin, Germany.
⁴⁶ Institute for Translational Psychiatry, University of Münster, Münster, Germany.
⁴⁷ AMEOS Clinical Center Hildesheim, Hildesheim, Germany.
⁴⁸ Center for Systems Neuroscience, Hannover, Germany.
⁴⁹ Karl-Jaspers Clinic, European Medical School Oldenburg-Groningen, Oldenburg, Germany.
⁵⁰ Department of Psychiatry II, Ulm University, Bezirkskrankenhaus Günzburg, Günzburg, Germany.
⁵¹ Department of Psychiatry, Ruhr University Bochum, LWL University Hospital, Bochum, Germany.
⁵² Department of Psychiatry and Psychotherapy, Agaplesion Diakonieklinikum, Rotenburg, Germany.
⁵³ Department of Psychiatry and Psychotherapy, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
⁵⁴ Department of Psychiatry, Health North Hospital Group, Bremen, Germany.
⁵⁵ Department of Psychiatry and Psychotherapy, Bezirkskrankenhaus Augsburg, Augsburg, Germany.
⁵⁶ Laboratory of Neuroscience, Institute of Psychiatry, University of Sao Paulo, São Paulo, Brazil.
⁵⁷ Department of Psychosomatic Medicine and Psychotherapy, University Medical Center Rostock, Rostock, Germany.
⁵⁸ Clinic for Psychiatry and Psychotherapy, Clinical Center Werra-Meißner, Eschwege, Germany.
⁵⁹ Department of Psychiatry and Psychotherapy, University Medical Center Göttingen, Göttingen, Germany.
⁶⁰ German Center for Neurodegenerative Diseases, University of Göttingen, Göttingen, Germany.
⁶¹ Psychiatrieverbund Oldenburger Land GmbH, Karl-Jaspers-Klinik, Bad Zwischenahn, Germany.
⁶² Department of Neurology, University Hospital Rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany.
⁶³ Department of Psychiatry and Psychotherapy, University Hospital Carl Gustav Carus, Medical Faculty, Technische Universität Dresden, Dresden, Germany.
⁶⁴ Department of Psychiatry and Psychotherapy, Philipps-University, Marburg, Germany.
⁶⁵ Institute for Medical Informatics, University Medical Center Göttingen, Göttingen, Germany.
⁶⁶ Mood Disorders Center of Ottawa, Ottawa, Ontario, Canada.
⁶⁷ Department of Pathology of Mental Diseases, National Institute of Mental Health, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan.
⁶⁸ Service de Psychiatrie et Psychologie Clinique, Centre Psychothérapique de Nancy, Université de Lorraine, Nancy, France.
⁶⁹ Department of Public Health & Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan.
⁷⁰ Laboratory for Molecular Dynamics of Mental Disorders, RIKEN Brain Science Institute, Saitama, Saitama, Japan.
⁷¹ Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt, Frankfurt, Germany.
⁷² Department of Psychiatry, Psychotherapy and Psychosomatic Medicine, University Hospital of Würzburg, Würzburg, Germany.
⁷³ Department of Adult Psychiatry, Poznan University of Medical Sciences, Poznań, Poland.
⁷⁴ Department of Psychiatry and Psychotherapeutic Medicine, Landesklinikum Neunkirchen, Neunkirchen, Austria.
⁷⁵ Department of Psychiatry, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
⁷⁶ Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the Gothenburg University, Gothenburg, Sweden.
⁷⁷ Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
⁷⁸ Inserm U955, Translational Psychiatry Laboratory, Université Paris-Est-Créteil, Department of Psychiatry and Addictology of Mondor University Hospital, AP-HP, Fondation FondaMental, Créteil, France.
⁷⁹ Office of Mental Health, VA San Diego Healthcare System, San Diego, California.
⁸⁰ Department of Psychiatry, University of Perugia, Perugia, Italy.
⁸¹ Section of Psychiatry, Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy.
⁸² Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada.
⁸³ Department of Clinical Neurosciences, Karolinska Institute, Stockholm, Sweden.
⁸⁴ Department of Psychiatry, VA San Diego Healthcare System, San Diego, California.
⁸⁵ Department of Psychiatry, Lindner Center of Hope, University of Cincinnati, Mason, Ohio.
⁸⁶ Mental Health Research Group, Hospital del Mar Medical Research Institute, Barcelona, Catalonia, Spain.
⁸⁷ Department of Genetics, Microbiology and Statistics, Faculty of Biology, University of Barcelona, Barcelona, Spain.
⁸⁸ Department of Psychiatry and Psychotherapy, Medical University of Vienna, Vienna, Austria.
⁸⁹ CIBERSAM, Instituto de Salud Carlos III, Madrid, Spain.
⁹⁰ Institut de Biomedicina de la Universität de Barcelona, Barcelona, Spain.
⁹¹ Institut de Recerca Sant Joan de Déu, Esplugues de Llobregat, Spain.
⁹² Neurosciences Section, Department of Medicine, Surgery and Dentistry "Scuola Medica Salernitana", University of Salerno, Salerno, Italy.
⁹³ Department of Psychiatry, University of Campania "Luigi Vanvitelli", Naples, Italy.
⁹⁴ National Institute of Mental Health, Klecany, Czechia.
⁹⁵ Department of Psychiatry & Department of Child and Adolescent Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Japan.
⁹⁶ Montreal Neurological Institute and Hospital, McGill University, Montreal, Quebec, Canada.
⁹⁷ Department of Psychiatry, Dokkyo Medical University School of Medicine, Tochigi, Japan.
⁹⁸ Bipolar Center Wiener Neustadt, Sigmund Freud University, Medical Faculty, Vienna, Austria.
⁹⁹ Department of Clinical Psychiatry and Psychotherapy, Brandenburg Medical School, Brandenburg, Germany.
¹⁰⁰ Department of Psychiatry, National Institute of Mental Health and Neuroscience, Bangalore, India.
¹⁰¹ Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
¹⁰² School of Psychiatry, University of New South Wales and Black Dog Institute, Sydney, New South Wales, Australia.
¹⁰³ Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.
¹⁰⁴ Department of Psychiatry and Behavioral Sciences, Norton College of Medicine, SUNY Upstate Medical University, Syracuse, New York.
¹⁰⁵ Department of Psychiatry and Psychotherapy, University Medical Center, Georg-August University Göttingen, Göttingen, Germany.
¹⁰⁶ Department of Psychiatry and Psychotherapy, University of Münster, Münster, Germany.
¹⁰⁷ Department of Psychiatry, Melbourne Medical School, University of Melbourne, Parkville, Victoria, Australia.
¹⁰⁸ Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, Victoria, Australia.
¹⁰⁹ Northern Adelaide Local Health Network, Mental Health Services, Adelaide, South Australia, Australia.

PMID: 40821394
PMCID: PMC12357302
DOI: 10.1016/j.bpsgos.2025.100558

Abstract

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 (PS_PGSs) 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 PS_PGSs 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 PS_PGS 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 PS_PGSs that showed significant associations in the univariate analysis (combined PS_PGS) 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: PS_PGSs achieved predictive performance comparable to the conventional genome-wide PGSs, with the added advantage of biological interpretability using a smaller list of genetic variants.

Keywords: Bipolar disorder; Lithium; Pharmacogenomics; Polygenic score; Psychiatry.

Plain language summary

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 (PS_PGSs) 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 PS_PGSs 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 PS_PGS 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). PS_PGSs achieved predictive performance comparable to conventional genome-wide PGSs, with better biological interpretability and a more focused set of genetic variants.

PubMed Disclaimer

Figures

**Figure 1**
Examples of potential targets of lithium (pathways) and detailed steps of the data analysis process. Ach, acetylcholine; Ca²⁺, calcium ion; GABA, gamma-aminobutyric acid; GSEA, Gene Set Enrichment Analysis; GSK, glycogen synthase kinase; GWAS, genome-wide association study; HGNC, HUGO Gene Nomenclature Committee; KEGG, Kyoto Encyclopedia of Genes and Genomes; Li⁺, lithium; LOC, leave-one-country-out; PRS-CS, polygenic risk score with continuous shrinkage; PS_PGS, pathway-specific polygenic score; SNP, single nucleotide polymorphism.

**Figure 2**
Trends in the odds ratios for favorable lithium treatment response [with the categorical **(A)** and beta coefficeints in the continuous **(B)** outcomes in patients with bipolar disorder, comparing patients with a high pathway-specific PGS, deciles (2nd–10th) with patients with the lowest genetic scores (1st decile; n = 2367)] for the pathways that had a significant association after multiple testing. The dot points and error bars represent the odds ratios and 95% CIs for the respective polygenic deciles. The PGS deciles that crossed an odds ratio of 1 on the y-axis in the categorical outcome **(A)** and a beta coefficient of 0 in the continuous outcome **(B)** are not statistically significant. GABA, gamma-aminobutyric acid; GSK, glycogen synthase kinase; PGS, polygenic score.

See this image and copyright information in PMC

Update of

Pathway-Specific Polygenic Scores for Lithium Response for Predicting Clinical Lithium Treatment Response in Patients with Bipolar Disorder.
Sharew NT, Clark SR, Papiol S, Heilbronner U, Degenhardt F, Fullerton JM, Hou L, Shekhtman T, Adli M, Akula N, Akiyama K, Ardau R, Arias B, Hasler R, Richard-Lepouriel H, Perroud N, Backlund L, Bhattacharjee AK, Bellivier F, Benabarre A, Bengesser S, Biernacka JM, Birner A, Marie-Claire C, Cervantes P, Chen HC, Chillotti C, Cichon S, Cruceanu C, Czerski PM, Dalkner N, Del Zompo M, DePaulo JR, Étain B, Jamain S, Falkai P, Forstner AJ, Frisen L, Frye MA, Gard S, Garnham JS, Goes FS, Grigoroiu-Serbanescu M, Fallgatter AJ, Stegmaier S, Ethofer T, Biere S, Petrova K, Schuster C, Adorjan K, Budde M, Heilbronner M, Kalman JL, Kohshour MO, Reich-Erkelenz D, Schaupp SK, Schulte EC, Senner F, Vogl T, Anghelescu IG, Arolt V, Dannlowski U, Dietrich DE, Figge C, Jäger M, Lang FU, Juckel G, Konrad C, Reimer J, Schmauß M, Schmitt A, Spitzer C, von Hagen M, Wiltfang J, Zimmermann J, Andlauer TFM, Fischer A, Bermpohl F, Ritter P, Matura S, Gryaznova A, Falkenberg I, Yildiz C, Kircher T, Schmidt J, Koch M, Gade K, Trost S, Haussleiter IS, Lambert M, Rohenkohl AC, Kraft V, Grof P, Hashimoto R, Hauser J, Herms S, Hoffmann P, Jiménez E, Kahn JP, Kassem L, Kuo PH, Kato T, Kelsoe J, Kittel-Schneider S, … See abstract for full author list ➔ Sharew NT, et al. medRxiv [Preprint]. 2025 Mar 24:2025.03.20.25324216. doi: 10.1101/2025.03.20.25324216. medRxiv. 2025. Update in: Biol Psychiatry Glob Open Sci. 2025 Jun 25;5(5):100558. doi: 10.1016/j.bpsgos.2025.100558. PMID: 40196273 Free PMC article. Updated. Preprint.

References

1. International Schizophrenia Consortium. Purcell S.M., Wray N.R., Stone J.L., Visscher P.M., O’Donovan M.C., et al. Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature. 2009;460:748–752. - PMC - PubMed
1. Wray N.R., Kemper K.E., Hayes B.J., Goddard M.E., Visscher P.M. Complex trait prediction from genome data: Contrasting EBV in livestock to PRS in humans: Genomic prediction. Genetics. 2019;211:1131–1141. - PMC - PubMed
1. Evans D.M., Visscher P.M., Wray N.R. Harnessing the information contained within genome-wide association studies to improve individual prediction of complex disease risk. Hum Mol Genet. 2009;18:3525–3531. - PubMed
1. Wray N.R., Lin T., Austin J., McGrath J.J., Hickie I.B., Murray G.K., Visscher P.M. From basic science to clinical application of polygenic risk scores: A primer. JAMA Psychiatry. 2021;78:101–109. - PubMed
1. Sharew N.T., Clark S.R., Schubert K.O., Amare A.T. Pharmacogenomic scores in psychiatry: Systematic review of current evidence. Transl Psychiatry. 2024;14:322. - PMC - PubMed

LinkOut - more resources

Full Text Sources
- Elsevier Science
- PubMed Central
Miscellaneous
- NCI CPTAC Assay Portal

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

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

Affiliations

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

Authors

Affiliations

Abstract

Plain language summary

Figures

Update of

References

LinkOut - more resources

Full Text Sources

Miscellaneous