. 2023 Dec;28(12):5251-5261.

doi: 10.1038/s41380-023-02149-1. Epub 2023 Jul 11.

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

Azmeraw T Amare¹, Anbupalam Thalamuthu², Klaus Oliver Schubert^{3

4}, Janice M Fullerton^{5

6}, Muktar Ahmed³, Simon Hartmann³, Sergi Papiol^{7

8}, Urs Heilbronner⁷, Franziska Degenhardt^{9

10}, Fasil Tekola-Ayele¹¹, Liping Hou¹², Yi-Hsiang Hsu^{13

14}, Tatyana Shekhtman¹⁵, Mazda Adli¹⁶, Nirmala Akula¹², Kazufumi Akiyama¹⁷, Raffaella Ardau¹⁸, Bárbara Arias¹⁹, Jean-Michel Aubry²⁰, Roland Hasler²⁰, Hélène Richard-Lepouriel²⁰, Nader Perroud²⁰, Lena Backlund^{21

22}, Abesh Kumar Bhattacharjee¹⁵, Frank Bellivier²³, Antonio Benabarre²⁴, Susanne Bengesser²⁵, Joanna M Biernacka^{26

27}, Armin Birner²⁵, Cynthia Marie-Claire^{23

28}, Pablo Cervantes²⁹, Hsi-Chung Chen³⁰, Caterina Chillotti¹⁸, Sven Cichon^{9

31

32}, Cristiana Cruceanu³³, Piotr M Czerski³⁴, Nina Dalkner²⁵, Maria Del Zompo³⁵, J Raymond DePaulo³⁶, Bruno Étain²³, Stephane Jamain³⁷, Peter Falkai^{8

38}, Andreas J Forstner^{9

32}, Louise Frisen^{21

22}, Mark A Frye²⁷, Sébastien Gard³⁹, Julie S Garnham⁴⁰, Fernando S Goes³⁶, Maria Grigoroiu-Serbanescu⁴¹, Andreas J Fallgatter⁴², Sophia Stegmaier⁴³, Thomas Ethofer^{43

44}, Silvia Biere⁴⁵, Kristiyana Petrova⁴⁵, Ceylan Schuster⁴⁵, Kristina Adorjan^{7

8}, Monika Budde⁷, Maria Heilbronner⁷, Janos L Kalman^{7

8}, Mojtaba Oraki Kohshour^{7

46}, Daniela Reich-Erkelenz⁷, Sabrina K Schaupp⁷, Eva C Schulte^{7

8}, Fanny Senner^{7

8}, Thomas Vogl⁷, Ion-George Anghelescu⁴⁷, Volker Arolt⁴⁸, Udo Dannlowski⁴⁸, Detlef Dietrich^{49

50}, Christian Figge⁵¹, Markus Jäger⁵², Fabian U Lang⁵², Georg Juckel⁵³, Carsten Konrad⁵⁴, Jens Reimer^{55

56}, Max Schmauß⁵⁷, Andrea Schmitt^{8

58}, Carsten Spitzer⁵⁹, Martin von Hagen⁶⁰, Jens Wiltfang^{61

62}, Jörg Zimmermann⁶³, Till F M Andlauer⁶⁴, Andre Fischer⁶², Felix Bermpohl¹⁶, Philipp Ritter⁶⁵, Silke Matura⁴⁵, Anna Gryaznova⁷, Irina Falkenberg⁶⁶, Cüneyt Yildiz⁶⁶, Tilo Kircher⁶⁶, Julia Schmidt⁶⁷, Marius Koch⁶⁷, Kathrin Gade⁶¹, Sarah Trost⁶¹, Ida S Haussleiter⁵³, Martin Lambert⁵⁵, Anja C Rohenkohl⁵⁵, Vivien Kraft⁵⁵, Paul Grof⁶⁸, Ryota Hashimoto⁶⁹, Joanna Hauser³⁴, Stefan Herms^{9

31}, Per Hoffmann^{9

31}, Esther Jiménez²⁴, Jean-Pierre Kahn⁷⁰, Layla Kassem¹², Po-Hsiu Kuo⁷¹, Tadafumi Kato⁷², John Kelsoe¹⁵, Sarah Kittel-Schneider^{73

74}, Ewa Ferensztajn-Rochowiak⁷⁵, Barbara König⁷⁶, Ichiro Kusumi⁷⁷, Gonzalo Laje¹², Mikael Landén^{78

79}, Catharina Lavebratt^{21

22}, Marion Leboyer⁸⁰, Susan G Leckband⁸¹, Alfonso Tortorella⁸², Mirko Manchia^{83

84}, Lina Martinsson⁸⁵, Michael J McCarthy^{15

86}, Susan McElroy⁸⁷, Francesc Colom^{88

89}, Vincent Millischer^{21

22

90}, Marina Mitjans^{89

91

92}, Francis M Mondimore³⁶, Palmiero Monteleone^{93

94}, Caroline M Nievergelt¹⁵, Markus M Nöthen⁹, Tomas Novák⁹⁵, Claire O'Donovan⁴⁰, Norio Ozaki⁹⁶, Andrea Pfennig⁶⁵, Claudia Pisanu³⁵, James B Potash³⁶, Andreas Reif⁷³, Eva Reininghaus²⁵, Guy A Rouleau⁹⁷, Janusz K Rybakowski⁷⁵, Martin Schalling^{21

22}, Peter R Schofield^{5

6}, Barbara W Schweizer³⁶, Giovanni Severino³⁵, Paul D Shilling¹⁵, Katzutaka Shimoda⁹⁸, Christian Simhandl⁹⁹, Claire M Slaney⁴⁰, Alessio Squassina³⁵, Thomas Stamm^{16

100}, Pavla Stopkova⁹⁵, Mario Maj⁹⁴, Gustavo Turecki³³, Eduard Vieta²⁴, Julia Veeh⁷³, Stephanie H Witt¹⁰¹, Adam Wright¹⁰², Peter P Zandi¹⁰³, Philip B Mitchell¹⁰², Michael Bauer⁶⁵, Martin Alda^{40

95}, Marcella Rietschel¹⁰¹, Francis J McMahon¹², Thomas G Schulze^{7

36

104}, Scott R Clark³, Bernhard T Baune^{105

106

107}

Affiliations

¹ Discipline of Psychiatry, School of Medicine, University of Adelaide, Adelaide, SA, Australia. azmeraw.amare@adelaide.edu.au.
² Centre for Healthy Brain Ageing (CHeBA), Discipline of Psychiatry and Mental Health, UNSW Medicine & Health, University of New South Wales, Sydney, Australia.
³ Discipline of Psychiatry, School of Medicine, University of Adelaide, Adelaide, SA, Australia.
⁴ Northern Adelaide Local Health Network, Mental Health Services, Adelaide, SA, Australia.
⁵ Neuroscience Research Australia, Sydney, NSW, Australia.
⁶ School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia.
⁷ Institute of Psychiatric Phenomics and Genomics (IPPG), University Hospital, LMU Munich, Munich, Germany.
⁸ Department of Psychiatry and Psychotherapy, University Hospital, Ludwig-Maximilian-University Munich, Munich, Germany.
⁹ Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany.
¹⁰ Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, LVR Klinikum Essen, University of Duisburg-Essen, Rheinische Kliniken, Essen, Germany.
¹¹ Epidemiology Branch, Division of Population Health Research, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.
¹² Intramural Research Program, National Institute of Mental Health, National Institutes of Health, US Department of Health & Human Services, Bethesda, MD, USA.
¹³ HSL Institute for Aging Research, Harvard Medical School, Boston, MA, USA.
¹⁴ Program for Quantitative Genomics, Harvard School of Public Health, Boston, MA, USA.
¹⁵ Department of Psychiatry, University of California San Diego, San Diego, CA, USA.
¹⁶ Department of Psychiatry and Psychotherapy, Charité - Universitätsmedizin Berlin, Campus Charité Mitte, Berlin, Germany.
¹⁷ Department of Biological Psychiatry and Neuroscience, Dokkyo Medical University School of Medicine, Mibu, Tochigi, Japan.
¹⁸ Unit of Clinical Pharmacology, Hospital University Agency of Cagliari, Cagliari, Italy.
¹⁹ Unitat de Zoologia i Antropologia Biològica (Dpt. Biologia Evolutiva, Ecologia i Ciències Ambientals), Facultat de Biologia and Institut de Biomedicina (IBUB), University of Barcelona, CIBERSAM, Barcelona, Spain.
²⁰ Department of Psychiatry, Mood Disorders Unit, HUG - Geneva University Hospitals, Geneva, Switzerland.
²¹ Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden.
²² Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden.
²³ INSERM UMR-S 1144, Université Paris Cité, Département de Psychiatrie et de Médecine Addictologique, AP-HP, Groupe Hospitalier Saint-Louis-Lariboisière-F.Widal, Paris, France.
²⁴ Bipolar and Depressive Disorders Program,, Institute of Neuroscience, Hospital Clinic, University of Barcelona, IDIBAPS, CIBERSAM, Barcelona, Catalonia, Spain.
²⁵ Department of Psychiatry and Psychotherapeutic Medicine, Research Unit for bipolar affective disorder, Medical University of Graz, Graz, Austria.
²⁶ Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, USA.
²⁷ Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN, USA.
²⁸ Université Paris Cité, Inserm, Optimisation Thérapeutique en Neuropsychopharmacologie, F-75006, Paris, France.
²⁹ The Neuromodulation Unit, McGill University Health Centre, Montreal, Canada.
³⁰ Department of Psychiatry & Center of Sleep Disorders, National Taiwan University Hospital, Taipei, Taiwan.
³¹ Department of Biomedicine, University Hospital Basel, Basel, Switzerland.
³² Institute of Neuroscience and Medicine (INM-1), Research Center Jülich, Jülich, Germany.
³³ Douglas Mental Health University Institute, McGill University, Montreal, Canada.
³⁴ Psychiatric Genetic Unit, Poznan University of Medical Sciences, Poznan, Poland.
³⁵ Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy.
³⁶ Department of Psychiatry and Behavioral Sciences, Johns Hopkins University, Baltimore, MD, USA.
³⁷ Inserm U955, Translational Psychiatry laboratory, Fondation FondaMental, Créteil, France.
³⁸ Max Planck Institute of Psychiatry, Munich, Germany.
³⁹ Pôle de Psychiatrie Générale Universitaire, Hôpital Charles Perrens, Bordeaux, France.
⁴⁰ Department of Psychiatry, Dalhousie University, Halifax, Nova Scotia, Canada.
⁴¹ Biometric Psychiatric Genetics Research Unit, Alexandru Obregia Clinical Psychiatric Hospital, Bucharest, Romania.
⁴² University Department of Psychiatry and Psychotherapy Tuebingen, University of Tübingen, Tuebingen, Germany.
⁴³ Department of General Psychiatry, University of Tuebingen, Tuebingen, Germany.
⁴⁴ Department of Biomedical Resonance, University of Tuebingen, Tuebingen, Germany.
⁴⁵ Department of Psychiatry, Psychotherapy and Psychosomatics, University Hospital of Frankfurt, Goethe University, Frankfurt, Germany.
⁴⁶ Department of Immunology, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
⁴⁷ Department of Psychiatry and Psychotherapy, Mental Health Institute Berlin, Berlin, Germany.
⁴⁸ Institute for Translational Psychiatry, University of Münster, Münster, Germany.
⁴⁹ AMEOS Clinical Center Hildesheim, Hildesheim, Germany.
⁵⁰ Center for Systems Neuroscience (ZSN), Hannover, Germany.
⁵¹ Karl-Jaspers Clinic, European Medical School Oldenburg-Groningen, Oldenburg, 26160, Germany.
⁵² Department of Psychiatry II, Ulm University, Bezirkskrankenhaus Günzburg, Günzburg, Germany.
⁵³ Department of Psychiatry, Ruhr University Bochum, LWL University Hospital, Bochum, Germany.
⁵⁴ Department of Psychiatry and Psychotherapy, Agaplesion Diakonieklinikum, Rotenburg, Germany.
⁵⁵ Department of Psychiatry and Psychotherapy, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
⁵⁶ Department of Psychiatry, Health North Hospital Group, Bremen, Germany.
⁵⁷ Department of Psychiatry and Psychotherapy, Bezirkskrankenhaus Augsburg, Augsburg, Germany.
⁵⁸ Laboratory of Neuroscience (LIM27), Institute of Psychiatry, University of Sao Paulo, São Paulo, Brazil.
⁵⁹ Department of Psychosomatic Medicine and Psychotherapy, University Medical Center Rostock, Rostock, Germany.
⁶⁰ Clinic for Psychiatry and Psychotherapy, Clinical Center Werra-Meißner, Eschwege, Germany.
⁶¹ Department of Psychiatry and Psychotherapy, University Medical Center Göttingen, Göttingen, Germany.
⁶² German Center for Neurodegenerative Diseases (DZNE), Göttingen, Germany.
⁶³ Psychiatrieverbund Oldenburger Land gGmbH, Karl-Jaspers-Klinik, Bad Zwischenahn, Germany.
⁶⁴ Department of Neurology, University Hospital rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany.
⁶⁵ Department of Psychiatry and Psychotherapy, University Hospital Carl Gustav Carus, Medical Faculty, Technische Universität Dresden, Dresden, Germany.
⁶⁶ Department of Psychiatry and Psychotherapy, Philipps-University Marburg, Marburg, Germany.
⁶⁷ Institute for Medical Informatics, University Medical Center Göttingen, Göttingen, Germany.
⁶⁸ Mood Disorders Center of Ottawa, Ontario, Canada.
⁶⁹ Department of Pathology of Mental Diseases, National Institute of Mental Health, National Center of Neurology and Psychiatry, 4-1-1 Ogawahigashi, Kodaira, Tokyo, 187-8553, Japan.
⁷⁰ Service de Psychiatrie et Psychologie Clinique, Centre Psychothérapique de Nancy - Université de Lorraine, Nancy, France.
⁷¹ Department of Public Health & Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan.
⁷² Laboratory for Molecular Dynamics of Mental Disorders, RIKEN Brain Science Institute, Saitama, Japan.
⁷³ Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt, Frankfurt, Germany.
⁷⁴ Department of Psychiatry, Psychotherapy and Psychosomatic Medicine, University Hospital of Würzburg, Wurzburg, Germany.
⁷⁵ Department of Adult Psychiatry, Poznan University of Medical Sciences, Poznan, Poland.
⁷⁶ Department of Psychiatry and Psychotherapeutic Medicine, Landesklinikum Neunkirchen, Neunkirchen, Austria.
⁷⁷ Department of Psychiatry, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
⁷⁸ Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the Gothenburg University, Gothenburg, Sweden.
⁷⁹ Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
⁸⁰ Inserm U955, Translational Psychiatry laboratory, Université Paris-Est-Créteil, Department of Psychiatry and Addictology of Mondor University Hospital, AP-HP, Fondation FondaMental, Créteil, France.
⁸¹ Office of Mental Health, VA San Diego Healthcare System, San Diego, CA, USA.
⁸² Department of Psychiatry, University of Perugia, Perugia, Italy.
⁸³ Section of Psychiatry, Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy.
⁸⁴ Department of Pharmacology, Dalhousie University, Halifax, NS, Canada.
⁸⁵ Department of Clinical Neurosciences, Karolinska Institutet, Stockholm, Sweden.
⁸⁶ Department of Psychiatry, VA San Diego Healthcare System, San Diego, CA, USA.
⁸⁷ Department of Psychiatry, Lindner Center of Hope / University of Cincinnati, Mason, OH, USA.
⁸⁸ Mental Health Research Group, IMIM-Hospital del Mar, Barcelona, Catalonia, Spain.
⁸⁹ Department of Genetics, Microbiology and Statistics, Faculty of Biology, University of Barcelona, Barcelona, Spain.
⁹⁰ Department of Psychiatry and Psychotherapy, Medical University of Vienna, Vienna, Austria.
⁹¹ Institut de Biomedicina de la Universitat de Barcelona (IBUB), Barcelona, Spain.
⁹² Centro de Investigación Biomédica en Salud Mental (CIBERSAM), Instituto de Salud Carlos III, Madrid, Spain.
⁹³ Neurosciences Section, Department of Medicine, Surgery and Dentistry "Scuola Medica Salernitana", University of Salerno, Salerno, Italy.
⁹⁴ Department of Psychiatry, University of Campania "Luigi Vanvitelli", Naples, Italy.
⁹⁵ National Institute of Mental Health, Klecany, Czech Republic.
⁹⁶ Department of Psychiatry & Department of Child and Adolescent Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Japan.
⁹⁷ Montreal Neurological Institute and Hospital, McGill University, Montreal, Canada.
⁹⁸ Department of Psychiatry, Dokkyo Medical University School of Medicine, Mibu, Tochigi, Japan.
⁹⁹ Bipolar Center Wiener Neustadt, Sigmund Freud University, Medical Faculty, Vienna, Austria.
¹⁰⁰ Department of Clinical Psychiatry and Psychotherapy, Brandenburg Medical School, Brandenburg, Germany.
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, Australia.
¹⁰³ Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
¹⁰⁴ Department of Psychiatry and Behavioral Sciences, SUNY Upstate Medical University, Norton College of Medicine, Syracuse, NY, USA.
¹⁰⁵ Department of Psychiatry and Psychotherapy, University of Münster, Münster, Germany.
¹⁰⁶ Department of Psychiatry, Melbourne Medical School, University of Melbourne, Parkville, VIC, Australia.
¹⁰⁷ The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, VIC, Australia.

PMID: 37433967
PMCID: PMC11041653
DOI: 10.1038/s41380-023-02149-1

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

Azmeraw T Amare et al. Mol Psychiatry. 2023 Dec.

. 2023 Dec;28(12):5251-5261.

doi: 10.1038/s41380-023-02149-1. Epub 2023 Jul 11.

Authors

Affiliations

¹ Discipline of Psychiatry, School of Medicine, University of Adelaide, Adelaide, SA, Australia. azmeraw.amare@adelaide.edu.au.
² Centre for Healthy Brain Ageing (CHeBA), Discipline of Psychiatry and Mental Health, UNSW Medicine & Health, University of New South Wales, Sydney, Australia.
³ Discipline of Psychiatry, School of Medicine, University of Adelaide, Adelaide, SA, Australia.
⁴ Northern Adelaide Local Health Network, Mental Health Services, Adelaide, SA, Australia.
⁵ Neuroscience Research Australia, Sydney, NSW, Australia.
⁶ School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia.
⁷ Institute of Psychiatric Phenomics and Genomics (IPPG), University Hospital, LMU Munich, Munich, Germany.
⁸ Department of Psychiatry and Psychotherapy, University Hospital, Ludwig-Maximilian-University Munich, Munich, Germany.
⁹ Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany.
¹⁰ Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, LVR Klinikum Essen, University of Duisburg-Essen, Rheinische Kliniken, Essen, Germany.
¹¹ Epidemiology Branch, Division of Population Health Research, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.
¹² Intramural Research Program, National Institute of Mental Health, National Institutes of Health, US Department of Health & Human Services, Bethesda, MD, USA.
¹³ HSL Institute for Aging Research, Harvard Medical School, Boston, MA, USA.
¹⁴ Program for Quantitative Genomics, Harvard School of Public Health, Boston, MA, USA.
¹⁵ Department of Psychiatry, University of California San Diego, San Diego, CA, USA.
¹⁶ Department of Psychiatry and Psychotherapy, Charité - Universitätsmedizin Berlin, Campus Charité Mitte, Berlin, Germany.
¹⁷ Department of Biological Psychiatry and Neuroscience, Dokkyo Medical University School of Medicine, Mibu, Tochigi, Japan.
¹⁸ Unit of Clinical Pharmacology, Hospital University Agency of Cagliari, Cagliari, Italy.
¹⁹ Unitat de Zoologia i Antropologia Biològica (Dpt. Biologia Evolutiva, Ecologia i Ciències Ambientals), Facultat de Biologia and Institut de Biomedicina (IBUB), University of Barcelona, CIBERSAM, Barcelona, Spain.
²⁰ Department of Psychiatry, Mood Disorders Unit, HUG - Geneva University Hospitals, Geneva, Switzerland.
²¹ Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden.
²² Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden.
²³ INSERM UMR-S 1144, Université Paris Cité, Département de Psychiatrie et de Médecine Addictologique, AP-HP, Groupe Hospitalier Saint-Louis-Lariboisière-F.Widal, Paris, France.
²⁴ Bipolar and Depressive Disorders Program,, Institute of Neuroscience, Hospital Clinic, University of Barcelona, IDIBAPS, CIBERSAM, Barcelona, Catalonia, Spain.
²⁵ Department of Psychiatry and Psychotherapeutic Medicine, Research Unit for bipolar affective disorder, Medical University of Graz, Graz, Austria.
²⁶ Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, USA.
²⁷ Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN, USA.
²⁸ Université Paris Cité, Inserm, Optimisation Thérapeutique en Neuropsychopharmacologie, F-75006, Paris, France.
²⁹ The Neuromodulation Unit, McGill University Health Centre, Montreal, Canada.
³⁰ Department of Psychiatry & Center of Sleep Disorders, National Taiwan University Hospital, Taipei, Taiwan.
³¹ Department of Biomedicine, University Hospital Basel, Basel, Switzerland.
³² Institute of Neuroscience and Medicine (INM-1), Research Center Jülich, Jülich, Germany.
³³ Douglas Mental Health University Institute, McGill University, Montreal, Canada.
³⁴ Psychiatric Genetic Unit, Poznan University of Medical Sciences, Poznan, Poland.
³⁵ Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy.
³⁶ Department of Psychiatry and Behavioral Sciences, Johns Hopkins University, Baltimore, MD, USA.
³⁷ Inserm U955, Translational Psychiatry laboratory, Fondation FondaMental, Créteil, France.
³⁸ Max Planck Institute of Psychiatry, Munich, Germany.
³⁹ Pôle de Psychiatrie Générale Universitaire, Hôpital Charles Perrens, Bordeaux, France.
⁴⁰ Department of Psychiatry, Dalhousie University, Halifax, Nova Scotia, Canada.
⁴¹ Biometric Psychiatric Genetics Research Unit, Alexandru Obregia Clinical Psychiatric Hospital, Bucharest, Romania.
⁴² University Department of Psychiatry and Psychotherapy Tuebingen, University of Tübingen, Tuebingen, Germany.
⁴³ Department of General Psychiatry, University of Tuebingen, Tuebingen, Germany.
⁴⁴ Department of Biomedical Resonance, University of Tuebingen, Tuebingen, Germany.
⁴⁵ Department of Psychiatry, Psychotherapy and Psychosomatics, University Hospital of Frankfurt, Goethe University, Frankfurt, Germany.
⁴⁶ Department of Immunology, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
⁴⁷ Department of Psychiatry and Psychotherapy, Mental Health Institute Berlin, Berlin, Germany.
⁴⁸ Institute for Translational Psychiatry, University of Münster, Münster, Germany.
⁴⁹ AMEOS Clinical Center Hildesheim, Hildesheim, Germany.
⁵⁰ Center for Systems Neuroscience (ZSN), Hannover, Germany.
⁵¹ Karl-Jaspers Clinic, European Medical School Oldenburg-Groningen, Oldenburg, 26160, Germany.
⁵² Department of Psychiatry II, Ulm University, Bezirkskrankenhaus Günzburg, Günzburg, Germany.
⁵³ Department of Psychiatry, Ruhr University Bochum, LWL University Hospital, Bochum, Germany.
⁵⁴ Department of Psychiatry and Psychotherapy, Agaplesion Diakonieklinikum, Rotenburg, Germany.
⁵⁵ Department of Psychiatry and Psychotherapy, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
⁵⁶ Department of Psychiatry, Health North Hospital Group, Bremen, Germany.
⁵⁷ Department of Psychiatry and Psychotherapy, Bezirkskrankenhaus Augsburg, Augsburg, Germany.
⁵⁸ Laboratory of Neuroscience (LIM27), Institute of Psychiatry, University of Sao Paulo, São Paulo, Brazil.
⁵⁹ Department of Psychosomatic Medicine and Psychotherapy, University Medical Center Rostock, Rostock, Germany.
⁶⁰ Clinic for Psychiatry and Psychotherapy, Clinical Center Werra-Meißner, Eschwege, Germany.
⁶¹ Department of Psychiatry and Psychotherapy, University Medical Center Göttingen, Göttingen, Germany.
⁶² German Center for Neurodegenerative Diseases (DZNE), Göttingen, Germany.
⁶³ Psychiatrieverbund Oldenburger Land gGmbH, Karl-Jaspers-Klinik, Bad Zwischenahn, Germany.
⁶⁴ Department of Neurology, University Hospital rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany.
⁶⁵ Department of Psychiatry and Psychotherapy, University Hospital Carl Gustav Carus, Medical Faculty, Technische Universität Dresden, Dresden, Germany.
⁶⁶ Department of Psychiatry and Psychotherapy, Philipps-University Marburg, Marburg, Germany.
⁶⁷ Institute for Medical Informatics, University Medical Center Göttingen, Göttingen, Germany.
⁶⁸ Mood Disorders Center of Ottawa, Ontario, Canada.
⁶⁹ Department of Pathology of Mental Diseases, National Institute of Mental Health, National Center of Neurology and Psychiatry, 4-1-1 Ogawahigashi, Kodaira, Tokyo, 187-8553, Japan.
⁷⁰ Service de Psychiatrie et Psychologie Clinique, Centre Psychothérapique de Nancy - Université de Lorraine, Nancy, France.
⁷¹ Department of Public Health & Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan.
⁷² Laboratory for Molecular Dynamics of Mental Disorders, RIKEN Brain Science Institute, Saitama, Japan.
⁷³ Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt, Frankfurt, Germany.
⁷⁴ Department of Psychiatry, Psychotherapy and Psychosomatic Medicine, University Hospital of Würzburg, Wurzburg, Germany.
⁷⁵ Department of Adult Psychiatry, Poznan University of Medical Sciences, Poznan, Poland.
⁷⁶ Department of Psychiatry and Psychotherapeutic Medicine, Landesklinikum Neunkirchen, Neunkirchen, Austria.
⁷⁷ Department of Psychiatry, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
⁷⁸ Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the Gothenburg University, Gothenburg, Sweden.
⁷⁹ Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
⁸⁰ Inserm U955, Translational Psychiatry laboratory, Université Paris-Est-Créteil, Department of Psychiatry and Addictology of Mondor University Hospital, AP-HP, Fondation FondaMental, Créteil, France.
⁸¹ Office of Mental Health, VA San Diego Healthcare System, San Diego, CA, USA.
⁸² Department of Psychiatry, University of Perugia, Perugia, Italy.
⁸³ Section of Psychiatry, Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy.
⁸⁴ Department of Pharmacology, Dalhousie University, Halifax, NS, Canada.
⁸⁵ Department of Clinical Neurosciences, Karolinska Institutet, Stockholm, Sweden.
⁸⁶ Department of Psychiatry, VA San Diego Healthcare System, San Diego, CA, USA.
⁸⁷ Department of Psychiatry, Lindner Center of Hope / University of Cincinnati, Mason, OH, USA.
⁸⁸ Mental Health Research Group, IMIM-Hospital del Mar, Barcelona, Catalonia, Spain.
⁸⁹ Department of Genetics, Microbiology and Statistics, Faculty of Biology, University of Barcelona, Barcelona, Spain.
⁹⁰ Department of Psychiatry and Psychotherapy, Medical University of Vienna, Vienna, Austria.
⁹¹ Institut de Biomedicina de la Universitat de Barcelona (IBUB), Barcelona, Spain.
⁹² Centro de Investigación Biomédica en Salud Mental (CIBERSAM), Instituto de Salud Carlos III, Madrid, Spain.
⁹³ Neurosciences Section, Department of Medicine, Surgery and Dentistry "Scuola Medica Salernitana", University of Salerno, Salerno, Italy.
⁹⁴ Department of Psychiatry, University of Campania "Luigi Vanvitelli", Naples, Italy.
⁹⁵ National Institute of Mental Health, Klecany, Czech Republic.
⁹⁶ Department of Psychiatry & Department of Child and Adolescent Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Japan.
⁹⁷ Montreal Neurological Institute and Hospital, McGill University, Montreal, Canada.
⁹⁸ Department of Psychiatry, Dokkyo Medical University School of Medicine, Mibu, Tochigi, Japan.
⁹⁹ Bipolar Center Wiener Neustadt, Sigmund Freud University, Medical Faculty, Vienna, Austria.
¹⁰⁰ Department of Clinical Psychiatry and Psychotherapy, Brandenburg Medical School, Brandenburg, Germany.
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, Australia.
¹⁰³ Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
¹⁰⁴ Department of Psychiatry and Behavioral Sciences, SUNY Upstate Medical University, Norton College of Medicine, Syracuse, NY, USA.
¹⁰⁵ Department of Psychiatry and Psychotherapy, University of Münster, Münster, Germany.
¹⁰⁶ Department of Psychiatry, Melbourne Medical School, University of Melbourne, Parkville, VIC, Australia.
¹⁰⁷ The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, VIC, Australia.

PMID: 37433967
PMCID: PMC11041653
DOI: 10.1038/s41380-023-02149-1

Abstract

Lithium is regarded as the first-line treatment for bipolar disorder (BD), a severe and disabling mental health disorder that affects about 1% of the population worldwide. Nevertheless, lithium is not consistently effective, with only 30% of patients showing a favorable response to treatment. To provide personalized treatment options for bipolar patients, it is essential to identify prediction biomarkers such as polygenic scores. In this study, we developed a polygenic score for lithium treatment response (Li⁺_PGS) in patients with BD. To gain further insights into lithium's possible molecular mechanism of action, we performed a genome-wide gene-based analysis. Using polygenic score modeling, via methods incorporating Bayesian regression and continuous shrinkage priors, Li⁺_PGS was developed in the International Consortium of Lithium Genetics cohort (ConLi⁺Gen: N = 2367) and replicated in the combined PsyCourse (N = 89) and BipoLife (N = 102) studies. The associations of Li⁺_PGS and lithium treatment response - defined in a continuous ALDA scale and a categorical outcome (good response vs. poor response) were tested using regression models, each adjusted for the covariates: age, sex, and the first four genetic principal components. Statistical significance was determined at P < 0.05. Li⁺_PGS was positively associated with lithium treatment response in the ConLi⁺Gen cohort, in both the categorical (P = 9.8 × 10^-¹², R² = 1.9%) and continuous (P = 6.4 × 10^-⁹, R² = 2.6%) outcomes. Compared to bipolar patients in the 1^st decile of the risk distribution, individuals in the 10^th decile had 3.47-fold (95%CI: 2.22-5.47) higher odds of responding favorably to lithium. The results were replicated in the independent cohorts for the categorical treatment outcome (P = 3.9 × 10^-⁴, R² = 0.9%), but not for the continuous outcome (P = 0.13). Gene-based analyses revealed 36 candidate genes that are enriched in biological pathways controlled by glutamate and acetylcholine. Li⁺_PGS may be useful in the development of pharmacogenomic testing strategies by enabling a classification of bipolar patients according to their response to treatment.

PubMed Disclaimer

Conflict of interest statement

Eduard Vieta has received grants and served as consultant, advisor or CME speaker for the following entities: AB-Biotics, Allergan, Angelini, AstraZeneca, Bristol-Myers Squibb, Dainippon Sumitomo Pharma, Farmindustria, Ferrer, Forest Research Institute, Gedeon Richter, GlaxoSmith-Kline, Janssen, Lundbeck, Otsuka, Pfizer, Roche, Sanofi-Aventis, Servier, Shire, Sunovion, Takeda, the Brain and Behaviour Foundation, the Spanish Ministry of Science and Innovation (CIBERSAM), and the Stanley Medical Research Institute. Michael Bauer has received grants from the Deutsche Forschungsgemeinschaft (DFG), and Bundesministeriums für Bildung und Forschung (BMBF), and served as consultant, advisor or CME speaker for the following entities: Allergan, Aristo, Janssen, Lilly, Lundbeck, neuraxpharm, Otsuka, Sandoz, Servier and Sunovion outside the submitted work. Sarah Kittel-Schneider has received grants and served as consultant, advisor or speaker for the following entities: Medice Arzneimittel Pütter GmbH and Shire/Takeda. Bernhard Baune has received grants and served as consultant, advisor or CME speaker for the following entities: AstraZeneca, Bristol-Myers Squibb, Janssen, Lundbeck, Otsuka, Servier, the National Health and Medical Research Council, the Fay Fuller Foundation, the James and Diana Ramsay Foundation. Scott Clark has received grants and served as consultant, advisor or CME speaker for the following entities: Otsuka Austalia, Lundbeck Australia, Janssen-Cilag Australia, Servier Australia. Tadafumi Kato received honoraria for lectures, manuscripts, and/or consultancy, from Kyowa Hakko Kirin Co, Ltd, Eli Lilly Japan K.K., Otsuka Pharmaceutical Co, Ltd, GlaxoSmithKline K.K., Taisho Toyama Pharmaceutical Co, Ltd, Dainippon Sumitomo Pharma Co, Ltd, Meiji Seika Pharma Co, Ltd, Pfizer Japan Inc., Mochida Pharmaceutical Co, Ltd, Shionogi & Co, Ltd, Janssen Pharmaceutical K.K., Janssen Asia Pacific, Yoshitomiyakuhin, Astellas Pharma Inc, Wako Pure Chemical Industries, Ltd, Wiley Publishing Japan, Nippon Boehringer Ingelheim Co Ltd, Kanae Foundation for the Promotion of Medical Science, MSD K.K., Kyowa Pharmaceutical Industry Co, Ltd and Takeda Pharmaceutical Co, Ltd. Tadafumi Kato also received a research grant from Takeda Pharmaceutical Co, Ltd. Peter Falkai has received grants and served as consultant, advisor or CME speaker for the following entities Abbott, GlaxoSmithKline, Janssen, Essex, Lundbeck, Otsuka, Gedeon Richter, Servier and Takeda as well as the German Ministry of Science and the German Ministry of Health. Eva Reininghaus has received grants and served as consultant, advisor or CME speaker for the following entities: Janssen and Institut Allergosan. Mikael Landén declares that, over the past 36 months, he has received lecture honoraria from Lundbeck and served as a scientific consultant for EPID Research Oy; no other equity ownership, profit-sharing agreements, royalties or patent. Kazufumi Akiyama has received consulting honoraria from Taisho Toyama Pharmaceutical Co, Ltd. In 2021, Jörg Zimmermann served as an advisor for Biogen concerning Aducanumab (Alzheimer’s Disease).The other authors have no other conflict of interest to disclose.

Figures

**Fig. 1. Overview of input datasets and steps of data analyses.**
ConLi⁺Gen = The International Consortium on Lithium Genetics, ALDA = Retrospective Criteria of Long-Term Treatment Response in Research Subjects with Bipolar Disorder scale, HRC = Haplotype Reference Consortium, SNPs = Single Nucleotide Polymorphisms, MAF=Minor Allele Frequency, GWAS = Genome Wide Association analysis, Li⁺_PGS = Polygenic score for lithium treatment response, LOG = Leave-one-group out procedure; PsyCourse = Pathomechanisms and Signature in the Longitudinal Course of Psychosis study and BipoLife = German research consortium for the study of bipolar disorder.

Fig. 2. Trends in the odds ratios (ORs) for favourable treatment response to lithium for patients with bipolar disorder in the higher genetic loading for lithium responsive variants, (2^nd to 10^th deciles) compared with patients in the lowest (1^st decile) of genetic loading for lithium response (n = 2367).
The X mark on the line plot indicates that the association is not statistically significant at that decile. OR Odds ratio, CI Confidence interval, Li⁺_PGS Polygenic score for lithium treatment response.

**Fig. 3. Manhattan plots showing the SNP-based GWAS results of lithium treatment response in patients with bipolar disorder.**
A In the categorical outcome and (B) continuous scale, highlighting the loci that showed genome-wide significance (orange).The −log10 (p-value) is plotted against the physical position of each SNP on each chromosome. The threshold for genome-wide significance (p-value < 5 × 10^–8) is indicated by the red dotted horizontal line.

See this image and copyright information in PMC

Update of

Association of Polygenic Score and the involvement of Cholinergic and Glutamatergic Pathways with Lithium Treatment Response in Patients with Bipolar Disorder.
Amare A, Thalamuthu A, Schubert KO, Fullerton J, Ahmed M, Hartmann S, Papiol S, Heilbronner U, Degenhardt F, Tekola-Ayele F, Hou L, Hsu YH, Shekhtman T, Adli M, Akula N, Akiyama K, Ardau R, Arias B, Aubry JM, Backlund L, Bhattacharjee AK, Bellivier F, Benabarre A, Bengesser S, Biernacka J, Birner A, Marie-Claire C, Cervantes P, Chen HC, Chillotti C, Cichon S, Cruceanu C, Czerski P, Dalkner N, Del Zompo M, DePaulo JR, Etain B, Jamain S, Falkai P, Forstner AJ, Frisén L, Frye M, Gard S, Garnham J, Goes F, Grigoroiu-Serbanescu M, Fallgatter A, Stegmaier S, Ethofer T, Biere S, Petrova K, Schuster C, Adorjan K, Budde M, Heilbronner M, Kalman J, Oraki Kohshour M, Reich-Erkelenz D, Schaupp S, Schulte E, Senner F, Vogl T, Anghelescu IG, Arolt V, Dannlowski U, Dietrich DE, Figge C, Jäger M, Lang F, Juckel G, Spitzer C, Reimer J, Schmauß M, Schmitt A, Konrad C, von Hagen M, Wiltfang J, Zimmermann J, Andlauer T, Fischer A, Bermpohl F, Kraft V, Matura S, Gryaznova A, Falkenberg I, Yildiz C, Kircher T, Schmidt J, Koch M, Gade K, Trost S, Haußleiter I, 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, Kit… See abstract for full author list ➔ Amare A, et al. Res Sq [Preprint]. 2023 Feb 14:rs.3.rs-2580252. doi: 10.21203/rs.3.rs-2580252/v1. Res Sq. 2023. Update in: Mol Psychiatry. 2023 Dec;28(12):5251-5261. doi: 10.1038/s41380-023-02149-1. PMID: 36824922 Free PMC article. Updated. Preprint.

References

1. Grande I, Berk M, Birmaher B, Vieta E. Bipolar disorder. Lancet. 2016;387:1561–72. - PubMed
1. DALYs GBD, Collaborators H. Global, regional, and national disability-adjusted life-years (DALYs) for 359 diseases and injuries and healthy life expectancy (HALE) for 195 countries and territories, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet. 2018;392:1859–922. - PMC - PubMed
1. Walker S, Mackay E, Barnett P, Sheridan Rains L, Leverton M, Dalton-Locke C, et al. Clinical and social factors associated with increased risk for involuntary psychiatric hospitalisation: a systematic review, meta-analysis, and narrative synthesis. Lancet Psychiatry. 2019;6:1039–53. - PMC - PubMed
1. Chesney E, Goodwin GM, Fazel S. Risks of all-cause and suicide mortality in mental disorders: a meta-review. World Psychiatry. 2014;13:153–60. - PMC - PubMed
1. Cade JF. Lithium salts in the treatment of psychotic excitement. Med J Aust. 1949;2:349–52. - PubMed

Publication types

Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Substances

Actions
Actions
Actions
Actions
Actions

Grants and funding

LinkOut - more resources

Full Text Sources
Medical
- MedlinePlus Consumer Health Information
- MedlinePlus Health Information
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

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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

Update of

References

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Medical

Miscellaneous