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

Azmeraw T Amare^#^{1

2}, Klaus Oliver Schubert^#^{1

3}, Liping Hou⁴, Scott R Clark¹, Sergi Papiol^{5

6}, Micah Cearns¹, Urs Heilbronner^{5

7}, Franziska Degenhardt⁸, Fasil Tekola-Ayele⁹, Yi-Hsiang Hsu^{10

11}, Tatyana Shekhtman¹², Mazda Adli¹³, Nirmala Akula⁴, Kazufumi Akiyama¹⁴, Raffaella Ardau¹⁵, Bárbara Arias¹⁶, Jean-Michel Aubry¹⁷, Lena Backlund^{18

19}, Abesh Kumar Bhattacharjee¹², Frank Bellivier²⁰, Antonio Benabarre²¹, Susanne Bengesser²², Joanna M Biernacka^{23

24}, Armin Birner²², Clara Brichant-Petitjean²⁰, Pablo Cervantes²⁵, Hsi-Chung Chen²⁶, Caterina Chillotti¹⁵, Sven Cichon^{8

27}, Cristiana Cruceanu²⁸, Piotr M Czerski²⁹, Nina Dalkner²², Alexandre Dayer¹⁷, Maria Del Zompo³⁰, J Raymond DePaulo³¹, Bruno Étain²⁰, Stephane Jamain³², Peter Falkai⁶, Andreas J Forstner^{8

27

33}, Louise Frisen^{18

19}, Mark A Frye²⁴, Janice M Fullerton^{34

35}, Sébastien Gard³⁶, Julie S Garnham³⁷, Fernando S Goes³¹, Maria Grigoroiu-Serbanescu³⁸, Paul Grof³⁹, Ryota Hashimoto^{40

41}, Joanna Hauser²⁹, Stefan Herms^{8

27}, Per Hoffmann^{8

27}, Andrea Hofmann⁸, Esther Jiménez²¹, Jean-Pierre Kahn⁴², Layla Kassem⁴, Po-Hsiu Kuo⁴³, Tadafumi Kato⁴⁴, John R Kelsoe¹², Sarah Kittel-Schneider⁴⁵, Sebastian Kliwicki⁴⁶, Barbara König⁴⁷, Ichiro Kusumi⁴⁸, Gonzalo Laje⁴, Mikael Landén^{49

50}, Catharina Lavebratt^{18

19}, Marion Leboyer⁵¹, Susan G Leckband⁵², Alfonso Tortorella⁵³, Mirko Manchia^{54

55}, Lina Martinsson⁵⁶, Michael J McCarthy^{12

57}, Susan L McElroy⁵⁸, Francesc Colom^{59

60}, Marina Mitjans^{16

60

61}, Francis M Mondimore³¹, Palmiero Monteleone^{62

63}, Caroline M Nievergelt¹², Markus M Nöthen⁸, Tomas Novák⁶⁴, Claire O'Donovan³⁷, Norio Ozaki⁶⁵, Urban Ösby⁶⁶, Andrea Pfennig⁶⁷, James B Potash³¹, Andreas Reif⁴⁵; Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium; Eva Reininghaus²², Guy A Rouleau⁶⁸, Janusz K Rybakowski⁴⁶, Martin Schalling^{18

19}, Peter R Schofield^{34

35}, Barbara W Schweizer³¹, Giovanni Severino³⁰, Paul D Shilling¹², Katzutaka Shimoda⁶⁹, Christian Simhandl⁷⁰, Claire M Slaney³⁷, Alessio Squassina³⁰, Thomas Stamm¹³, Pavla Stopkova⁶⁴, Mario Maj⁶³, Gustavo Turecki²⁸, Eduard Vieta²¹, Julia Veeh⁴⁵, Stephanie H Witt⁷¹, Adam Wright⁷², Peter P Zandi⁷³, Philip B Mitchell⁷², Michael Bauer⁶⁷, Martin Alda^{37

64}, Marcella Rietschel⁷¹, Francis J McMahon⁴, Thomas G Schulze^{4

5

7

31

71}, Bernhard T Baune^{74

75

76}

Collaborators, Affiliations

Collaborators

Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium:
Naomi R Wray, Stephan Ripke, Manuel Mattheisen, Maciej Trzaskowski, Enda M Byrne, Abdel Abdellaoui, Mark J Adams, Esben Agerbo, Tracy M Air, Till F M Andlauer, Silviu-Alin Bacanu, Marie Bækvad-Hansen, Aartjan T F Beekman, Tim B Bigdeli, Elisabeth B Binder, Douglas H R Blackwood, Julien Bryois, Henriette N Buttenschøn, Jonas Bybjerg-Grauholm, Na Cai, Enrique Castelao, Jane Varregaard Christensen, Toni-Kim Clarke, Jonathan R I Coleman, Lucía Colodro-Conde, Baptiste Couvy-Duchesne, Nick Craddock, Gregory E Crawford, Gail Davies, Ian J Deary, Franziska Degenhardt, Eske M Derks, Nese Direk, Conor V Dolan, Erin C Dunn, Thalia C Eley, Valentina Escott-Price, Farnush Farhadi Hassan Kiadeh, Hilary K Finucane, Andreas J Forstner, Josef Frank, Héléna A Gaspar, Michael Gill, Fernando S Goes, Scott D Gordon, Jakob Grove, Lynsey S Hall, Christine Søholm Hansen, Thomas F Hansen, Stefan Herms, Ian B Hickie, Per Hoffmann, Georg Homuth, Carsten Horn, Jouke-Jan Hottenga, David M Hougaard, Marcus Ising, Rick Jansen, Eric Jorgenson, James A Knowles, Isaac S Kohane, Julia Kraft, Warren W Kretzschmar, Jesper Krogh, Zoltán Kutalik, Yihan Li, Penelope A Lind, Donald J MacIntyre, Dean F MacKinnon, Robert M Maier, Wolfgang Maier, Jonathan Marchini, Hamdi Mbarek, Patrick McGrath, Peter McGuffin, Sarah E Medland, Divya Mehta, Christel M Middeldorp, Evelin Mihailov, Yuri Milaneschi, Lili Milani, Francis M Mondimore, Grant W Montgomery, Sara Mostafavi, Niamh Mullins, Matthias Nauck, Bernard Ng, Michel G Nivard, Dale R Nyholt, Paul F O'Reilly, Hogni Oskarsson, Michael J Owen, Jodie N Painter, Carsten Bøcker Pedersen, Marianne Giørtz Pedersen, Roseann E Peterson, Erik Pettersson, Wouter J Peyrot, Giorgio Pistis, Danielle Posthuma, Jorge A Quiroz, Per Qvist, John P Rice, Brien P Riley, Margarita Rivera, Saira Saeed Mirza, Robert Schoevers, Eva C Schulte, Ling Shen, Jianxin Shi, Stanley I Shyn, Engilbert Sigurdsson, Grant C B Sinnamon, Johannes H Smit, Daniel J Smith, Hreinn Stefansson, Stacy Steinberg, Fabian Streit, Jana Strohmaier, Katherine E Tansey, Henning Teismann, Alexander Teumer, Wesley Thompson, Pippa A Thomson, Thorgeir E Thorgeirsson, Matthew Traylor, Jens Treutlein, Vassily Trubetskoy, André G Uitterlinden, Daniel Umbricht, Sandra Van der Auwera, Albert M van Hemert, Alexander Viktorin, Peter M Visscher, Yunpeng Wang, Bradley T Webb, Shantel Marie Weinsheimer, Jürgen Wellmann, Gonneke Willemsen, Stephanie H Witt, Yang Wu, Hualin S Xi, Jian Yang, Futao Zhang, Volker Arolt, Bernhard T Baune, Klaus Berger, Dorret I Boomsma, Sven Cichon, Udo Dannlowski, E J C de Geus, J Raymond DePaulo, Enrico Domenici, Katharina Domschke, Tõnu Esko, Hans J Grabe, Steven P Hamilton, Caroline Hayward, Andrew C Heath, Kenneth S Kendler, Stefan Kloiber, Glyn Lewis, Qingqin S Li, Susanne Lucae, Pamela A F Madden, Patrik K Magnusson, Nicholas G Martin, Andrew M McIntosh, Andres Metspalu, Ole Mors, Preben Bo Mortensen, Bertram Müller-Myhsok, Merete Nordentoft, Markus M Nöthen, Michael C O'Donovan, Sara A Paciga, Nancy L Pedersen, Brenda W J H Penninx, Roy H Perlis, David J Porteous, James B Potash, Martin Preisig, Marcella Rietschel, Catherine Schaefer, Thomas G Schulze, Jordan W Smoller, Kari Stefansson, Henning Tiemeier, Rudolf Uher, Henry Völzke, Myrna M Weissman, Thomas Werge, Cathryn M Lewis, Douglas F Levinson, Gerome Breen, Anders D Børglum, Patrick F Sullivan

Affiliations

¹ Discipline of Psychiatry, School of Medicine, University of Adelaide, Adelaide, SA, Australia.
² South Australian Academic Health Science and Translation Centre, South Australian Health and Medical Research Institute (SAHMRI), Adelaide, SA, Australia.
³ Northern Adelaide Local Health Network, Mental Health Services, Adelaide, SA, Australia.
⁴ Intramural Research Program, National Institute of Mental Health, National Institutes of Health, US Department of Health & Human Services, Bethesda, MD, USA.
⁵ Institute of Psychiatric Phenomics and Genomics (IPPG), University Hospital, LMU Munich, Munich, Germany.
⁶ Department of Psychiatry and Psychotherapy, Ludwig-Maximilian-University Munich, Munich, Germany.
⁷ Department of Psychiatry and Psychotherapy, University Medical Center (UMG), Georg-August University Göttingen, Göttingen, Germany.
⁸ Institute of Human Genetics, University of Bonn and Department of Genomics, Life & Brain Center, Bonn, Germany.
⁹ 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.
¹⁰ HSL Institute for Aging Research, Harvard Medical School, Boston, MA, USA.
¹¹ Program for Quantitative Genomics, Harvard School of Public Health, Boston, MA, USA.
¹² Department of Psychiatry, University of California San Diego, San Diego, CA, USA.
¹³ Department of Psychiatry and Psychotherapy, Charité - Universitätsmedizin Berlin, Campus Charité Mitte, Berlin, Germany.
¹⁴ Department of Biological Psychiatry and Neuroscience, Dokkyo Medical University School of Medicine, Mibu, Tochigi, Japan.
¹⁵ Unit of Clinical Pharmacology, Hospital University Agency of Cagliari, Cagliari, Italy.
¹⁶ 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.
¹⁷ Department of Psychiatry, Mood Disorders Unit, HUG - Geneva University Hospitals, Geneva, Switzerland.
¹⁸ Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden.
¹⁹ Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden.
²⁰ 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.
²¹ Bipolar Disorder Program, Institute of Neuroscience, Hospital Clinic, University of Barcelona, IDIBAPS, CIBERSAM, Barcelona, Catalonia, Spain.
²² Department of Psychiatry and Psychotherapeutic Medicine, Research Unit for bipolar affective disorder, Medical University of Graz, Graz, Austria.
²³ Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
²⁴ Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN, USA.
²⁵ The Neuromodulation Unit, McGill University Health Centre, Montreal, QC, Canada.
²⁶ Department of Psychiatry & Center of Sleep Disorders, National Taiwan University Hospital, Taipei, Taiwan.
²⁷ Human Genomics Research Group, Department of Biomedicine, University Hospital Basel, Basel, Switzerland.
²⁸ Douglas Mental Health University Institute, McGill University, Montreal, QC, Canada.
²⁹ Psychiatric Genetic Unit, Poznan University of Medical Sciences, Poznan, Poland.
³⁰ Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy.
³¹ Department of Psychiatry and Behavioral Sciences, Johns Hopkins University, Baltimore, MD, USA.
³² Inserm U955, Translational Psychiatry laboratory, Fondation FondaMental, Créteil, France.
³³ Department of Psychiatry (UPK), University of Basel, Basel, Switzerland.
³⁴ Neuroscience Research Australia, Sydney, NSW, Australia.
³⁵ School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia.
³⁶ Service de psychiatrie, Hôpital Charles Perrens, Bordeaux, France.
³⁷ Department of Psychiatry, Dalhousie University, Halifax, NS, Canada.
³⁸ Biometric Psychiatric Genetics Research Unit, Alexandru Obregia Clinical Psychiatric Hospital, Bucharest, Romania.
³⁹ Mood Disorders Center of Ottawa, Ottawa, ON, Canada.
⁴⁰ Molecular Research Center for Children's Mental Development, United Graduate School of Child Development, Osaka University, Osaka, Japan.
⁴¹ Department of Psychiatry, Osaka University Graduate School of Medicine, Osaka, Japan.
⁴² Service de Psychiatrie et Psychologie Clinique, Centre Psychothérapique de Nancy - Université de Lorraine, Nancy, France.
⁴³ Department of Public Health & Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan.
⁴⁴ Laboratory for Molecular Dynamics of Mental Disorders, RIKEN Center for Brain Science, Saitama, Japan.
⁴⁵ Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt, Frankfurt, Germany.
⁴⁶ Department of Adult Psychiatry, Poznan University of Medical Sciences, Poznan, Poland.
⁴⁷ Department of Psychiatry and Psychotherapeutic Medicine, Landesklinikum Neunkirchen, Neunkirchen, Austria.
⁴⁸ Department of Psychiatry, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
⁴⁹ Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the Gothenburg University, Gothenburg, Sweden.
⁵⁰ Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
⁵¹ Inserm U955, Translational Psychiatry laboratory, Université Paris-Est-Créteil, Department of Psychiatry and Addictology of Mondor University Hospital, AP-HP, Fondation FondaMental, Créteil, France.
⁵² Office of Mental Health, VA San Diego Healthcare System, San Diego, CA, USA.
⁵³ Department of Psychiatry, University of Perugia, Perugia, Italy.
⁵⁴ Section of Psychiatry, Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy.
⁵⁵ Department of Pharmacology, Dalhousie University, Halifax, NS, Canada.
⁵⁶ Department of Clinical Neurosciences, Karolinska Institutet, Stockholm, Sweden.
⁵⁷ Department of Psychiatry, VA San Diego Healthcare System, San Diego, CA, USA.
⁵⁸ Department of Psychiatry, Lindner Center of Hope / University of Cincinnati, Mason, OH, USA.
⁵⁹ Mental Health Research Group, IMIM-Hospital del Mar, Barcelona, Catalonia, Spain.
⁶⁰ Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Instituto de Salud Carlos III, Madrid, Spain.
⁶¹ Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Göttingen, Germany.
⁶² Neurosciences Section, Department of Medicine, Surgery and Dentistry "Scuola Medica Salernitana", University of Salerno, Salerno, Italy.
⁶³ Department of Psychiatry, University of Campania "Luigi Vanvitelli", Naples, Italy.
⁶⁴ National Institute of Mental Health, Klecany, Czech Republic.
⁶⁵ Department of Psychiatry & Department of Child and Adolescent Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Japan.
⁶⁶ Department of Neurobiology, Care Sciences, and Society, Karolinska Institutet and Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden.
⁶⁷ Department of Psychiatry and Psychotherapy, University Hospital Carl Gustav Carus, Medical Faculty, Technische Universität Dresden, Dresden, Germany.
⁶⁸ Montreal Neurological Institute and Hospital, McGill University, Montreal, QC, Canada.
⁶⁹ Department of Psychiatry, Dokkyo Medical University School of Medicine, Mibu, Tochigi, Japan.
⁷⁰ Bipolar Center Wiener Neustadt, Sigmund Freud University, Medical Faculty, Vienna, Austria.
⁷¹ Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
⁷² School of Psychiatry, University of New South Wales, and Black Dog Institute, Sydney, NSW, Australia.
⁷³ Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
⁷⁴ Department of Psychiatry and Psychotherapy, University of Münster, Münster, Germany. bernhard.baune@ukmuenster.de.
⁷⁵ Department of Psychiatry, Melbourne Medical School, University of Melbourne, Parkville, VIC, Australia. bernhard.baune@ukmuenster.de.
⁷⁶ The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, VIC, Australia. bernhard.baune@ukmuenster.de.

^# Contributed equally.

PMID: 32203155
DOI: 10.1038/s41380-020-0689-5

Free article

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

Azmeraw T Amare et al. Mol Psychiatry. 2021 Jun.

Free article

. 2021 Jun;26(6):2457-2470.

doi: 10.1038/s41380-020-0689-5. Epub 2020 Mar 16.

Authors

Collaborators

Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium:
Naomi R Wray, Stephan Ripke, Manuel Mattheisen, Maciej Trzaskowski, Enda M Byrne, Abdel Abdellaoui, Mark J Adams, Esben Agerbo, Tracy M Air, Till F M Andlauer, Silviu-Alin Bacanu, Marie Bækvad-Hansen, Aartjan T F Beekman, Tim B Bigdeli, Elisabeth B Binder, Douglas H R Blackwood, Julien Bryois, Henriette N Buttenschøn, Jonas Bybjerg-Grauholm, Na Cai, Enrique Castelao, Jane Varregaard Christensen, Toni-Kim Clarke, Jonathan R I Coleman, Lucía Colodro-Conde, Baptiste Couvy-Duchesne, Nick Craddock, Gregory E Crawford, Gail Davies, Ian J Deary, Franziska Degenhardt, Eske M Derks, Nese Direk, Conor V Dolan, Erin C Dunn, Thalia C Eley, Valentina Escott-Price, Farnush Farhadi Hassan Kiadeh, Hilary K Finucane, Andreas J Forstner, Josef Frank, Héléna A Gaspar, Michael Gill, Fernando S Goes, Scott D Gordon, Jakob Grove, Lynsey S Hall, Christine Søholm Hansen, Thomas F Hansen, Stefan Herms, Ian B Hickie, Per Hoffmann, Georg Homuth, Carsten Horn, Jouke-Jan Hottenga, David M Hougaard, Marcus Ising, Rick Jansen, Eric Jorgenson, James A Knowles, Isaac S Kohane, Julia Kraft, Warren W Kretzschmar, Jesper Krogh, Zoltán Kutalik, Yihan Li, Penelope A Lind, Donald J MacIntyre, Dean F MacKinnon, Robert M Maier, Wolfgang Maier, Jonathan Marchini, Hamdi Mbarek, Patrick McGrath, Peter McGuffin, Sarah E Medland, Divya Mehta, Christel M Middeldorp, Evelin Mihailov, Yuri Milaneschi, Lili Milani, Francis M Mondimore, Grant W Montgomery, Sara Mostafavi, Niamh Mullins, Matthias Nauck, Bernard Ng, Michel G Nivard, Dale R Nyholt, Paul F O'Reilly, Hogni Oskarsson, Michael J Owen, Jodie N Painter, Carsten Bøcker Pedersen, Marianne Giørtz Pedersen, Roseann E Peterson, Erik Pettersson, Wouter J Peyrot, Giorgio Pistis, Danielle Posthuma, Jorge A Quiroz, Per Qvist, John P Rice, Brien P Riley, Margarita Rivera, Saira Saeed Mirza, Robert Schoevers, Eva C Schulte, Ling Shen, Jianxin Shi, Stanley I Shyn, Engilbert Sigurdsson, Grant C B Sinnamon, Johannes H Smit, Daniel J Smith, Hreinn Stefansson, Stacy Steinberg, Fabian Streit, Jana Strohmaier, Katherine E Tansey, Henning Teismann, Alexander Teumer, Wesley Thompson, Pippa A Thomson, Thorgeir E Thorgeirsson, Matthew Traylor, Jens Treutlein, Vassily Trubetskoy, André G Uitterlinden, Daniel Umbricht, Sandra Van der Auwera, Albert M van Hemert, Alexander Viktorin, Peter M Visscher, Yunpeng Wang, Bradley T Webb, Shantel Marie Weinsheimer, Jürgen Wellmann, Gonneke Willemsen, Stephanie H Witt, Yang Wu, Hualin S Xi, Jian Yang, Futao Zhang, Volker Arolt, Bernhard T Baune, Klaus Berger, Dorret I Boomsma, Sven Cichon, Udo Dannlowski, E J C de Geus, J Raymond DePaulo, Enrico Domenici, Katharina Domschke, Tõnu Esko, Hans J Grabe, Steven P Hamilton, Caroline Hayward, Andrew C Heath, Kenneth S Kendler, Stefan Kloiber, Glyn Lewis, Qingqin S Li, Susanne Lucae, Pamela A F Madden, Patrik K Magnusson, Nicholas G Martin, Andrew M McIntosh, Andres Metspalu, Ole Mors, Preben Bo Mortensen, Bertram Müller-Myhsok, Merete Nordentoft, Markus M Nöthen, Michael C O'Donovan, Sara A Paciga, Nancy L Pedersen, Brenda W J H Penninx, Roy H Perlis, David J Porteous, James B Potash, Martin Preisig, Marcella Rietschel, Catherine Schaefer, Thomas G Schulze, Jordan W Smoller, Kari Stefansson, Henning Tiemeier, Rudolf Uher, Henry Völzke, Myrna M Weissman, Thomas Werge, Cathryn M Lewis, Douglas F Levinson, Gerome Breen, Anders D Børglum, Patrick F Sullivan

Affiliations

¹ Discipline of Psychiatry, School of Medicine, University of Adelaide, Adelaide, SA, Australia.
² South Australian Academic Health Science and Translation Centre, South Australian Health and Medical Research Institute (SAHMRI), Adelaide, SA, Australia.
³ Northern Adelaide Local Health Network, Mental Health Services, Adelaide, SA, Australia.
⁴ Intramural Research Program, National Institute of Mental Health, National Institutes of Health, US Department of Health & Human Services, Bethesda, MD, USA.
⁵ Institute of Psychiatric Phenomics and Genomics (IPPG), University Hospital, LMU Munich, Munich, Germany.
⁶ Department of Psychiatry and Psychotherapy, Ludwig-Maximilian-University Munich, Munich, Germany.
⁷ Department of Psychiatry and Psychotherapy, University Medical Center (UMG), Georg-August University Göttingen, Göttingen, Germany.
⁸ Institute of Human Genetics, University of Bonn and Department of Genomics, Life & Brain Center, Bonn, Germany.
⁹ 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.
¹⁰ HSL Institute for Aging Research, Harvard Medical School, Boston, MA, USA.
¹¹ Program for Quantitative Genomics, Harvard School of Public Health, Boston, MA, USA.
¹² Department of Psychiatry, University of California San Diego, San Diego, CA, USA.
¹³ Department of Psychiatry and Psychotherapy, Charité - Universitätsmedizin Berlin, Campus Charité Mitte, Berlin, Germany.
¹⁴ Department of Biological Psychiatry and Neuroscience, Dokkyo Medical University School of Medicine, Mibu, Tochigi, Japan.
¹⁵ Unit of Clinical Pharmacology, Hospital University Agency of Cagliari, Cagliari, Italy.
¹⁶ 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.
¹⁷ Department of Psychiatry, Mood Disorders Unit, HUG - Geneva University Hospitals, Geneva, Switzerland.
¹⁸ Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden.
¹⁹ Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden.
²⁰ 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.
²¹ Bipolar Disorder Program, Institute of Neuroscience, Hospital Clinic, University of Barcelona, IDIBAPS, CIBERSAM, Barcelona, Catalonia, Spain.
²² Department of Psychiatry and Psychotherapeutic Medicine, Research Unit for bipolar affective disorder, Medical University of Graz, Graz, Austria.
²³ Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
²⁴ Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN, USA.
²⁵ The Neuromodulation Unit, McGill University Health Centre, Montreal, QC, Canada.
²⁶ Department of Psychiatry & Center of Sleep Disorders, National Taiwan University Hospital, Taipei, Taiwan.
²⁷ Human Genomics Research Group, Department of Biomedicine, University Hospital Basel, Basel, Switzerland.
²⁸ Douglas Mental Health University Institute, McGill University, Montreal, QC, Canada.
²⁹ Psychiatric Genetic Unit, Poznan University of Medical Sciences, Poznan, Poland.
³⁰ Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy.
³¹ Department of Psychiatry and Behavioral Sciences, Johns Hopkins University, Baltimore, MD, USA.
³² Inserm U955, Translational Psychiatry laboratory, Fondation FondaMental, Créteil, France.
³³ Department of Psychiatry (UPK), University of Basel, Basel, Switzerland.
³⁴ Neuroscience Research Australia, Sydney, NSW, Australia.
³⁵ School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia.
³⁶ Service de psychiatrie, Hôpital Charles Perrens, Bordeaux, France.
³⁷ Department of Psychiatry, Dalhousie University, Halifax, NS, Canada.
³⁸ Biometric Psychiatric Genetics Research Unit, Alexandru Obregia Clinical Psychiatric Hospital, Bucharest, Romania.
³⁹ Mood Disorders Center of Ottawa, Ottawa, ON, Canada.
⁴⁰ Molecular Research Center for Children's Mental Development, United Graduate School of Child Development, Osaka University, Osaka, Japan.
⁴¹ Department of Psychiatry, Osaka University Graduate School of Medicine, Osaka, Japan.
⁴² Service de Psychiatrie et Psychologie Clinique, Centre Psychothérapique de Nancy - Université de Lorraine, Nancy, France.
⁴³ Department of Public Health & Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan.
⁴⁴ Laboratory for Molecular Dynamics of Mental Disorders, RIKEN Center for Brain Science, Saitama, Japan.
⁴⁵ Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt, Frankfurt, Germany.
⁴⁶ Department of Adult Psychiatry, Poznan University of Medical Sciences, Poznan, Poland.
⁴⁷ Department of Psychiatry and Psychotherapeutic Medicine, Landesklinikum Neunkirchen, Neunkirchen, Austria.
⁴⁸ Department of Psychiatry, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
⁴⁹ Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the Gothenburg University, Gothenburg, Sweden.
⁵⁰ Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
⁵¹ Inserm U955, Translational Psychiatry laboratory, Université Paris-Est-Créteil, Department of Psychiatry and Addictology of Mondor University Hospital, AP-HP, Fondation FondaMental, Créteil, France.
⁵² Office of Mental Health, VA San Diego Healthcare System, San Diego, CA, USA.
⁵³ Department of Psychiatry, University of Perugia, Perugia, Italy.
⁵⁴ Section of Psychiatry, Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy.
⁵⁵ Department of Pharmacology, Dalhousie University, Halifax, NS, Canada.
⁵⁶ Department of Clinical Neurosciences, Karolinska Institutet, Stockholm, Sweden.
⁵⁷ Department of Psychiatry, VA San Diego Healthcare System, San Diego, CA, USA.
⁵⁸ Department of Psychiatry, Lindner Center of Hope / University of Cincinnati, Mason, OH, USA.
⁵⁹ Mental Health Research Group, IMIM-Hospital del Mar, Barcelona, Catalonia, Spain.
⁶⁰ Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Instituto de Salud Carlos III, Madrid, Spain.
⁶¹ Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Göttingen, Germany.
⁶² Neurosciences Section, Department of Medicine, Surgery and Dentistry "Scuola Medica Salernitana", University of Salerno, Salerno, Italy.
⁶³ Department of Psychiatry, University of Campania "Luigi Vanvitelli", Naples, Italy.
⁶⁴ National Institute of Mental Health, Klecany, Czech Republic.
⁶⁵ Department of Psychiatry & Department of Child and Adolescent Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Japan.
⁶⁶ Department of Neurobiology, Care Sciences, and Society, Karolinska Institutet and Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden.
⁶⁷ Department of Psychiatry and Psychotherapy, University Hospital Carl Gustav Carus, Medical Faculty, Technische Universität Dresden, Dresden, Germany.
⁶⁸ Montreal Neurological Institute and Hospital, McGill University, Montreal, QC, Canada.
⁶⁹ Department of Psychiatry, Dokkyo Medical University School of Medicine, Mibu, Tochigi, Japan.
⁷⁰ Bipolar Center Wiener Neustadt, Sigmund Freud University, Medical Faculty, Vienna, Austria.
⁷¹ Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
⁷² School of Psychiatry, University of New South Wales, and Black Dog Institute, Sydney, NSW, Australia.
⁷³ Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
⁷⁴ Department of Psychiatry and Psychotherapy, University of Münster, Münster, Germany. bernhard.baune@ukmuenster.de.
⁷⁵ Department of Psychiatry, Melbourne Medical School, University of Melbourne, Parkville, VIC, Australia. bernhard.baune@ukmuenster.de.
⁷⁶ The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, VIC, Australia. bernhard.baune@ukmuenster.de.

^# Contributed equally.

PMID: 32203155
DOI: 10.1038/s41380-020-0689-5

Abstract

Lithium is a first-line medication for bipolar disorder (BD), but only one in three patients respond optimally to the drug. Since evidence shows a strong clinical and genetic overlap between depression and bipolar disorder, we investigated whether a polygenic susceptibility to major depression is associated with response to lithium treatment in patients with BD. Weighted polygenic scores (PGSs) were computed for major depression (MD) at different GWAS p value thresholds using genetic data obtained from 2586 bipolar patients who received lithium treatment and took part in the Consortium on Lithium Genetics (ConLi⁺Gen) study. Summary statistics from genome-wide association studies in MD (135,458 cases and 344,901 controls) from the Psychiatric Genomics Consortium (PGC) were used for PGS weighting. Response to lithium treatment was defined by continuous scores and categorical outcome (responders versus non-responders) using measurements on the Alda scale. Associations between PGSs of MD and lithium treatment response were assessed using a linear and binary logistic regression modeling for the continuous and categorical outcomes, respectively. The analysis was performed for the entire cohort, and for European and Asian sub-samples. The PGSs for MD were significantly associated with lithium treatment response in multi-ethnic, European or Asian populations, at various p value thresholds. Bipolar patients with a low polygenic load for MD were more likely to respond well to lithium, compared to those patients with high polygenic load [lowest vs highest PGS quartiles, multi-ethnic sample: OR = 1.54 (95% CI: 1.18-2.01) and European sample: OR = 1.75 (95% CI: 1.30-2.36)]. While our analysis in the Asian sample found equivalent effect size in the same direction: OR = 1.71 (95% CI: 0.61-4.90), this was not statistically significant. Using PGS decile comparison, we found a similar trend of association between a high genetic loading for MD and lower response to lithium. Our findings underscore the genetic contribution to lithium response in BD and support the emerging concept of a lithium-responsive biotype in BD.

Trial registration: ClinicalTrials.gov NCT00001174.

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References

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

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

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