Characterisation of age and polarity at onset in bipolar disorder

Janos L Kalman¹, Loes M Olde Loohuis², Annabel Vreeker³, Andrew McQuillin⁴, Eli A Stahl⁵, Douglas Ruderfer⁶, Maria Grigoroiu-Serbanescu⁷, Georgia Panagiotaropoulou⁸, Stephan Ripke⁹, Tim B Bigdeli¹⁰, Frederike Stein¹¹, Tina Meller¹², Susanne Meinert¹³, Helena Pelin¹⁴, Fabian Streit¹⁵, Sergi Papiol¹⁶, Mark J Adams¹⁷, Rolf Adolfsson¹⁸, Kristina Adorjan¹⁹, Ingrid Agartz²⁰, Sofie R Aminoff²¹, Heike Anderson-Schmidt²², Ole A Andreassen²³, Raffaella Ardau²⁴, Jean-Michel Aubry²⁵, Ceylan Balaban²⁶, Nicholas Bass⁴, Bernhard T Baune²⁷, Frank Bellivier²⁸, Antoni Benabarre²⁹, Susanne Bengesser³⁰, Wade H Berrettini³¹, Marco P Boks³², Evelyn J Bromet³³, Katharina Brosch¹¹, Monika Budde³⁴, William Byerley³⁵, Pablo Cervantes³⁶, Catina Chillotti²⁴, Sven Cichon³⁷, Scott R Clark³⁸, Ashley L Comes¹, Aiden Corvin³⁹, William Coryell⁴⁰, Nick Craddock⁴¹, David W Craig⁴², Paul E Croarkin⁴³, Cristiana Cruceanu⁴⁴, Piotr M Czerski⁴⁵, Nina Dalkner³⁰, Udo Dannlowski⁴⁶, Franziska Degenhardt⁴⁷, Maria Del Zompo⁴⁸, J Raymond DePaulo⁴⁹, Srdjan Djurovic⁵⁰, Howard J Edenberg⁵¹, Mariam Al Eissa⁴, Torbjørn Elvsåshagen⁵², Bruno Etain²⁸, Ayman H Fanous¹⁰, Frederike Fellendorf³⁰, Alessia Fiorentino⁴, Andreas J Forstner⁵³, Mark A Frye⁴³, Janice M Fullerton⁵⁴, Katrin Gade²², Julie Garnham⁵⁵, Elliot Gershon⁵⁶, Michael Gill³⁹, Fernando S Goes⁴⁹, Katherine Gordon-Smith⁵⁷, Paul Grof⁵⁸, Jose Guzman-Parra⁵⁹, Tim Hahn⁴⁶, Roland Hasler⁶⁰, Maria Heilbronner³⁴, Urs Heilbronner³⁴, Stephane Jamain⁶¹, Esther Jimenez²⁹, Ian Jones⁴¹, Lisa Jones⁵⁷, Lina Jonsson⁶², Rene S Kahn⁶³, John R Kelsoe⁶⁴, James L Kennedy⁶⁵, Tilo Kircher¹¹, George Kirov⁴¹, Sarah Kittel-Schneider⁶⁶, Farah Klöhn-Saghatolislam³⁴, James A Knowles⁶⁰, Thorsten M Kranz²⁶, Trine Vik Lagerberg⁶⁷, Mikael Landen⁶⁸, William B Lawson⁶⁹, Marion Leboyer⁶¹, Qingqin S Li⁷⁰, Mario Maj⁷¹, Dolores Malaspina⁷², Mirko Manchia⁷³, Fermin Mayoral⁵⁹, Susan L McElroy⁷⁴, Melvin G McInnis⁷⁵, Andrew M McIntosh¹⁷, Helena Medeiros⁷⁶, Ingrid Melle⁷⁷, Vihra Milanova⁷⁸, Philip B Mitchell⁷⁹, Palmiero Monteleone⁸⁰, Alessio Maria Monteleone⁷¹, Markus M Nöthen⁸¹, Tomas Novak⁸², John I Nurnberger⁸³, Niamh O'Brien⁴, Kevin S O'Connell²¹, Claire O'Donovan⁸⁴, Michael C O'Donovan⁴¹, Nils Opel⁴⁶, Abigail Ortiz⁸⁵, Michael J Owen⁴¹, Erik Pålsson⁶², Carlos Pato⁷⁶, Michele T Pato⁷⁶, Joanna Pawlak⁴⁵, Julia-Katharina Pfarr¹¹, Claudia Pisanu⁸⁶, James B Potash⁴⁹, Mark H Rapaport⁸⁷, Daniela Reich-Erkelenz³⁴, Andreas Reif²⁶, Eva Reininghaus³⁰, Jonathan Repple⁴⁶, Hélène Richard-Lepouriel⁸⁸, Marcella Rietschel¹⁵, Kai Ringwald¹¹, Gloria Roberts⁷⁹, Guy Rouleau⁸⁹, Sabrina Schaupp³⁴, William A Scheftner⁹⁰, Simon Schmitt¹¹, Peter R Schofield⁵⁴, K Oliver Schubert⁹¹, Eva C Schulte¹⁹, Barbara Schweizer⁴⁹, Fanny Senner¹⁹, Giovanni Severino⁸⁶, Sally Sharp⁴, Claire Slaney⁵⁵, Olav B Smeland²¹, Janet L Sobell⁹², Alessio Squassina⁹³, Pavla Stopkova⁸², John Strauss⁶⁵, Alfonso Tortorella⁹⁴, Gustavo Turecki⁹⁵, Joanna Twarowska-Hauser⁴⁵, Marin Veldic⁴³, Eduard Vieta²⁹, John B Vincent⁶⁵, Wei Xu⁹⁶, Clement C Zai⁹⁷, Peter P Zandi⁴⁹; Psychiatric Genomics Consortium (PGC) Bipolar Disorder Working Group; International Consortium on Lithium Genetics (ConLiGen); Colombia-US Cross Disorder Collaboration in Psychiatric Genetics; Arianna Di Florio⁴¹, Jordan W Smoller⁹⁸, Joanna M Biernacka⁹⁹, Francis J McMahon¹⁰⁰, Martin Alda¹⁰¹, Bertram Müller-Myhsok¹⁰², Nikolaos Koutsouleris¹⁰³, Peter Falkai¹⁰⁴, Nelson B Freimer¹⁰⁵, Till F M Andlauer¹⁰⁶, Thomas G Schulze¹⁰⁷, Roel A Ophoff¹⁰⁸

Affiliations

¹ Institute of Psychiatric Phenomics and Genomics (IPPG), University Hospital, LMU Munich, Germany; Department of Psychiatry and Psychotherapy, University Hospital Munich, Germany; and International Max Planck Research School for Translational Psychiatry, Germany.
² Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles, USA.
³ Department of Child and Adolescent Psychiatry/Psychology, Erasmus University Medical Centre-Sophia Children's Hospital, the Netherlands.
⁴ Division of Psychiatry, University College London, UK.
⁵ Division of Psychiatric Genomics, Mount Sinai School of Medicine, USA.
⁶ Division of Genetic Medicine, Department of Medicine, Vanderbilt Genetics Institute, Vanderbilt University Medical Center, USA; Department of Biomedical Informatics, Vanderbilt University Medical Center, USA; and Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center, USA.
⁷ Alexandru Obregia Clinical Psychiatric Hospital, Bucharest, Romania.
⁸ Department of Psychiatry and Psychotherapy, Charite - Universitätsmedizin, Germany.
⁹ Analytic and Translational Genetics Unit, Massachusetts General Hospital, USA; and Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, USA.
¹⁰ Department of Psychiatry and Behavioral Sciences, SUNY Downstate Health Sciences University, USA; and VA NY Harbor Healthcare System, USA.
¹¹ Department of Psychiatry and Psychotherapy, Philipps-University Marburg, Germany.
¹² Department of Psychiatry and Psychotherapy, Philipps-University Marburg, Germany; and Center for Mind, Brain and Behavior (CMBB), Germany.
¹³ Institute for Translational Psychiatry, Westfälische Wilhelms-Universität Münster, Germany; and Institute for Translational Neuroscience, University of Münster, Germany.
¹⁴ International Max Planck Research School for Translational Psychiatry, Germany; and Max Planck Institute of Psychiatry, Germany.
¹⁵ Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Germany.
¹⁶ Institute of Psychiatric Phenomics and Genomics (IPPG), University Hospital, LMU Munich, Germany; Department of Psychiatry and Psychotherapy, University Hospital Munich, Germany; and Centro de Investigación Biomedica en Red de Salud Mental (CIBERSAM), Spain.
¹⁷ Division of Psychiatry, University of Edinburgh, UK.
¹⁸ Department of Clinical Sciences, Medical Faculty, Umeå University, Sweden.
¹⁹ Institute of Psychiatric Phenomics and Genomics (IPPG), University Hospital, LMU Munich, Germany; and Department of Psychiatry and Psychotherapy, University Hospital Munich, Germany.
²⁰ Department of Clinical Neuroscience, Centre for Psychiatry Research, Karolinska Institutet, Sweden; Department of Psychiatric Research, Diakonhjemmet Hospital, Norway; and NORMENT Centre, Division of Mental Health and Addiction, Institute of Clinical Medicine, University of Oslo, Norway.
²¹ Division of Mental Health and Addiction, Oslo University Hospital, Norway; and NORMENT Centre, Inst of Clinical Medicine, University of Oslo, Norway.
²² Department of Psychiatry and Psychotherapy, University Medical Center Göttingen, Germany.
²³ NORMENT Centre, Inst of Clinical Medicine, University of Oslo, Norway; and Division of Mental Health and Addiction, Oslo University Hosptial, Norway.
²⁴ Unit of Clinical Pharmacology, University Hospital Agency of Cagliari, Italy.
²⁵ Faculty of medicine, University of Geneva, Switzerland; and Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt, Germany.
²⁶ Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt, Germany.
²⁷ Department of Psychiatry, University of Münster, Germany; Department of Psychiatry, Melbourne Medical School, The University of Melbourne, Australia; The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Australia; and Discipline of Psychiatry, Adelaide Medical School, The University of Adelaide, Australia.
²⁸ Universite de Paris, France; INSERM UMRS 1144, France; and DMU Neurosciences, GHU Lariboisière Fernand Widal, Departement de Psychiatrie, APHP, France.
²⁹ Hospital Clinic, University of Barcelona, IDIBAPS, CIBERSAM, Spain.
³⁰ Department of Psychiatry and Psychotherapeutic Medicine, Medical University Graz, Austria.
³¹ Psychiatry, University of Pennsylvania, USA.
³² Psychiatry, UMC Utrecht Brain Center, the Netherlands.
³³ Department of Psychiatry, Stony Brook University, USA.
³⁴ Institute of Psychiatric Phenomics and Genomics (IPPG), University Hospital, LMU Munich, Germany.
³⁵ Psychiatry, University of California San Francisco, USA.
³⁶ Department of Psychiatry, McGill University, Canada.
³⁷ Department of Biomedicine, University of Basel, Switzerland; Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, Germany; Institute of Medical Genetics and Pathology, University Hospital Basel, Switzerland; and Institute of Neuroscience and Medicine (INM-1), Research Centre Julich, Germany.
³⁸ Discipline of Psychiatry, University of Adelaide, Australia; and Bazil Hetzel Institute, Australia.
³⁹ Department of Psychiatry & Trinity Translational Medicine Institute, Trinity College Dublin, Ireland.
⁴⁰ University of Iowa Hospitals and Clinics, USA.
⁴¹ Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, UK.
⁴² Translational Genomics, USC, USA.
⁴³ Department of Psychiatry and Psychology, Mayo Clinic, USA.
⁴⁴ Department of Translational Research, Max Planck Institute of Psychiatry, Germany.
⁴⁵ Department of Psychiatric Genetics, Poznan University of Medical Sciences, Poland.
⁴⁶ Institute for Translational Psychiatry, Westfälische Wilhelms-Universität Münster, Germany.
⁴⁷ Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, Germany; and Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital Essen, University of Duisburg-Essen, Germany.
⁴⁸ Department of Biomedical Science, Section of Neuroscience & Clinical Pharmacology, University of Cagliari, Italy; and Unit of Clinical Pharmacology, University Hospital Agency of Cagliari, Italy.
⁴⁹ Department of Psychiatry and Behavioral Sciences, Johns Hopkins University, USA.
⁵⁰ Department of Medical Genetics, Oslo University Hospital Ullevål, Norway; and NORMENT, Department of Clinical Science, University of Bergen, Norway.
⁵¹ Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, USA.
⁵² NORMENT, Division of Mental Health and Addiction, Oslo University Hospital, Norway.
⁵³ Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, Germany; and Centre for Human Genetics, University of Marburg, Germany.
⁵⁴ Neuroscience Research Australia, Australia; and School of Medical Sciences, University of New South Wales, Australia.
⁵⁵ Nova Scotia Health Authority, Canada.
⁵⁶ Department of Psychiatry and Behavioral Neuroscience, University of Chicago, USA; and Department of Human Genetics, University of Chicago, USA.
⁵⁷ Psychological Medicine, University of Worcester, UK.
⁵⁸ Mood Disorders Centre of Ottawa, Canada; and Department of Psychiatry, University of Toronto, Canada.
⁵⁹ Mental Health Department, University Regional Hospital, Biomedicine Institute (IBIMA), Spain.
⁶⁰ Cell Biology, SUNY Downstate Medical Center College of Medicine, USA; and Institute for Genomic Health, SUNY Downstate Medical Center College of Medicine, USA.
⁶¹ Universite Paris Est Creteil, France; and INSERM U 955, Neuropsychiatrie Translationnelle, France.
⁶² Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Sweden.
⁶³ Department of Psychiatry, Icahn School of Medicine at Mount Sinai, USA.
⁶⁴ Department of Psychiatry, University of California San Diego, USA.
⁶⁵ Department of Psychiatry, University of Toronto, Canada; The Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Canada; and Institute of Medical Science, University of Toronto, Canada.
⁶⁶ Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt, Germany; and Department of Psychiatry, Psychotherapy and Psychosomatics, University Hospital Wurzburg, Germany.
⁶⁷ NORMENT Centre, Division of Mental Health and Addiction, Oslo University Hosptial, Norway.
⁶⁸ Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Sweden; and Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Sweden.
⁶⁹ Department of Psychiatry and Behavioral Sciences, Howard University Hospital, USA.
⁷⁰ Neuroscience, Janssen Research & Development, USA.
⁷¹ Department of Psychiatry, University of Campania 'Luigi Vanvitelli', Italy.
⁷² Department of Psychiatry, Icahn School of Medicine at Mount Sinai, USA; and Department of Genetics & Genomics, Icahn School of Medicine at Mount Sinai, USA.
⁷³ Unit of Psychiatry, Department of Medical Sciences and Public Health, University of Cagliari, Italy and Department of Pharmacology, Dalhousie University, Canada.
⁷⁴ Research Institute, Lindner Center of HOPE, USA.
⁷⁵ Department of Psychiatry, University of Michigan, USA.
⁷⁶ Institute for Genomic Health, SUNY Downstate Medical Center College of Medicine, USA.
⁷⁷ NORMENT Centre, Division of Mental Health and Addiction, Institute of Clinical Medicine and Diakonhjemmet Hospital, University of Oslo, Norway; and Division of Mental Health and Addiction, Oslo University Hospital, Norway.
⁷⁸ Psychiatric Clinic, Alexander University Hospital, Bulgaria.
⁷⁹ School of Psychiatry, University of New South Wales, Australia.
⁸⁰ Department of Medicine, Surgery and Dentistry 'Scuola Medica Salernitana', University of Salerno, Italy.
⁸¹ Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, Germany.
⁸² National Institute of Mental Health, Czech Republic.
⁸³ Psychiatry, Indiana University School of Medicine, USA.
⁸⁴ Department of Psychiatry, Dalhousie University, Canada.
⁸⁵ Department of Psychiatry, University of Toronto, Toronto, Canada; and Centre for Addiction and Mental Health, Toronto, Canada.
⁸⁶ Department of Biomedical Science, Section of Neuroscience & Clinical Pharmacology, University of Cagliari, Italy.
⁸⁷ Department of Psychiatry and Behavioral Sciences, Emory University, USA.
⁸⁸ Department of Psychiatry, Geneva University Hospitals, Switzerland.
⁸⁹ Montreal Neurological Institute, Canada and Department of Neurology, McGill University, Canada.
⁹⁰ Department of Psychiatry, Rush Medical College, USA.
⁹¹ Discipline of Psychiatry, University of Adelaide, Australia; and Northern Adelaide Mental Health Service, SA Health, Australia.
⁹² Psychiatry and the Behavioral Sciences, University of Southern California, USA.
⁹³ Department of Psychiatry, Dalhousie University, Canada; and Department of Biomedical Science, Section of Neuroscience & Clinical Pharmacology, University of Cagliari, Italy.
⁹⁴ Department of Psychiatry, University of Perugia, Italy.
⁹⁵ Department of Psychiatry, McGill University, Canada; and Douglas Institute, McGill University, Canada.
⁹⁶ Dalla Lana School of Public Health, Biostatistics Division, University of Toronto, Canada.
⁹⁷ Department of Psychiatry, University of Toronto, Canada; The Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Canada; Institute of Medical Science, University of Toronto, Canada; Laboratory Medicine and Pathobiology, University of Toronto, Canada; and Harvard T.H. Chan School of Public Health, USA.
⁹⁸ Psychiatric and Neurodevelopmental Genetics Unit, Department of Psychiatry and Center for Genomic Medicine, Massachusetts General Hospital, USA; and Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, USA.
⁹⁹ Department of Psychiatry and Psychology, Mayo Clinic, USA; and Department of Health Sciences Research, Mayo Clinic, USA.
¹⁰⁰ Human Genetics Branch, Intramural Research Program, National Institute of Mental Health, USA.
¹⁰¹ National Institute of Mental Health, Czech Republic; and Department of Psychiatry, Dalhousie University, Canada.
¹⁰² Max Planck Institute of Psychiatry, Germany.
¹⁰³ Department of Psychiatry and Psychotherapy, University Hospital Munich, Germany; Max Planck Institute of Psychiatry, Germany; and Institute of Psychiatry, Psychology and Neuroscience, Kings College London, UK.
¹⁰⁴ Department of Psychiatry and Psychotherapy, University Hospital Munich, Germany.
¹⁰⁵ Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles, USA; and Human Genetics, University of California Los Angeles, USA.
¹⁰⁶ Department of Neurology, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Germany.
¹⁰⁷ Institute of Psychiatric Phenomics and Genomics (IPPG), University Hospital, LMU Munich, Germany; Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Germany; Department of Psychiatry and Psychotherapy, University Medical Center Göttingen, Germany; Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, USA; and Department of Psychiatry and Behavioral Sciences, SUNY Upstate Medical University, USA.
¹⁰⁸ Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles, USA; Human Genetics, University of California Los Angeles, USA; and Psychiatry, Erasmus University Medical Center, the Netherlands.

PMID: 35048876
PMCID: PMC8636611
DOI: 10.1192/bjp.2021.102

Characterisation of age and polarity at onset in bipolar disorder

Janos L Kalman et al. Br J Psychiatry. 2021 Dec.

. 2021 Dec;219(6):659-669.

doi: 10.1192/bjp.2021.102.

Authors

Affiliations

¹ Institute of Psychiatric Phenomics and Genomics (IPPG), University Hospital, LMU Munich, Germany; Department of Psychiatry and Psychotherapy, University Hospital Munich, Germany; and International Max Planck Research School for Translational Psychiatry, Germany.
² Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles, USA.
³ Department of Child and Adolescent Psychiatry/Psychology, Erasmus University Medical Centre-Sophia Children's Hospital, the Netherlands.
⁴ Division of Psychiatry, University College London, UK.
⁵ Division of Psychiatric Genomics, Mount Sinai School of Medicine, USA.
⁶ Division of Genetic Medicine, Department of Medicine, Vanderbilt Genetics Institute, Vanderbilt University Medical Center, USA; Department of Biomedical Informatics, Vanderbilt University Medical Center, USA; and Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center, USA.
⁷ Alexandru Obregia Clinical Psychiatric Hospital, Bucharest, Romania.
⁸ Department of Psychiatry and Psychotherapy, Charite - Universitätsmedizin, Germany.
⁹ Analytic and Translational Genetics Unit, Massachusetts General Hospital, USA; and Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, USA.
¹⁰ Department of Psychiatry and Behavioral Sciences, SUNY Downstate Health Sciences University, USA; and VA NY Harbor Healthcare System, USA.
¹¹ Department of Psychiatry and Psychotherapy, Philipps-University Marburg, Germany.
¹² Department of Psychiatry and Psychotherapy, Philipps-University Marburg, Germany; and Center for Mind, Brain and Behavior (CMBB), Germany.
¹³ Institute for Translational Psychiatry, Westfälische Wilhelms-Universität Münster, Germany; and Institute for Translational Neuroscience, University of Münster, Germany.
¹⁴ International Max Planck Research School for Translational Psychiatry, Germany; and Max Planck Institute of Psychiatry, Germany.
¹⁵ Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Germany.
¹⁶ Institute of Psychiatric Phenomics and Genomics (IPPG), University Hospital, LMU Munich, Germany; Department of Psychiatry and Psychotherapy, University Hospital Munich, Germany; and Centro de Investigación Biomedica en Red de Salud Mental (CIBERSAM), Spain.
¹⁷ Division of Psychiatry, University of Edinburgh, UK.
¹⁸ Department of Clinical Sciences, Medical Faculty, Umeå University, Sweden.
¹⁹ Institute of Psychiatric Phenomics and Genomics (IPPG), University Hospital, LMU Munich, Germany; and Department of Psychiatry and Psychotherapy, University Hospital Munich, Germany.
²⁰ Department of Clinical Neuroscience, Centre for Psychiatry Research, Karolinska Institutet, Sweden; Department of Psychiatric Research, Diakonhjemmet Hospital, Norway; and NORMENT Centre, Division of Mental Health and Addiction, Institute of Clinical Medicine, University of Oslo, Norway.
²¹ Division of Mental Health and Addiction, Oslo University Hospital, Norway; and NORMENT Centre, Inst of Clinical Medicine, University of Oslo, Norway.
²² Department of Psychiatry and Psychotherapy, University Medical Center Göttingen, Germany.
²³ NORMENT Centre, Inst of Clinical Medicine, University of Oslo, Norway; and Division of Mental Health and Addiction, Oslo University Hosptial, Norway.
²⁴ Unit of Clinical Pharmacology, University Hospital Agency of Cagliari, Italy.
²⁵ Faculty of medicine, University of Geneva, Switzerland; and Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt, Germany.
²⁶ Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt, Germany.
²⁷ Department of Psychiatry, University of Münster, Germany; Department of Psychiatry, Melbourne Medical School, The University of Melbourne, Australia; The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Australia; and Discipline of Psychiatry, Adelaide Medical School, The University of Adelaide, Australia.
²⁸ Universite de Paris, France; INSERM UMRS 1144, France; and DMU Neurosciences, GHU Lariboisière Fernand Widal, Departement de Psychiatrie, APHP, France.
²⁹ Hospital Clinic, University of Barcelona, IDIBAPS, CIBERSAM, Spain.
³⁰ Department of Psychiatry and Psychotherapeutic Medicine, Medical University Graz, Austria.
³¹ Psychiatry, University of Pennsylvania, USA.
³² Psychiatry, UMC Utrecht Brain Center, the Netherlands.
³³ Department of Psychiatry, Stony Brook University, USA.
³⁴ Institute of Psychiatric Phenomics and Genomics (IPPG), University Hospital, LMU Munich, Germany.
³⁵ Psychiatry, University of California San Francisco, USA.
³⁶ Department of Psychiatry, McGill University, Canada.
³⁷ Department of Biomedicine, University of Basel, Switzerland; Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, Germany; Institute of Medical Genetics and Pathology, University Hospital Basel, Switzerland; and Institute of Neuroscience and Medicine (INM-1), Research Centre Julich, Germany.
³⁸ Discipline of Psychiatry, University of Adelaide, Australia; and Bazil Hetzel Institute, Australia.
³⁹ Department of Psychiatry & Trinity Translational Medicine Institute, Trinity College Dublin, Ireland.
⁴⁰ University of Iowa Hospitals and Clinics, USA.
⁴¹ Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, UK.
⁴² Translational Genomics, USC, USA.
⁴³ Department of Psychiatry and Psychology, Mayo Clinic, USA.
⁴⁴ Department of Translational Research, Max Planck Institute of Psychiatry, Germany.
⁴⁵ Department of Psychiatric Genetics, Poznan University of Medical Sciences, Poland.
⁴⁶ Institute for Translational Psychiatry, Westfälische Wilhelms-Universität Münster, Germany.
⁴⁷ Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, Germany; and Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital Essen, University of Duisburg-Essen, Germany.
⁴⁸ Department of Biomedical Science, Section of Neuroscience & Clinical Pharmacology, University of Cagliari, Italy; and Unit of Clinical Pharmacology, University Hospital Agency of Cagliari, Italy.
⁴⁹ Department of Psychiatry and Behavioral Sciences, Johns Hopkins University, USA.
⁵⁰ Department of Medical Genetics, Oslo University Hospital Ullevål, Norway; and NORMENT, Department of Clinical Science, University of Bergen, Norway.
⁵¹ Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, USA.
⁵² NORMENT, Division of Mental Health and Addiction, Oslo University Hospital, Norway.
⁵³ Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, Germany; and Centre for Human Genetics, University of Marburg, Germany.
⁵⁴ Neuroscience Research Australia, Australia; and School of Medical Sciences, University of New South Wales, Australia.
⁵⁵ Nova Scotia Health Authority, Canada.
⁵⁶ Department of Psychiatry and Behavioral Neuroscience, University of Chicago, USA; and Department of Human Genetics, University of Chicago, USA.
⁵⁷ Psychological Medicine, University of Worcester, UK.
⁵⁸ Mood Disorders Centre of Ottawa, Canada; and Department of Psychiatry, University of Toronto, Canada.
⁵⁹ Mental Health Department, University Regional Hospital, Biomedicine Institute (IBIMA), Spain.
⁶⁰ Cell Biology, SUNY Downstate Medical Center College of Medicine, USA; and Institute for Genomic Health, SUNY Downstate Medical Center College of Medicine, USA.
⁶¹ Universite Paris Est Creteil, France; and INSERM U 955, Neuropsychiatrie Translationnelle, France.
⁶² Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Sweden.
⁶³ Department of Psychiatry, Icahn School of Medicine at Mount Sinai, USA.
⁶⁴ Department of Psychiatry, University of California San Diego, USA.
⁶⁵ Department of Psychiatry, University of Toronto, Canada; The Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Canada; and Institute of Medical Science, University of Toronto, Canada.
⁶⁶ Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt, Germany; and Department of Psychiatry, Psychotherapy and Psychosomatics, University Hospital Wurzburg, Germany.
⁶⁷ NORMENT Centre, Division of Mental Health and Addiction, Oslo University Hosptial, Norway.
⁶⁸ Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Sweden; and Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Sweden.
⁶⁹ Department of Psychiatry and Behavioral Sciences, Howard University Hospital, USA.
⁷⁰ Neuroscience, Janssen Research & Development, USA.
⁷¹ Department of Psychiatry, University of Campania 'Luigi Vanvitelli', Italy.
⁷² Department of Psychiatry, Icahn School of Medicine at Mount Sinai, USA; and Department of Genetics & Genomics, Icahn School of Medicine at Mount Sinai, USA.
⁷³ Unit of Psychiatry, Department of Medical Sciences and Public Health, University of Cagliari, Italy and Department of Pharmacology, Dalhousie University, Canada.
⁷⁴ Research Institute, Lindner Center of HOPE, USA.
⁷⁵ Department of Psychiatry, University of Michigan, USA.
⁷⁶ Institute for Genomic Health, SUNY Downstate Medical Center College of Medicine, USA.
⁷⁷ NORMENT Centre, Division of Mental Health and Addiction, Institute of Clinical Medicine and Diakonhjemmet Hospital, University of Oslo, Norway; and Division of Mental Health and Addiction, Oslo University Hospital, Norway.
⁷⁸ Psychiatric Clinic, Alexander University Hospital, Bulgaria.
⁷⁹ School of Psychiatry, University of New South Wales, Australia.
⁸⁰ Department of Medicine, Surgery and Dentistry 'Scuola Medica Salernitana', University of Salerno, Italy.
⁸¹ Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, Germany.
⁸² National Institute of Mental Health, Czech Republic.
⁸³ Psychiatry, Indiana University School of Medicine, USA.
⁸⁴ Department of Psychiatry, Dalhousie University, Canada.
⁸⁵ Department of Psychiatry, University of Toronto, Toronto, Canada; and Centre for Addiction and Mental Health, Toronto, Canada.
⁸⁶ Department of Biomedical Science, Section of Neuroscience & Clinical Pharmacology, University of Cagliari, Italy.
⁸⁷ Department of Psychiatry and Behavioral Sciences, Emory University, USA.
⁸⁸ Department of Psychiatry, Geneva University Hospitals, Switzerland.
⁸⁹ Montreal Neurological Institute, Canada and Department of Neurology, McGill University, Canada.
⁹⁰ Department of Psychiatry, Rush Medical College, USA.
⁹¹ Discipline of Psychiatry, University of Adelaide, Australia; and Northern Adelaide Mental Health Service, SA Health, Australia.
⁹² Psychiatry and the Behavioral Sciences, University of Southern California, USA.
⁹³ Department of Psychiatry, Dalhousie University, Canada; and Department of Biomedical Science, Section of Neuroscience & Clinical Pharmacology, University of Cagliari, Italy.
⁹⁴ Department of Psychiatry, University of Perugia, Italy.
⁹⁵ Department of Psychiatry, McGill University, Canada; and Douglas Institute, McGill University, Canada.
⁹⁶ Dalla Lana School of Public Health, Biostatistics Division, University of Toronto, Canada.
⁹⁷ Department of Psychiatry, University of Toronto, Canada; The Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Canada; Institute of Medical Science, University of Toronto, Canada; Laboratory Medicine and Pathobiology, University of Toronto, Canada; and Harvard T.H. Chan School of Public Health, USA.
⁹⁸ Psychiatric and Neurodevelopmental Genetics Unit, Department of Psychiatry and Center for Genomic Medicine, Massachusetts General Hospital, USA; and Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, USA.
⁹⁹ Department of Psychiatry and Psychology, Mayo Clinic, USA; and Department of Health Sciences Research, Mayo Clinic, USA.
¹⁰⁰ Human Genetics Branch, Intramural Research Program, National Institute of Mental Health, USA.
¹⁰¹ National Institute of Mental Health, Czech Republic; and Department of Psychiatry, Dalhousie University, Canada.
¹⁰² Max Planck Institute of Psychiatry, Germany.
¹⁰³ Department of Psychiatry and Psychotherapy, University Hospital Munich, Germany; Max Planck Institute of Psychiatry, Germany; and Institute of Psychiatry, Psychology and Neuroscience, Kings College London, UK.
¹⁰⁴ Department of Psychiatry and Psychotherapy, University Hospital Munich, Germany.
¹⁰⁵ Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles, USA; and Human Genetics, University of California Los Angeles, USA.
¹⁰⁶ Department of Neurology, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Germany.
¹⁰⁷ Institute of Psychiatric Phenomics and Genomics (IPPG), University Hospital, LMU Munich, Germany; Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Germany; Department of Psychiatry and Psychotherapy, University Medical Center Göttingen, Germany; Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, USA; and Department of Psychiatry and Behavioral Sciences, SUNY Upstate Medical University, USA.
¹⁰⁸ Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles, USA; Human Genetics, University of California Los Angeles, USA; and Psychiatry, Erasmus University Medical Center, the Netherlands.

PMID: 35048876
PMCID: PMC8636611
DOI: 10.1192/bjp.2021.102

Abstract

Background: Studying phenotypic and genetic characteristics of age at onset (AAO) and polarity at onset (PAO) in bipolar disorder can provide new insights into disease pathology and facilitate the development of screening tools.

Aims: To examine the genetic architecture of AAO and PAO and their association with bipolar disorder disease characteristics.

Method: Genome-wide association studies (GWASs) and polygenic score (PGS) analyses of AAO (n = 12 977) and PAO (n = 6773) were conducted in patients with bipolar disorder from 34 cohorts and a replication sample (n = 2237). The association of onset with disease characteristics was investigated in two of these cohorts.

Results: Earlier AAO was associated with a higher probability of psychotic symptoms, suicidality, lower educational attainment, not living together and fewer episodes. Depressive onset correlated with suicidality and manic onset correlated with delusions and manic episodes. Systematic differences in AAO between cohorts and continents of origin were observed. This was also reflected in single-nucleotide variant-based heritability estimates, with higher heritabilities for stricter onset definitions. Increased PGS for autism spectrum disorder (β = -0.34 years, s.e. = 0.08), major depression (β = -0.34 years, s.e. = 0.08), schizophrenia (β = -0.39 years, s.e. = 0.08), and educational attainment (β = -0.31 years, s.e. = 0.08) were associated with an earlier AAO. The AAO GWAS identified one significant locus, but this finding did not replicate. Neither GWAS nor PGS analyses yielded significant associations with PAO.

Conclusions: AAO and PAO are associated with indicators of bipolar disorder severity. Individuals with an earlier onset show an increased polygenic liability for a broad spectrum of psychiatric traits. Systematic differences in AAO across cohorts, continents and phenotype definitions introduce significant heterogeneity, affecting analyses.

Keywords: Bipolar disorder; GWAS; age at onset; polarity at onset; polygenic score.

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Conflict of interest statement

Amare T. Azmeraw: has received 2020–2022 NARSAD Young Investigator Grant from the Brain & Behaviour Research Foundation. Ole A. Andreassen: speaker's honorarium Sunovion, Lundbeck. Consultant HealthLytix. Bernhard Baune: Honoraria: Lundbeck, Janssen, LivaNova, Servier. Carrie Bearden: Novartis Scientific Advisory Board. Clark Scott: Honoraria and Investigator-initiated project funding from Jannsen-Cilag Australia, Lundbeck-Otsuka Australia. J. Raymond DePaulo: owns stock in CVS Health; JRD was unpaid consultant for Myriad Neuroscience 2017 & 2019. Michael C. O´Donovan: research unrelated to this manuscript supported by a collaborative research grant from Takeda Pharmaceuticals. Bruno Etain: honoraria for Sanofi. Mark A. Frye: grant Support Assurex Health, Mayo Foundation, Medibio Consultant (Mayo) Actify Neurotherapies, Allergan, Intra-Cellular Therapies, Inc., Janssen, Myriad, Neuralstem Inc., Sanofi, Takeda, Teva Pharmaceuticals. Per Hoffmann: employee of Life&Brain GmbH, Member of the Scientific Advisory Board of HMG Systems Engeneering GmbH. Mikael Landen: Speaker's honoraria Lundbeck pharmaceuticals. Andrew M McIntosh: research funding from The Sackler Trust, speaker fees from Illumina and Janssen. Philip B. Mitchell: remuneration for lectures in China on bipolar disorder research by Sanofi (Hangzhou). John Nurnberger: investigator for Janssen. Benjamin M. Neale: is a member of the scientific advisory board at Deep Genomics and RBNC Therapeutics. A consultant for Camp4 Therapeutics, Takeda Pharmaceutical and Biogen. Andreas Reif: apeaker's honoraria / Advisory boards: Janssen, Shire/Takeda, Medice, SAGE and Servier. Eli Stahl: now employed by the Regeneron Genetics Center. Kato Tadafumi: honoraria: Kyowa Hakko Kirin Co., Ltd., Eli Lilly Japan K.K., Otsuka Pharmaceutical Co., Ltd., GlaxoSmithKline K.K., Taisho Pharma Co., Ltd., Taisho Pharmaceutical Co., Ltd., 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., Nippon, Boehringer Ingelheim Co. Ltd., MSD K.K., Kyowa Pharmaceutical Industry Co., Ltd., Takeda Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Eisai Co., Ltd. Grants: Takeda Pharmaceutical Co., Ltd., Dainippon Sumitomo Pharma Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Shionogi & Co., Ltd., Eisai Co., Ltd., Mitsubishi Tanabe Pharma Corporation. Thomas G. Schulze: is a member of the editorial board of The British Journal of Psychiatry. He did not take part in the review or decision-making process of this paper. Eduard Vieta: has received grants and served as consultant, advisor or CME speaker for the following entities: AB-Biotics, Abbott, Allergan, Angelini, Dainippon Sumitomo Pharma, Ferrer, Gedeon Richter, Janssen, Lundbeck, Otsuka, Sage, Sanofi-Aventis, Sunovion and Takeda. None of the other authors reported any biomedical financial interests or potential conflicts of interest. ICMJE forms are in the supplementary material, available online at https://doi.org/10.1192/10.1192/bjp.2021.102.

Figures

**Fig. 1**
Differences between phenotype definitions and continents across the 34 data-sets used for discovery-stage genetic analyses. (a) The various data-sets used four different definitions for age at onset: diagnostic interview, impairment/help-seeking, pharmacotherapy and mixed. (b) The untransformed age at onset differed significantly between cohorts, depending on the phenotype definition used and the continent of origin. Au, Australia; Diagnostic, diagnostic interview; D, diagnostic interview; I, impairment/help-seeking; M, mixed; P, pharmacotherapy. n.s., not significant; P > 0.05; *** P < 0.001.

**Fig. 2**
Results from the genome-wide association study (GWAS), polygenic score (PGS) analyses, and heritability analyses. (a) and (b) Results from analyses of PGS. For detailed results, see Supplementary Table S8. Significance levels: n.s., not significant, P > 0.05; nominal: P < 0.05; Bonferroni, below the Bonferroni-corrected significance threshold corrected for 96 tests (P < 5.2 × 10⁻⁴). (a) Associations of PGSs with the AAO. For interpretability, the plot shows the untransformed AAO. Significance levels are based on the analyses of the AAO after rank-based inverse-normal transformation (which was performed because the distribution of AAO was highly skewed and differed greatly across the study cohorts). (b) Associations of the top versus bottom AAO quartiles with the top versus bottom PGS quartiles. A higher odds ratio (OR) indicates an association with higher AAO. (c) Manhattan plot of the discovery-stage AAO GWAS. (d) Locus-specific Manhattan plot of the top-associated AAO variant. (e) Estimation of the variance in different phenotype definitions explained by genotyped single-nucleotide variants (SNV) (*h²_SNV*). For the cohort *wtccc*, we directly estimated *h²_SNV* from genotype data in GCTA GREML; we estimated all other heritabilities from GWAS summary statistics using LDSC. The plot shows *h²_SNV* estimates and s.e. ADHD, attention-deficit/hyperactivity disorder; ASD, autism spectrum disorder; BD, bipolar disorder; cM, centi Morgan. Mbp, mega base pairs; MD, major depression; EA, educational attainment; SNV, single-nucleotide variant; cont, continent; disorder type I; PAO, polarity at onset; PAO-M, mania/hypomania before depression; PAO-D, depression before mania/hypomania; PAO-X, mixed; SZ, schizophrenia.

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Characterisation of age and polarity at onset in bipolar disorder

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Characterisation of age and polarity at onset in bipolar disorder

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