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Published Online: 12 September 2024
High Burden of Ileus and Pneumonia in Clozapine-Treated Individuals With Schizophrenia: A Finnish 25-Year Follow-Up Register Study
Juulia J. Partanen, M.D., Paavo Häppölä, Ph.D., Anders Kämpe, M.D., Ph.D., Ari Ahola-Olli, M.D., Ph.D., Anni Hellsten, M.D., Susanna M. Rask, M.D., Willehard Haaki, M.D., … Show All … , Jarmo Hietala, M.D., Ph.D., Olli Kampman, M.D., Ph.D., Jari Tiihonen, M.D., Ph.D., Antti J. Tanskanen, Ph.D., FinnGen, SUPER-Finland, Mark J. Daly, Ph.D., Samuli Ripatti, Ph.D., Aarno Palotie, M.D., Ph.D., Heidi Taipale, Ph.D., Markku Lähteenvuo, M.D., Ph.D., and Jukka T. Koskela, M.D., Ph.D. [email protected] Show FewerAuthors Info & Affiliations
Publication: American Journal of Psychiatry
Abstract
Objective:
The authors used longitudinal biobank data with up to 25 years of follow-up on over 2,600 clozapine users to derive reliable estimates of the real-world burden of clozapine adverse drug events (ADEs).
Methods:
A total of 2,659 participants in the FinnGen biobank project had a schizophrenia diagnosis and clozapine purchases with longitudinal electronic health record follow-up for up to 25 years after clozapine initiation. Diseases and health-related events enriched during clozapine use were identified, adjusting for disease severity. The incidence and recurrence of ADEs over years of clozapine use, their effect on clozapine discontinuation and deaths, and their pharmacogenetics were studied.
Results:
Median follow-up time after clozapine initiation was 12.7 years. Across 2,157 diseases and health-related events, 27 were enriched during clozapine use, falling into five disease categories: gastrointestinal hypomotility, seizures, pneumonia, other acute respiratory tract infections, and tachycardia, along with a heterogeneous group including neutropenia and type 2 diabetes, among others. Cumulative incidence estimates for ileus (severe gastrointestinal hypomotility) and pneumonia were 5.3% and 29.5%, respectively, 20 years after clozapine initiation. Both events were significantly associated with increased mortality among clozapine users (ileus: odds ratio=4.5; pneumonia: odds ratio=2.8). Decreased genotype-predicted CYP2C19 and CYP1A2 activities were associated with higher pneumonia risk.
Conclusions:
Clozapine-induced ileus and pneumonia were notably more frequent than has previously been reported and were associated with increased mortality. Two CYP genes influenced pneumonia risk. Pneumonia and ileus call for improved utilization of available preventive measures.
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History
Received: 15 September 2023
Revision received: 19 January 2024
Accepted: 21 February 2024
Published online: 12 September 2024
Published in print: October 01, 2024
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Juulia J. Partanen, M.D.
Institute for Molecular Medicine Finland (FIMM), Helsinki Institute of Life Science (Partanen, Häppölä, Kämpe, Daly, Ripatti, Palotie, Koskela), and Faculty of Medicine (Ripatti), University of Helsinki, Helsinki; Department of Molecular Medicine and Surgery (Kämpe) and Department of Clinical Neuroscience (Tiihonen, Tanskanen, Taipale), Karolinska Institutet, Stockholm; Department of Internal Medicine (Ahola-Olli) and Department of Psychiatry (Haaki, Hietala), Turku University Hospital, Turku, Finland; Aurora Hospital, City of Helsinki, Helsinki (Hellsten); Department of Psychiatry, Faculty of Medicine and Health Technology (Rask), and Faculty of Medicine and Health Technology (Kampman), Tampere University, Tampere, Finland; Department of Psychiatry, Tampere University Hospital, Tampere, Finland (Rask); Department of Psychiatry, University of Turku, Turku, Finland (Haaki, Hietala); Department of Clinical Sciences, Psychiatry, Umeå University, Umeå, Sweden (Kampman); Department of Clinical Medicine, Psychiatry, Faculty of Medicine, University of Turku, Turku, Finland (Kampman); Department of Psychiatry, Wellbeing Services County of Ostrobothnia, Vaasa, Finland (Kampman); Department of Psychiatry, Wellbeing Services County of Pirkanmaa, Tampere, Finland (Kampman); Department of Forensic Psychiatry, University of Eastern Finland, Niuvanniemi Hospital, Kuopio, Finland (Tiihonen, Tanskanen, Taipale, Lähteenvuo); Center for Psychiatry Research, Stockholm City Council, Stockholm (Tiihonen); Stanley Center for Psychiatric Research (Daly, Palotie) and Program in Medical and Population Genetics (Daly, Ripatti, Palotie), Broad Institute of Harvard and MIT, Cambridge, MA; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston (Daly, Ripatti, Palotie).
Paavo Häppölä, Ph.D.
Institute for Molecular Medicine Finland (FIMM), Helsinki Institute of Life Science (Partanen, Häppölä, Kämpe, Daly, Ripatti, Palotie, Koskela), and Faculty of Medicine (Ripatti), University of Helsinki, Helsinki; Department of Molecular Medicine and Surgery (Kämpe) and Department of Clinical Neuroscience (Tiihonen, Tanskanen, Taipale), Karolinska Institutet, Stockholm; Department of Internal Medicine (Ahola-Olli) and Department of Psychiatry (Haaki, Hietala), Turku University Hospital, Turku, Finland; Aurora Hospital, City of Helsinki, Helsinki (Hellsten); Department of Psychiatry, Faculty of Medicine and Health Technology (Rask), and Faculty of Medicine and Health Technology (Kampman), Tampere University, Tampere, Finland; Department of Psychiatry, Tampere University Hospital, Tampere, Finland (Rask); Department of Psychiatry, University of Turku, Turku, Finland (Haaki, Hietala); Department of Clinical Sciences, Psychiatry, Umeå University, Umeå, Sweden (Kampman); Department of Clinical Medicine, Psychiatry, Faculty of Medicine, University of Turku, Turku, Finland (Kampman); Department of Psychiatry, Wellbeing Services County of Ostrobothnia, Vaasa, Finland (Kampman); Department of Psychiatry, Wellbeing Services County of Pirkanmaa, Tampere, Finland (Kampman); Department of Forensic Psychiatry, University of Eastern Finland, Niuvanniemi Hospital, Kuopio, Finland (Tiihonen, Tanskanen, Taipale, Lähteenvuo); Center for Psychiatry Research, Stockholm City Council, Stockholm (Tiihonen); Stanley Center for Psychiatric Research (Daly, Palotie) and Program in Medical and Population Genetics (Daly, Ripatti, Palotie), Broad Institute of Harvard and MIT, Cambridge, MA; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston (Daly, Ripatti, Palotie).
Anders Kämpe, M.D., Ph.D.
Institute for Molecular Medicine Finland (FIMM), Helsinki Institute of Life Science (Partanen, Häppölä, Kämpe, Daly, Ripatti, Palotie, Koskela), and Faculty of Medicine (Ripatti), University of Helsinki, Helsinki; Department of Molecular Medicine and Surgery (Kämpe) and Department of Clinical Neuroscience (Tiihonen, Tanskanen, Taipale), Karolinska Institutet, Stockholm; Department of Internal Medicine (Ahola-Olli) and Department of Psychiatry (Haaki, Hietala), Turku University Hospital, Turku, Finland; Aurora Hospital, City of Helsinki, Helsinki (Hellsten); Department of Psychiatry, Faculty of Medicine and Health Technology (Rask), and Faculty of Medicine and Health Technology (Kampman), Tampere University, Tampere, Finland; Department of Psychiatry, Tampere University Hospital, Tampere, Finland (Rask); Department of Psychiatry, University of Turku, Turku, Finland (Haaki, Hietala); Department of Clinical Sciences, Psychiatry, Umeå University, Umeå, Sweden (Kampman); Department of Clinical Medicine, Psychiatry, Faculty of Medicine, University of Turku, Turku, Finland (Kampman); Department of Psychiatry, Wellbeing Services County of Ostrobothnia, Vaasa, Finland (Kampman); Department of Psychiatry, Wellbeing Services County of Pirkanmaa, Tampere, Finland (Kampman); Department of Forensic Psychiatry, University of Eastern Finland, Niuvanniemi Hospital, Kuopio, Finland (Tiihonen, Tanskanen, Taipale, Lähteenvuo); Center for Psychiatry Research, Stockholm City Council, Stockholm (Tiihonen); Stanley Center for Psychiatric Research (Daly, Palotie) and Program in Medical and Population Genetics (Daly, Ripatti, Palotie), Broad Institute of Harvard and MIT, Cambridge, MA; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston (Daly, Ripatti, Palotie).
Ari Ahola-Olli, M.D., Ph.D.
Institute for Molecular Medicine Finland (FIMM), Helsinki Institute of Life Science (Partanen, Häppölä, Kämpe, Daly, Ripatti, Palotie, Koskela), and Faculty of Medicine (Ripatti), University of Helsinki, Helsinki; Department of Molecular Medicine and Surgery (Kämpe) and Department of Clinical Neuroscience (Tiihonen, Tanskanen, Taipale), Karolinska Institutet, Stockholm; Department of Internal Medicine (Ahola-Olli) and Department of Psychiatry (Haaki, Hietala), Turku University Hospital, Turku, Finland; Aurora Hospital, City of Helsinki, Helsinki (Hellsten); Department of Psychiatry, Faculty of Medicine and Health Technology (Rask), and Faculty of Medicine and Health Technology (Kampman), Tampere University, Tampere, Finland; Department of Psychiatry, Tampere University Hospital, Tampere, Finland (Rask); Department of Psychiatry, University of Turku, Turku, Finland (Haaki, Hietala); Department of Clinical Sciences, Psychiatry, Umeå University, Umeå, Sweden (Kampman); Department of Clinical Medicine, Psychiatry, Faculty of Medicine, University of Turku, Turku, Finland (Kampman); Department of Psychiatry, Wellbeing Services County of Ostrobothnia, Vaasa, Finland (Kampman); Department of Psychiatry, Wellbeing Services County of Pirkanmaa, Tampere, Finland (Kampman); Department of Forensic Psychiatry, University of Eastern Finland, Niuvanniemi Hospital, Kuopio, Finland (Tiihonen, Tanskanen, Taipale, Lähteenvuo); Center for Psychiatry Research, Stockholm City Council, Stockholm (Tiihonen); Stanley Center for Psychiatric Research (Daly, Palotie) and Program in Medical and Population Genetics (Daly, Ripatti, Palotie), Broad Institute of Harvard and MIT, Cambridge, MA; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston (Daly, Ripatti, Palotie).
Anni Hellsten, M.D.
Institute for Molecular Medicine Finland (FIMM), Helsinki Institute of Life Science (Partanen, Häppölä, Kämpe, Daly, Ripatti, Palotie, Koskela), and Faculty of Medicine (Ripatti), University of Helsinki, Helsinki; Department of Molecular Medicine and Surgery (Kämpe) and Department of Clinical Neuroscience (Tiihonen, Tanskanen, Taipale), Karolinska Institutet, Stockholm; Department of Internal Medicine (Ahola-Olli) and Department of Psychiatry (Haaki, Hietala), Turku University Hospital, Turku, Finland; Aurora Hospital, City of Helsinki, Helsinki (Hellsten); Department of Psychiatry, Faculty of Medicine and Health Technology (Rask), and Faculty of Medicine and Health Technology (Kampman), Tampere University, Tampere, Finland; Department of Psychiatry, Tampere University Hospital, Tampere, Finland (Rask); Department of Psychiatry, University of Turku, Turku, Finland (Haaki, Hietala); Department of Clinical Sciences, Psychiatry, Umeå University, Umeå, Sweden (Kampman); Department of Clinical Medicine, Psychiatry, Faculty of Medicine, University of Turku, Turku, Finland (Kampman); Department of Psychiatry, Wellbeing Services County of Ostrobothnia, Vaasa, Finland (Kampman); Department of Psychiatry, Wellbeing Services County of Pirkanmaa, Tampere, Finland (Kampman); Department of Forensic Psychiatry, University of Eastern Finland, Niuvanniemi Hospital, Kuopio, Finland (Tiihonen, Tanskanen, Taipale, Lähteenvuo); Center for Psychiatry Research, Stockholm City Council, Stockholm (Tiihonen); Stanley Center for Psychiatric Research (Daly, Palotie) and Program in Medical and Population Genetics (Daly, Ripatti, Palotie), Broad Institute of Harvard and MIT, Cambridge, MA; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston (Daly, Ripatti, Palotie).
Susanna M. Rask, M.D.
Institute for Molecular Medicine Finland (FIMM), Helsinki Institute of Life Science (Partanen, Häppölä, Kämpe, Daly, Ripatti, Palotie, Koskela), and Faculty of Medicine (Ripatti), University of Helsinki, Helsinki; Department of Molecular Medicine and Surgery (Kämpe) and Department of Clinical Neuroscience (Tiihonen, Tanskanen, Taipale), Karolinska Institutet, Stockholm; Department of Internal Medicine (Ahola-Olli) and Department of Psychiatry (Haaki, Hietala), Turku University Hospital, Turku, Finland; Aurora Hospital, City of Helsinki, Helsinki (Hellsten); Department of Psychiatry, Faculty of Medicine and Health Technology (Rask), and Faculty of Medicine and Health Technology (Kampman), Tampere University, Tampere, Finland; Department of Psychiatry, Tampere University Hospital, Tampere, Finland (Rask); Department of Psychiatry, University of Turku, Turku, Finland (Haaki, Hietala); Department of Clinical Sciences, Psychiatry, Umeå University, Umeå, Sweden (Kampman); Department of Clinical Medicine, Psychiatry, Faculty of Medicine, University of Turku, Turku, Finland (Kampman); Department of Psychiatry, Wellbeing Services County of Ostrobothnia, Vaasa, Finland (Kampman); Department of Psychiatry, Wellbeing Services County of Pirkanmaa, Tampere, Finland (Kampman); Department of Forensic Psychiatry, University of Eastern Finland, Niuvanniemi Hospital, Kuopio, Finland (Tiihonen, Tanskanen, Taipale, Lähteenvuo); Center for Psychiatry Research, Stockholm City Council, Stockholm (Tiihonen); Stanley Center for Psychiatric Research (Daly, Palotie) and Program in Medical and Population Genetics (Daly, Ripatti, Palotie), Broad Institute of Harvard and MIT, Cambridge, MA; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston (Daly, Ripatti, Palotie).
Willehard Haaki, M.D.
Institute for Molecular Medicine Finland (FIMM), Helsinki Institute of Life Science (Partanen, Häppölä, Kämpe, Daly, Ripatti, Palotie, Koskela), and Faculty of Medicine (Ripatti), University of Helsinki, Helsinki; Department of Molecular Medicine and Surgery (Kämpe) and Department of Clinical Neuroscience (Tiihonen, Tanskanen, Taipale), Karolinska Institutet, Stockholm; Department of Internal Medicine (Ahola-Olli) and Department of Psychiatry (Haaki, Hietala), Turku University Hospital, Turku, Finland; Aurora Hospital, City of Helsinki, Helsinki (Hellsten); Department of Psychiatry, Faculty of Medicine and Health Technology (Rask), and Faculty of Medicine and Health Technology (Kampman), Tampere University, Tampere, Finland; Department of Psychiatry, Tampere University Hospital, Tampere, Finland (Rask); Department of Psychiatry, University of Turku, Turku, Finland (Haaki, Hietala); Department of Clinical Sciences, Psychiatry, Umeå University, Umeå, Sweden (Kampman); Department of Clinical Medicine, Psychiatry, Faculty of Medicine, University of Turku, Turku, Finland (Kampman); Department of Psychiatry, Wellbeing Services County of Ostrobothnia, Vaasa, Finland (Kampman); Department of Psychiatry, Wellbeing Services County of Pirkanmaa, Tampere, Finland (Kampman); Department of Forensic Psychiatry, University of Eastern Finland, Niuvanniemi Hospital, Kuopio, Finland (Tiihonen, Tanskanen, Taipale, Lähteenvuo); Center for Psychiatry Research, Stockholm City Council, Stockholm (Tiihonen); Stanley Center for Psychiatric Research (Daly, Palotie) and Program in Medical and Population Genetics (Daly, Ripatti, Palotie), Broad Institute of Harvard and MIT, Cambridge, MA; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston (Daly, Ripatti, Palotie).
Jarmo Hietala, M.D., Ph.D.
Institute for Molecular Medicine Finland (FIMM), Helsinki Institute of Life Science (Partanen, Häppölä, Kämpe, Daly, Ripatti, Palotie, Koskela), and Faculty of Medicine (Ripatti), University of Helsinki, Helsinki; Department of Molecular Medicine and Surgery (Kämpe) and Department of Clinical Neuroscience (Tiihonen, Tanskanen, Taipale), Karolinska Institutet, Stockholm; Department of Internal Medicine (Ahola-Olli) and Department of Psychiatry (Haaki, Hietala), Turku University Hospital, Turku, Finland; Aurora Hospital, City of Helsinki, Helsinki (Hellsten); Department of Psychiatry, Faculty of Medicine and Health Technology (Rask), and Faculty of Medicine and Health Technology (Kampman), Tampere University, Tampere, Finland; Department of Psychiatry, Tampere University Hospital, Tampere, Finland (Rask); Department of Psychiatry, University of Turku, Turku, Finland (Haaki, Hietala); Department of Clinical Sciences, Psychiatry, Umeå University, Umeå, Sweden (Kampman); Department of Clinical Medicine, Psychiatry, Faculty of Medicine, University of Turku, Turku, Finland (Kampman); Department of Psychiatry, Wellbeing Services County of Ostrobothnia, Vaasa, Finland (Kampman); Department of Psychiatry, Wellbeing Services County of Pirkanmaa, Tampere, Finland (Kampman); Department of Forensic Psychiatry, University of Eastern Finland, Niuvanniemi Hospital, Kuopio, Finland (Tiihonen, Tanskanen, Taipale, Lähteenvuo); Center for Psychiatry Research, Stockholm City Council, Stockholm (Tiihonen); Stanley Center for Psychiatric Research (Daly, Palotie) and Program in Medical and Population Genetics (Daly, Ripatti, Palotie), Broad Institute of Harvard and MIT, Cambridge, MA; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston (Daly, Ripatti, Palotie).
Olli Kampman, M.D., Ph.D.
Institute for Molecular Medicine Finland (FIMM), Helsinki Institute of Life Science (Partanen, Häppölä, Kämpe, Daly, Ripatti, Palotie, Koskela), and Faculty of Medicine (Ripatti), University of Helsinki, Helsinki; Department of Molecular Medicine and Surgery (Kämpe) and Department of Clinical Neuroscience (Tiihonen, Tanskanen, Taipale), Karolinska Institutet, Stockholm; Department of Internal Medicine (Ahola-Olli) and Department of Psychiatry (Haaki, Hietala), Turku University Hospital, Turku, Finland; Aurora Hospital, City of Helsinki, Helsinki (Hellsten); Department of Psychiatry, Faculty of Medicine and Health Technology (Rask), and Faculty of Medicine and Health Technology (Kampman), Tampere University, Tampere, Finland; Department of Psychiatry, Tampere University Hospital, Tampere, Finland (Rask); Department of Psychiatry, University of Turku, Turku, Finland (Haaki, Hietala); Department of Clinical Sciences, Psychiatry, Umeå University, Umeå, Sweden (Kampman); Department of Clinical Medicine, Psychiatry, Faculty of Medicine, University of Turku, Turku, Finland (Kampman); Department of Psychiatry, Wellbeing Services County of Ostrobothnia, Vaasa, Finland (Kampman); Department of Psychiatry, Wellbeing Services County of Pirkanmaa, Tampere, Finland (Kampman); Department of Forensic Psychiatry, University of Eastern Finland, Niuvanniemi Hospital, Kuopio, Finland (Tiihonen, Tanskanen, Taipale, Lähteenvuo); Center for Psychiatry Research, Stockholm City Council, Stockholm (Tiihonen); Stanley Center for Psychiatric Research (Daly, Palotie) and Program in Medical and Population Genetics (Daly, Ripatti, Palotie), Broad Institute of Harvard and MIT, Cambridge, MA; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston (Daly, Ripatti, Palotie).
Jari Tiihonen, M.D., Ph.D.
Institute for Molecular Medicine Finland (FIMM), Helsinki Institute of Life Science (Partanen, Häppölä, Kämpe, Daly, Ripatti, Palotie, Koskela), and Faculty of Medicine (Ripatti), University of Helsinki, Helsinki; Department of Molecular Medicine and Surgery (Kämpe) and Department of Clinical Neuroscience (Tiihonen, Tanskanen, Taipale), Karolinska Institutet, Stockholm; Department of Internal Medicine (Ahola-Olli) and Department of Psychiatry (Haaki, Hietala), Turku University Hospital, Turku, Finland; Aurora Hospital, City of Helsinki, Helsinki (Hellsten); Department of Psychiatry, Faculty of Medicine and Health Technology (Rask), and Faculty of Medicine and Health Technology (Kampman), Tampere University, Tampere, Finland; Department of Psychiatry, Tampere University Hospital, Tampere, Finland (Rask); Department of Psychiatry, University of Turku, Turku, Finland (Haaki, Hietala); Department of Clinical Sciences, Psychiatry, Umeå University, Umeå, Sweden (Kampman); Department of Clinical Medicine, Psychiatry, Faculty of Medicine, University of Turku, Turku, Finland (Kampman); Department of Psychiatry, Wellbeing Services County of Ostrobothnia, Vaasa, Finland (Kampman); Department of Psychiatry, Wellbeing Services County of Pirkanmaa, Tampere, Finland (Kampman); Department of Forensic Psychiatry, University of Eastern Finland, Niuvanniemi Hospital, Kuopio, Finland (Tiihonen, Tanskanen, Taipale, Lähteenvuo); Center for Psychiatry Research, Stockholm City Council, Stockholm (Tiihonen); Stanley Center for Psychiatric Research (Daly, Palotie) and Program in Medical and Population Genetics (Daly, Ripatti, Palotie), Broad Institute of Harvard and MIT, Cambridge, MA; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston (Daly, Ripatti, Palotie).
Antti J. Tanskanen, Ph.D.
Institute for Molecular Medicine Finland (FIMM), Helsinki Institute of Life Science (Partanen, Häppölä, Kämpe, Daly, Ripatti, Palotie, Koskela), and Faculty of Medicine (Ripatti), University of Helsinki, Helsinki; Department of Molecular Medicine and Surgery (Kämpe) and Department of Clinical Neuroscience (Tiihonen, Tanskanen, Taipale), Karolinska Institutet, Stockholm; Department of Internal Medicine (Ahola-Olli) and Department of Psychiatry (Haaki, Hietala), Turku University Hospital, Turku, Finland; Aurora Hospital, City of Helsinki, Helsinki (Hellsten); Department of Psychiatry, Faculty of Medicine and Health Technology (Rask), and Faculty of Medicine and Health Technology (Kampman), Tampere University, Tampere, Finland; Department of Psychiatry, Tampere University Hospital, Tampere, Finland (Rask); Department of Psychiatry, University of Turku, Turku, Finland (Haaki, Hietala); Department of Clinical Sciences, Psychiatry, Umeå University, Umeå, Sweden (Kampman); Department of Clinical Medicine, Psychiatry, Faculty of Medicine, University of Turku, Turku, Finland (Kampman); Department of Psychiatry, Wellbeing Services County of Ostrobothnia, Vaasa, Finland (Kampman); Department of Psychiatry, Wellbeing Services County of Pirkanmaa, Tampere, Finland (Kampman); Department of Forensic Psychiatry, University of Eastern Finland, Niuvanniemi Hospital, Kuopio, Finland (Tiihonen, Tanskanen, Taipale, Lähteenvuo); Center for Psychiatry Research, Stockholm City Council, Stockholm (Tiihonen); Stanley Center for Psychiatric Research (Daly, Palotie) and Program in Medical and Population Genetics (Daly, Ripatti, Palotie), Broad Institute of Harvard and MIT, Cambridge, MA; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston (Daly, Ripatti, Palotie).
FinnGen
Institute for Molecular Medicine Finland (FIMM), Helsinki Institute of Life Science (Partanen, Häppölä, Kämpe, Daly, Ripatti, Palotie, Koskela), and Faculty of Medicine (Ripatti), University of Helsinki, Helsinki; Department of Molecular Medicine and Surgery (Kämpe) and Department of Clinical Neuroscience (Tiihonen, Tanskanen, Taipale), Karolinska Institutet, Stockholm; Department of Internal Medicine (Ahola-Olli) and Department of Psychiatry (Haaki, Hietala), Turku University Hospital, Turku, Finland; Aurora Hospital, City of Helsinki, Helsinki (Hellsten); Department of Psychiatry, Faculty of Medicine and Health Technology (Rask), and Faculty of Medicine and Health Technology (Kampman), Tampere University, Tampere, Finland; Department of Psychiatry, Tampere University Hospital, Tampere, Finland (Rask); Department of Psychiatry, University of Turku, Turku, Finland (Haaki, Hietala); Department of Clinical Sciences, Psychiatry, Umeå University, Umeå, Sweden (Kampman); Department of Clinical Medicine, Psychiatry, Faculty of Medicine, University of Turku, Turku, Finland (Kampman); Department of Psychiatry, Wellbeing Services County of Ostrobothnia, Vaasa, Finland (Kampman); Department of Psychiatry, Wellbeing Services County of Pirkanmaa, Tampere, Finland (Kampman); Department of Forensic Psychiatry, University of Eastern Finland, Niuvanniemi Hospital, Kuopio, Finland (Tiihonen, Tanskanen, Taipale, Lähteenvuo); Center for Psychiatry Research, Stockholm City Council, Stockholm (Tiihonen); Stanley Center for Psychiatric Research (Daly, Palotie) and Program in Medical and Population Genetics (Daly, Ripatti, Palotie), Broad Institute of Harvard and MIT, Cambridge, MA; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston (Daly, Ripatti, Palotie).
SUPER-Finland
Institute for Molecular Medicine Finland (FIMM), Helsinki Institute of Life Science (Partanen, Häppölä, Kämpe, Daly, Ripatti, Palotie, Koskela), and Faculty of Medicine (Ripatti), University of Helsinki, Helsinki; Department of Molecular Medicine and Surgery (Kämpe) and Department of Clinical Neuroscience (Tiihonen, Tanskanen, Taipale), Karolinska Institutet, Stockholm; Department of Internal Medicine (Ahola-Olli) and Department of Psychiatry (Haaki, Hietala), Turku University Hospital, Turku, Finland; Aurora Hospital, City of Helsinki, Helsinki (Hellsten); Department of Psychiatry, Faculty of Medicine and Health Technology (Rask), and Faculty of Medicine and Health Technology (Kampman), Tampere University, Tampere, Finland; Department of Psychiatry, Tampere University Hospital, Tampere, Finland (Rask); Department of Psychiatry, University of Turku, Turku, Finland (Haaki, Hietala); Department of Clinical Sciences, Psychiatry, Umeå University, Umeå, Sweden (Kampman); Department of Clinical Medicine, Psychiatry, Faculty of Medicine, University of Turku, Turku, Finland (Kampman); Department of Psychiatry, Wellbeing Services County of Ostrobothnia, Vaasa, Finland (Kampman); Department of Psychiatry, Wellbeing Services County of Pirkanmaa, Tampere, Finland (Kampman); Department of Forensic Psychiatry, University of Eastern Finland, Niuvanniemi Hospital, Kuopio, Finland (Tiihonen, Tanskanen, Taipale, Lähteenvuo); Center for Psychiatry Research, Stockholm City Council, Stockholm (Tiihonen); Stanley Center for Psychiatric Research (Daly, Palotie) and Program in Medical and Population Genetics (Daly, Ripatti, Palotie), Broad Institute of Harvard and MIT, Cambridge, MA; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston (Daly, Ripatti, Palotie).
Mark J. Daly, Ph.D.
Institute for Molecular Medicine Finland (FIMM), Helsinki Institute of Life Science (Partanen, Häppölä, Kämpe, Daly, Ripatti, Palotie, Koskela), and Faculty of Medicine (Ripatti), University of Helsinki, Helsinki; Department of Molecular Medicine and Surgery (Kämpe) and Department of Clinical Neuroscience (Tiihonen, Tanskanen, Taipale), Karolinska Institutet, Stockholm; Department of Internal Medicine (Ahola-Olli) and Department of Psychiatry (Haaki, Hietala), Turku University Hospital, Turku, Finland; Aurora Hospital, City of Helsinki, Helsinki (Hellsten); Department of Psychiatry, Faculty of Medicine and Health Technology (Rask), and Faculty of Medicine and Health Technology (Kampman), Tampere University, Tampere, Finland; Department of Psychiatry, Tampere University Hospital, Tampere, Finland (Rask); Department of Psychiatry, University of Turku, Turku, Finland (Haaki, Hietala); Department of Clinical Sciences, Psychiatry, Umeå University, Umeå, Sweden (Kampman); Department of Clinical Medicine, Psychiatry, Faculty of Medicine, University of Turku, Turku, Finland (Kampman); Department of Psychiatry, Wellbeing Services County of Ostrobothnia, Vaasa, Finland (Kampman); Department of Psychiatry, Wellbeing Services County of Pirkanmaa, Tampere, Finland (Kampman); Department of Forensic Psychiatry, University of Eastern Finland, Niuvanniemi Hospital, Kuopio, Finland (Tiihonen, Tanskanen, Taipale, Lähteenvuo); Center for Psychiatry Research, Stockholm City Council, Stockholm (Tiihonen); Stanley Center for Psychiatric Research (Daly, Palotie) and Program in Medical and Population Genetics (Daly, Ripatti, Palotie), Broad Institute of Harvard and MIT, Cambridge, MA; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston (Daly, Ripatti, Palotie).
Samuli Ripatti, Ph.D.
Institute for Molecular Medicine Finland (FIMM), Helsinki Institute of Life Science (Partanen, Häppölä, Kämpe, Daly, Ripatti, Palotie, Koskela), and Faculty of Medicine (Ripatti), University of Helsinki, Helsinki; Department of Molecular Medicine and Surgery (Kämpe) and Department of Clinical Neuroscience (Tiihonen, Tanskanen, Taipale), Karolinska Institutet, Stockholm; Department of Internal Medicine (Ahola-Olli) and Department of Psychiatry (Haaki, Hietala), Turku University Hospital, Turku, Finland; Aurora Hospital, City of Helsinki, Helsinki (Hellsten); Department of Psychiatry, Faculty of Medicine and Health Technology (Rask), and Faculty of Medicine and Health Technology (Kampman), Tampere University, Tampere, Finland; Department of Psychiatry, Tampere University Hospital, Tampere, Finland (Rask); Department of Psychiatry, University of Turku, Turku, Finland (Haaki, Hietala); Department of Clinical Sciences, Psychiatry, Umeå University, Umeå, Sweden (Kampman); Department of Clinical Medicine, Psychiatry, Faculty of Medicine, University of Turku, Turku, Finland (Kampman); Department of Psychiatry, Wellbeing Services County of Ostrobothnia, Vaasa, Finland (Kampman); Department of Psychiatry, Wellbeing Services County of Pirkanmaa, Tampere, Finland (Kampman); Department of Forensic Psychiatry, University of Eastern Finland, Niuvanniemi Hospital, Kuopio, Finland (Tiihonen, Tanskanen, Taipale, Lähteenvuo); Center for Psychiatry Research, Stockholm City Council, Stockholm (Tiihonen); Stanley Center for Psychiatric Research (Daly, Palotie) and Program in Medical and Population Genetics (Daly, Ripatti, Palotie), Broad Institute of Harvard and MIT, Cambridge, MA; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston (Daly, Ripatti, Palotie).
Aarno Palotie, M.D., Ph.D.
Institute for Molecular Medicine Finland (FIMM), Helsinki Institute of Life Science (Partanen, Häppölä, Kämpe, Daly, Ripatti, Palotie, Koskela), and Faculty of Medicine (Ripatti), University of Helsinki, Helsinki; Department of Molecular Medicine and Surgery (Kämpe) and Department of Clinical Neuroscience (Tiihonen, Tanskanen, Taipale), Karolinska Institutet, Stockholm; Department of Internal Medicine (Ahola-Olli) and Department of Psychiatry (Haaki, Hietala), Turku University Hospital, Turku, Finland; Aurora Hospital, City of Helsinki, Helsinki (Hellsten); Department of Psychiatry, Faculty of Medicine and Health Technology (Rask), and Faculty of Medicine and Health Technology (Kampman), Tampere University, Tampere, Finland; Department of Psychiatry, Tampere University Hospital, Tampere, Finland (Rask); Department of Psychiatry, University of Turku, Turku, Finland (Haaki, Hietala); Department of Clinical Sciences, Psychiatry, Umeå University, Umeå, Sweden (Kampman); Department of Clinical Medicine, Psychiatry, Faculty of Medicine, University of Turku, Turku, Finland (Kampman); Department of Psychiatry, Wellbeing Services County of Ostrobothnia, Vaasa, Finland (Kampman); Department of Psychiatry, Wellbeing Services County of Pirkanmaa, Tampere, Finland (Kampman); Department of Forensic Psychiatry, University of Eastern Finland, Niuvanniemi Hospital, Kuopio, Finland (Tiihonen, Tanskanen, Taipale, Lähteenvuo); Center for Psychiatry Research, Stockholm City Council, Stockholm (Tiihonen); Stanley Center for Psychiatric Research (Daly, Palotie) and Program in Medical and Population Genetics (Daly, Ripatti, Palotie), Broad Institute of Harvard and MIT, Cambridge, MA; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston (Daly, Ripatti, Palotie).
Heidi Taipale, Ph.D.
Institute for Molecular Medicine Finland (FIMM), Helsinki Institute of Life Science (Partanen, Häppölä, Kämpe, Daly, Ripatti, Palotie, Koskela), and Faculty of Medicine (Ripatti), University of Helsinki, Helsinki; Department of Molecular Medicine and Surgery (Kämpe) and Department of Clinical Neuroscience (Tiihonen, Tanskanen, Taipale), Karolinska Institutet, Stockholm; Department of Internal Medicine (Ahola-Olli) and Department of Psychiatry (Haaki, Hietala), Turku University Hospital, Turku, Finland; Aurora Hospital, City of Helsinki, Helsinki (Hellsten); Department of Psychiatry, Faculty of Medicine and Health Technology (Rask), and Faculty of Medicine and Health Technology (Kampman), Tampere University, Tampere, Finland; Department of Psychiatry, Tampere University Hospital, Tampere, Finland (Rask); Department of Psychiatry, University of Turku, Turku, Finland (Haaki, Hietala); Department of Clinical Sciences, Psychiatry, Umeå University, Umeå, Sweden (Kampman); Department of Clinical Medicine, Psychiatry, Faculty of Medicine, University of Turku, Turku, Finland (Kampman); Department of Psychiatry, Wellbeing Services County of Ostrobothnia, Vaasa, Finland (Kampman); Department of Psychiatry, Wellbeing Services County of Pirkanmaa, Tampere, Finland (Kampman); Department of Forensic Psychiatry, University of Eastern Finland, Niuvanniemi Hospital, Kuopio, Finland (Tiihonen, Tanskanen, Taipale, Lähteenvuo); Center for Psychiatry Research, Stockholm City Council, Stockholm (Tiihonen); Stanley Center for Psychiatric Research (Daly, Palotie) and Program in Medical and Population Genetics (Daly, Ripatti, Palotie), Broad Institute of Harvard and MIT, Cambridge, MA; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston (Daly, Ripatti, Palotie).
Markku Lähteenvuo, M.D., Ph.D.
Institute for Molecular Medicine Finland (FIMM), Helsinki Institute of Life Science (Partanen, Häppölä, Kämpe, Daly, Ripatti, Palotie, Koskela), and Faculty of Medicine (Ripatti), University of Helsinki, Helsinki; Department of Molecular Medicine and Surgery (Kämpe) and Department of Clinical Neuroscience (Tiihonen, Tanskanen, Taipale), Karolinska Institutet, Stockholm; Department of Internal Medicine (Ahola-Olli) and Department of Psychiatry (Haaki, Hietala), Turku University Hospital, Turku, Finland; Aurora Hospital, City of Helsinki, Helsinki (Hellsten); Department of Psychiatry, Faculty of Medicine and Health Technology (Rask), and Faculty of Medicine and Health Technology (Kampman), Tampere University, Tampere, Finland; Department of Psychiatry, Tampere University Hospital, Tampere, Finland (Rask); Department of Psychiatry, University of Turku, Turku, Finland (Haaki, Hietala); Department of Clinical Sciences, Psychiatry, Umeå University, Umeå, Sweden (Kampman); Department of Clinical Medicine, Psychiatry, Faculty of Medicine, University of Turku, Turku, Finland (Kampman); Department of Psychiatry, Wellbeing Services County of Ostrobothnia, Vaasa, Finland (Kampman); Department of Psychiatry, Wellbeing Services County of Pirkanmaa, Tampere, Finland (Kampman); Department of Forensic Psychiatry, University of Eastern Finland, Niuvanniemi Hospital, Kuopio, Finland (Tiihonen, Tanskanen, Taipale, Lähteenvuo); Center for Psychiatry Research, Stockholm City Council, Stockholm (Tiihonen); Stanley Center for Psychiatric Research (Daly, Palotie) and Program in Medical and Population Genetics (Daly, Ripatti, Palotie), Broad Institute of Harvard and MIT, Cambridge, MA; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston (Daly, Ripatti, Palotie).
Institute for Molecular Medicine Finland (FIMM), Helsinki Institute of Life Science (Partanen, Häppölä, Kämpe, Daly, Ripatti, Palotie, Koskela), and Faculty of Medicine (Ripatti), University of Helsinki, Helsinki; Department of Molecular Medicine and Surgery (Kämpe) and Department of Clinical Neuroscience (Tiihonen, Tanskanen, Taipale), Karolinska Institutet, Stockholm; Department of Internal Medicine (Ahola-Olli) and Department of Psychiatry (Haaki, Hietala), Turku University Hospital, Turku, Finland; Aurora Hospital, City of Helsinki, Helsinki (Hellsten); Department of Psychiatry, Faculty of Medicine and Health Technology (Rask), and Faculty of Medicine and Health Technology (Kampman), Tampere University, Tampere, Finland; Department of Psychiatry, Tampere University Hospital, Tampere, Finland (Rask); Department of Psychiatry, University of Turku, Turku, Finland (Haaki, Hietala); Department of Clinical Sciences, Psychiatry, Umeå University, Umeå, Sweden (Kampman); Department of Clinical Medicine, Psychiatry, Faculty of Medicine, University of Turku, Turku, Finland (Kampman); Department of Psychiatry, Wellbeing Services County of Ostrobothnia, Vaasa, Finland (Kampman); Department of Psychiatry, Wellbeing Services County of Pirkanmaa, Tampere, Finland (Kampman); Department of Forensic Psychiatry, University of Eastern Finland, Niuvanniemi Hospital, Kuopio, Finland (Tiihonen, Tanskanen, Taipale, Lähteenvuo); Center for Psychiatry Research, Stockholm City Council, Stockholm (Tiihonen); Stanley Center for Psychiatric Research (Daly, Palotie) and Program in Medical and Population Genetics (Daly, Ripatti, Palotie), Broad Institute of Harvard and MIT, Cambridge, MA; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston (Daly, Ripatti, Palotie).
Notes
Send correspondence to Dr. Koskela ([email protected]).
Funding Information
This study was supported by the Doctoral Program in Population Health, University of Helsinki (Dr. Partanen), the Finnish Medical Foundation (Dr. Partanen), the Swedish Society for Medical Research (Dr. Kämpe), the Academy of Finland (Drs. Daly, Taipale, and Koskela), and the Academy of Finland Center of Excellence in Complex Disease Genetics (Drs. Ripatti and Palotie). The FinnGen project is funded by two grants from Business Finland (HUS 4685/31/2016 and UH 4386/31/2016) and the following industry partners: AbbVie, AstraZeneca UK, Biogen, Bristol Myers Squibb (and Celgene Corporation and Celgene International II), Genentech, Merck Sharp & Dohme LLC, Pfizer, GlaxoSmithKline Intellectual Property Development, Sanofi US Services, Maze Therapeutics, Janssen Biotech, Novartis, and Boehringer Ingelheim.Dr. Ahola-Olli is an employee and shareholder of Abomics. Drs. Tiihonen, Tanskanen, and Taipale have participated in research projects funded by grants from Eli Lilly and Janssen-Cilag. Dr. Tiihonen has served as a consultant for HLS Therapeutics, Janssen, Orion, and WebMed Global and has received honoraria from Eli Lilly, Evidera, Janssen-Cilag, Lundbeck, Mediuutiset, Otsuka, Sidera, and Sunovion. Drs. Daly and Koskela are members of the Pfizer Finland FinnGen Advisory Board. Dr. Daly is a founder of Maze Therapeutics. Dr. Palotie is the chief scientific officer of the FinnGen project, which is funded in part by 13 pharmaceutical companies. Dr. Taipale has received lecture fees from Gedeon Richter, Janssen, Lundbeck, and Otsuka. The other authors report no financial relationships with commercial interests.
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