Translational Psychiatry (Nov 2021)
Combining schizophrenia and depression polygenic risk scores improves the genetic prediction of lithium response in bipolar disorder patients
- Klaus Oliver Schubert,
- Anbupalam Thalamuthu,
- Azmeraw T. Amare,
- Joseph Frank,
- Fabian Streit,
- Mazda Adl,
- Nirmala Akula,
- Kazufumi Akiyama,
- Raffaella Ardau,
- Bárbara Arias,
- Jean-Michel Aubry,
- Lena Backlund,
- Abesh Kumar Bhattacharjee,
- Frank Bellivier,
- Antonio Benabarre,
- Susanne Bengesser,
- Joanna M. Biernacka,
- Armin Birner,
- Cynthia Marie-Claire,
- Micah Cearns,
- Pablo Cervantes,
- Hsi-Chung Chen,
- Caterina Chillotti,
- Sven Cichon,
- Scott R. Clark,
- Cristiana Cruceanu,
- Piotr M. Czerski,
- Nina Dalkner,
- Alexandre Dayer,
- Franziska Degenhardt,
- Maria Del Zompo,
- J. Raymond DePaulo,
- Bruno Étain,
- Peter Falkai,
- Andreas J. Forstner,
- Louise Frisen,
- Mark A. Frye,
- Janice M. Fullerton,
- Sébastien Gard,
- Julie S. Garnham,
- Fernando S. Goes,
- Maria Grigoroiu-Serbanescu,
- Paul Grof,
- Ryota Hashimoto,
- Joanna Hauser,
- Urs Heilbronner,
- Stefan Herms,
- Per Hoffmann,
- Liping Hou,
- Yi-Hsiang Hsu,
- Stephane Jamain,
- Esther Jiménez,
- Jean-Pierre Kahn,
- Layla Kassem,
- Po-Hsiu Kuo,
- Tadafumi Kato,
- John Kelsoe,
- Sarah Kittel-Schneider,
- Ewa Ferensztajn-Rochowiak,
- Barbara König,
- Ichiro Kusumi,
- Gonzalo Laje,
- Mikael Landén,
- Catharina Lavebratt,
- Marion Leboyer,
- Susan G. Leckband,
- Mario Maj,
- Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium,
- Mirko Manchia,
- Lina Martinsson,
- Michael J. McCarthy,
- Susan McElroy,
- Francesc Colom,
- Marina Mitjans,
- Francis M. Mondimore,
- Palmiero Monteleone,
- Caroline M. Nievergelt,
- Markus M. Nöthen,
- Tomas Novák,
- Claire O’Donovan,
- Norio Ozaki,
- Urban Ösby,
- Sergi Papiol,
- Andrea Pfennig,
- Claudia Pisanu,
- James B. Potash,
- Andreas Reif,
- Eva Reininghaus,
- Guy A. Rouleau,
- Janusz K. Rybakowski,
- Martin Schalling,
- Peter R. Schofield,
- Barbara W. Schweizer,
- Giovanni Severino,
- Tatyana Shekhtman,
- Paul D. Shilling,
- Katzutaka Shimoda,
- Christian Simhandl,
- Claire M. Slaney,
- Alessio Squassina,
- Thomas Stamm,
- Pavla Stopkova,
- Fasil Tekola-Ayele,
- Alfonso Tortorella,
- Gustavo Turecki,
- Julia Veeh,
- Eduard Vieta,
- Stephanie H. Witt,
- Gloria Roberts,
- Peter P. Zandi,
- Martin Alda,
- Michael Bauer,
- Francis J. McMahon,
- Philip B. Mitchell,
- Thomas G. Schulze,
- Marcella Rietschel,
- Bernhard T. Baune
Affiliations
- Klaus Oliver Schubert
- Discipline of Psychiatry, School of Medicine, University of Adelaide
- Anbupalam Thalamuthu
- Centre for Healthy Brain Ageing (CHeBA), School of Psychiatry, University of New South Wales
- Azmeraw T. Amare
- Discipline of Psychiatry, School of Medicine, University of Adelaide
- Joseph Frank
- Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg
- Fabian Streit
- Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg
- Mazda Adl
- Department of Psychiatry and Psychotherapy, Charité—Universitätsmedizin Berlin, Campus Charité Mitte
- Nirmala Akula
- Intramural Research Program, National Institute of Mental Health, National Institutes of Health, US Department of Health & Human Services
- Kazufumi Akiyama
- Department of Biological Psychiatry and Neuroscience, Dokkyo Medical University School of Medicine
- Raffaella Ardau
- Unit of Clinical Pharmacology, Hospital University Agency of Cagliari
- Bárbara Arias
- 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
- Jean-Michel Aubry
- Department of Psychiatry, Mood Disorders Unit, HUG—Geneva University Hospitals
- Lena Backlund
- Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden, and Center for Molecular Medicine, Karolinska University Hospital
- Abesh Kumar Bhattacharjee
- Department of Psychiatry, University of California San Diego
- Frank Bellivier
- INSERM UMR-S 1144, Université Paris Diderot, Département de Psychiatrie et de Médecine Addictologique, AP-HP, Groupe Hospitalier Saint-Louis-Lariboisière-F.Widal
- Antonio Benabarre
- Bipolar Disorder Program, Institute of Neuroscience, Hospital Clinic, University of Barcelona, IDIBAPS, CIBERSAM
- Susanne Bengesser
- Department of Psychiatry and Psychotherapeutic Medicine, Research Unit for bipolar affective disorder, Medical University of Graz
- Joanna M. Biernacka
- Department of Psychiatry and Psychology, Mayo Clinic
- Armin Birner
- Department of Psychiatry and Psychotherapeutic Medicine, Research Unit for bipolar affective disorder, Medical University of Graz
- Cynthia Marie-Claire
- INSERM UMR-S 1144, Université Paris Diderot, Département de Psychiatrie et de Médecine Addictologique, AP-HP, Groupe Hospitalier Saint-Louis-Lariboisière-F.Widal
- Micah Cearns
- Discipline of Psychiatry, School of Medicine, University of Adelaide
- Pablo Cervantes
- The Neuromodulation Unit, McGill University Health Centre
- Hsi-Chung Chen
- Department of Psychiatry & Center of Sleep Disorders, National Taiwan University Hospital
- Caterina Chillotti
- Unit of Clinical Pharmacology, Hospital University Agency of Cagliari
- Sven Cichon
- Human Genomics Research Group, Department of Biomedicine, University Hospital Basel
- Scott R. Clark
- Discipline of Psychiatry, School of Medicine, University of Adelaide
- Cristiana Cruceanu
- Douglas Mental Health University Institute, McGill University
- Piotr M. Czerski
- Psychiatric Genetic Unit, Poznan University of Medical Sciences
- Nina Dalkner
- Department of Psychiatry and Psychotherapeutic Medicine, Research Unit for bipolar affective disorder, Medical University of Graz
- Alexandre Dayer
- Department of Psychiatry, Mood Disorders Unit, HUG—Geneva University Hospitals
- Franziska Degenhardt
- Institute of Human Genetics, University of Bonn and Department of Genomics, Life & Brain Center
- Maria Del Zompo
- Department of Biomedical Sciences, University of Cagliari
- J. Raymond DePaulo
- Department of Psychiatry and Behavioral Sciences, Johns Hopkins University
- Bruno Étain
- INSERM UMR-S 1144, Université Paris Diderot, Département de Psychiatrie et de Médecine Addictologique, AP-HP, Groupe Hospitalier Saint-Louis-Lariboisière-F.Widal
- Peter Falkai
- Department of Psychiatry and Psychotherapy, Ludwig-Maximilian-University Munich
- Andreas J. Forstner
- Human Genomics Research Group, Department of Biomedicine, University Hospital Basel
- Louise Frisen
- Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden, and Center for Molecular Medicine, Karolinska University Hospital
- Mark A. Frye
- Department of Psychiatry and Psychology, Mayo Clinic
- Janice M. Fullerton
- Neuroscience Research Australia
- Sébastien Gard
- Service de psychiatrie, Hôpital Charles Perrens
- Julie S. Garnham
- Department of Psychiatry, Dalhousie University
- Fernando S. Goes
- Department of Psychiatry and Behavioral Sciences, Johns Hopkins University
- Maria Grigoroiu-Serbanescu
- Biometric Psychiatric Genetics Research Unit, Alexandru Obregia Clinical Psychiatric Hospital
- Paul Grof
- Mood Disorders Center of Ottawa
- Ryota Hashimoto
- Molecular Research Center for Children’s Mental Development, United Graduate School of Child Development, Osaka University
- Joanna Hauser
- Psychiatric Genetic Unit, Poznan University of Medical Sciences
- Urs Heilbronner
- Institute of Psychiatric Phenomics and Genomics (IPPG), University Hospital, LMU Munich
- Stefan Herms
- Human Genomics Research Group, Department of Biomedicine, University Hospital Basel
- Per Hoffmann
- Human Genomics Research Group, Department of Biomedicine, University Hospital Basel
- Liping Hou
- Intramural Research Program, National Institute of Mental Health, National Institutes of Health, US Department of Health & Human Services
- Yi-Hsiang Hsu
- HSL Institute for Aging Research, Harvard Medical School
- Stephane Jamain
- Univ Paris Est Créteil, INSERM, IMRB, Translational Neuropsychiatry, Fondation FondaMental
- Esther Jiménez
- Bipolar Disorder Program, Institute of Neuroscience, Hospital Clinic, University of Barcelona, IDIBAPS, CIBERSAM
- Jean-Pierre Kahn
- Service de Psychiatrie et Psychologie Clinique, Centre Psychothérapique de Nancy—Université de Lorraine
- Layla Kassem
- Intramural Research Program, National Institute of Mental Health, National Institutes of Health, US Department of Health & Human Services
- Po-Hsiu Kuo
- Department of Public Health & Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University
- Tadafumi Kato
- Department of Psychiatry & Behavioral Science, Juntendo University, Graduate School of Medicine
- John Kelsoe
- Department of Psychiatry, University of California San Diego
- Sarah Kittel-Schneider
- Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt
- Ewa Ferensztajn-Rochowiak
- Department of Adult Psychiatry, Poznan University of Medical Sciences
- Barbara König
- Department of Psychiatry and Psychotherapeutic Medicine, Landesklinikum Neunkirchen
- Ichiro Kusumi
- Department of Psychiatry, Hokkaido University Graduate School of Medicine
- Gonzalo Laje
- Intramural Research Program, National Institute of Mental Health, National Institutes of Health, US Department of Health & Human Services
- Mikael Landén
- Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the Gothenburg University
- Catharina Lavebratt
- Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden, and Center for Molecular Medicine, Karolinska University Hospital
- Marion Leboyer
- Inserm U955, Translational Neuro-Psychiatry laboratory, Université Paris Est Créteil (UPEC), AP-HP, Department of Psychiatry and Addictology of Mondor University Hospital, AP-HP, Fondation FondaMental
- Susan G. Leckband
- Office of Mental Health, VA San Diego Healthcare System
- Mario Maj
- Department of Psychiatry, University of Campania “Luigi Vanvitelli”
- Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium
- Mirko Manchia
- Section of Psychiatry, Department of Medical Sciences and Public Health, University of Cagliari
- Lina Martinsson
- Department of Clinical Neurosciences, Karolinska Institutet
- Michael J. McCarthy
- Department of Psychiatry, University of California San Diego
- Susan McElroy
- Department of Psychiatry, Lindner Center of Hope / University of Cincinnati
- Francesc Colom
- Mental Health Research Group, IMIM-Hospital del Mar
- Marina Mitjans
- Departament de Genètica, Microbiologia i Estadística, Facultat de Biologia, Universitat de Barcelona
- Francis M. Mondimore
- Department of Psychiatry and Behavioral Sciences, Johns Hopkins University
- Palmiero Monteleone
- Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, University of Salerno
- Caroline M. Nievergelt
- Department of Psychiatry, University of California San Diego
- Markus M. Nöthen
- Institute of Human Genetics, University of Bonn and Department of Genomics, Life & Brain Center
- Tomas Novák
- National Institute of Mental Health
- Claire O’Donovan
- Department of Psychiatry, Dalhousie University
- Norio Ozaki
- Department of Psychiatry & Department of Child and Adolescent Psychiatry, Nagoya University Graduate School of Medicine
- Urban Ösby
- Department of Neurobiology, Care Sciences, and Society, Karolinska Institutet and Center for Molecular Medicine, Karolinska University Hospital
- Sergi Papiol
- Department of Psychiatry and Psychotherapy, Ludwig-Maximilian-University Munich
- Andrea Pfennig
- Department of Psychiatry and Psychotherapy, University Hospital Carl Gustav Carus, Medical Faculty, Technische Universität Dresden
- Claudia Pisanu
- Department of Biomedical Sciences, University of Cagliari
- James B. Potash
- Department of Psychiatry and Behavioral Sciences, Johns Hopkins University
- Andreas Reif
- Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt
- Eva Reininghaus
- Department of Psychiatry and Psychotherapeutic Medicine, Research Unit for bipolar affective disorder, Medical University of Graz
- Guy A. Rouleau
- Montreal Neurological Institute and Hospital, McGill University
- Janusz K. Rybakowski
- Department of Adult Psychiatry, Poznan University of Medical Sciences
- Martin Schalling
- Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden, and Center for Molecular Medicine, Karolinska University Hospital
- Peter R. Schofield
- Neuroscience Research Australia
- Barbara W. Schweizer
- Department of Psychiatry and Behavioral Sciences, Johns Hopkins University
- Giovanni Severino
- Department of Biomedical Sciences, University of Cagliari
- Tatyana Shekhtman
- Department of Psychiatry, University of California San Diego
- Paul D. Shilling
- Department of Psychiatry, University of California San Diego
- Katzutaka Shimoda
- Department of Psychiatry, Dokkyo Medical University School of Medicine
- Christian Simhandl
- Bipolar Center Wiener Neustadt, Sigmund Freud University, Medical Faculty
- Claire M. Slaney
- Department of Psychiatry, Dalhousie University
- Alessio Squassina
- Department of Biomedical Sciences, University of Cagliari
- Thomas Stamm
- Department of Psychiatry and Psychotherapy, Charité—Universitätsmedizin Berlin, Campus Charité Mitte
- Pavla Stopkova
- National Institute of Mental Health
- Fasil Tekola-Ayele
- Epidemiology Branch, Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health
- Alfonso Tortorella
- Department of Psychiatry, University of Perugia
- Gustavo Turecki
- Douglas Mental Health University Institute, McGill University
- Julia Veeh
- Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt
- Eduard Vieta
- Bipolar Disorder Program, Institute of Neuroscience, Hospital Clinic, University of Barcelona, IDIBAPS, CIBERSAM
- Stephanie H. Witt
- Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg
- Gloria Roberts
- School of Psychiatry, University of New South Wales
- Peter P. Zandi
- Department of Mental Health, Johns Hopkins Bloomberg School of Public Health
- Martin Alda
- Department of Psychiatry, Dalhousie University
- Michael Bauer
- Department of Psychiatry and Psychotherapy, University Hospital Carl Gustav Carus, Medical Faculty, Technische Universität Dresden
- Francis J. McMahon
- Intramural Research Program, National Institute of Mental Health, National Institutes of Health, US Department of Health & Human Services
- Philip B. Mitchell
- School of Psychiatry, University of New South Wales
- Thomas G. Schulze
- Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg
- Marcella Rietschel
- Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg
- Bernhard T. Baune
- Department of Psychiatry and Psychotherapy, University of Münster
- DOI
- https://doi.org/10.1038/s41398-021-01702-2
- Journal volume & issue
-
Vol. 11,
no. 1
pp. 1 – 8
Abstract
Abstract Lithium is the gold standard therapy for Bipolar Disorder (BD) but its effectiveness differs widely between individuals. The molecular mechanisms underlying treatment response heterogeneity are not well understood, and personalized treatment in BD remains elusive. Genetic analyses of the lithium treatment response phenotype may generate novel molecular insights into lithium’s therapeutic mechanisms and lead to testable hypotheses to improve BD management and outcomes. We used fixed effect meta-analysis techniques to develop meta-analytic polygenic risk scores (MET-PRS) from combinations of highly correlated psychiatric traits, namely schizophrenia (SCZ), major depression (MD) and bipolar disorder (BD). We compared the effects of cross-disorder MET-PRS and single genetic trait PRS on lithium response. For the PRS analyses, we included clinical data on lithium treatment response and genetic information for n = 2283 BD cases from the International Consortium on Lithium Genetics (ConLi+Gen; www.ConLiGen.org ). Higher SCZ and MD PRSs were associated with poorer lithium treatment response whereas BD-PRS had no association with treatment outcome. The combined MET2-PRS comprising of SCZ and MD variants (MET2-PRS) and a model using SCZ and MD-PRS sequentially improved response prediction, compared to single-disorder PRS or to a combined score using all three traits (MET3-PRS). Patients in the highest decile for MET2-PRS loading had 2.5 times higher odds of being classified as poor responders than patients with the lowest decile MET2-PRS scores. An exploratory functional pathway analysis of top MET2-PRS variants was conducted. Findings may inform the development of future testing strategies for personalized lithium prescribing in BD.
