Scientific Reports (Sep 2021)
HLA-DRB1 and HLA-DQB1 genetic diversity modulates response to lithium in bipolar affective disorders
- Sigrid Le Clerc,
- Laura Lombardi,
- Bernhard T. Baune,
- Azmeraw T. Amare,
- Klaus Oliver Schubert,
- Liping Hou,
- Scott R. Clark,
- Sergi Papiol,
- Micah Cearns,
- Urs Heilbronner,
- Franziska Degenhardt,
- Fasil Tekola-Ayele,
- Yi-Hsiang Hsu,
- Tatyana Shekhtman,
- Mazda Adli,
- 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,
- Clara Brichant-Petitjean,
- Pablo Cervantes,
- Hsi-Chung Chen,
- Caterina Chillotti,
- Sven Cichon,
- Cristiana Cruceanu,
- Piotr M. Czerski,
- Nina Dalkner,
- Alexandre Dayer,
- Maria Del Zompo,
- J. Raymond DePaulo,
- Bruno Étain,
- Stephane Jamain,
- 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,
- Stefan Herms,
- Per Hoffmann,
- Esther Jiménez,
- Jean-Pierre Kahn,
- Layla Kassem,
- Po-Hsiu Kuo,
- Tadafumi Kato,
- John R. Kelsoe,
- Sarah Kittel-Schneider,
- Ewa Ferensztajn-Rochowiak,
- Barbara König,
- Ichiro Kusumi,
- Gonzalo Laje,
- Mikael Landén,
- Catharina Lavebratt,
- Susan G. Leckband,
- Alfonso Tortorella,
- Mirko Manchia,
- Lina Martinsson,
- Michael J. McCarthy,
- Susan L. McElroy,
- Francesc Colom,
- Vincent Millischer,
- Marina Mitjans,
- Francis M. Mondimore,
- Palmiero Monteleone,
- Caroline M. Nievergelt,
- Markus M. Nöthen,
- Tomas Novák,
- Claire O’Donovan,
- Norio Ozaki,
- Urban Ösby,
- Andrea Pfennig,
- James B. Potash,
- Andreas Reif,
- Eva Reininghaus,
- Guy A. Rouleau,
- Janusz K. Rybakowski,
- Martin Schalling,
- Peter R. Schofield,
- Barbara W. Schweizer,
- Giovanni Severino,
- Paul D. Shilling,
- Katzutaka Shimoda,
- Christian Simhandl,
- Claire M. Slaney,
- Claudia Pisanu,
- Alessio Squassina,
- Thomas Stamm,
- Pavla Stopkova,
- Mario Maj,
- Gustavo Turecki,
- Eduard Vieta,
- Julia Veeh,
- Stephanie H. Witt,
- Adam Wright,
- Peter P. Zandi,
- Philip B. Mitchell,
- Michael Bauer,
- Martin Alda,
- Marcella Rietschel,
- Francis J. McMahon,
- Thomas G. Schulze,
- Jean-Louis Spadoni,
- Wahid Boukouaci,
- Jean-Romain Richard,
- Philippe Le Corvoisier,
- Caroline Barrau,
- Jean-François Zagury,
- Marion Leboyer,
- Ryad Tamouza
Affiliations
- Sigrid Le Clerc
- Laboratoire Génomique, Bio-Informatique et Chimie Moléculaire (EA7528), Conservatoire National des Arts et Métiers, HESAM Université
- Laura Lombardi
- AP-HP, Hôpital Henri Mondor, Département Médico-Universitaire de Psychiatrie et D’Addictologie (DMU IMPACT), Fédération Hospitalo-Universitaire de Médecine de Précision (FHU ADAPT)
- Bernhard T. Baune
- Department of Psychiatry, University of Münster
- Azmeraw T. Amare
- Discipline of Psychiatry, School of Medicine, University of Adelaide
- Klaus Oliver Schubert
- Discipline of Psychiatry, School of Medicine, University of Adelaide
- Liping Hou
- Intramural Research Program, National Institute of Mental Health, National Institutes of Health, US Department of Health & Human Services
- Scott R. Clark
- Discipline of Psychiatry, School of Medicine, University of Adelaide
- Sergi Papiol
- Institute of Psychiatric Phenomics and Genomics (IPPG), University Hospital, LMU Munich
- Micah Cearns
- Discipline of Psychiatry, School of Medicine, University of Adelaide
- Urs Heilbronner
- Institute of Psychiatric Phenomics and Genomics (IPPG), University Hospital, LMU Munich
- Franziska Degenhardt
- Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn
- 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
- Yi-Hsiang Hsu
- HSL Institute for Aging Research, Harvard Medical School
- Tatyana Shekhtman
- Department of Psychiatry, University of California San Diego
- Mazda Adli
- Department of Psychiatry and Psychotherapy, Charité - Universitätsmedizin Berlin
- 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
- Abesh Kumar Bhattacharjee
- Department of Psychiatry, University of California San Diego
- Frank Bellivier
- INSERM UMR-S 1144, Département de Psychiatrie et de Médecine Addictologique, AP-HP, Groupe Hospitalier Saint-Louis-Lariboisière-F.Widal, Université Paris Diderot
- 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 Health Sciences Research, Mayo Clinic
- Armin Birner
- Department of Psychiatry and Psychotherapeutic Medicine, Research Unit for Bipolar Affective Disorder, Medical University of Graz
- Clara Brichant-Petitjean
- INSERM UMR-S 1144, Département de Psychiatrie et de Médecine Addictologique, AP-HP, Groupe Hospitalier Saint-Louis-Lariboisière-F.Widal, Université Paris Diderot
- 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
- Institute of Medical Genetics and Pathology, University Hospital Basel
- 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
- 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, Département de Psychiatrie et de Médecine Addictologique, AP-HP, Groupe Hospitalier Saint-Louis-Lariboisière-F.Widal, Université Paris Diderot
- Stephane Jamain
- Univ Paris Est Créteil, INSERM, IMRB, Translational Neuropsychiatry, Fondation FondaMental
- Peter Falkai
- Department of Psychiatry and Psychotherapy, Ludwig-Maximilian-University Munich
- Andreas J. Forstner
- Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn
- Louise Frisen
- Department of Molecular Medicine and Surgery, Karolinska Institute
- 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
- Department of Pathology of Mental Diseases, National Institute of Mental Health, National Center of Neurology and Psychiatry
- Joanna Hauser
- Psychiatric Genetic Unit, Poznan University of Medical Sciences
- Stefan Herms
- Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn
- Per Hoffmann
- Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn
- 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 and Behavioral Science, Juntendo University Graduate School of Medicine
- John R. 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
- Susan G. Leckband
- Office of Mental Health, VA San Diego Healthcare System
- Alfonso Tortorella
- Department of Psychiatry, University of Perugia
- 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 L. McElroy
- Department of Psychiatry, Lindner Center of Hope/University of Cincinnati
- Francesc Colom
- Mental Health Research Group, IMIM-Hospital del Mar
- Vincent Millischer
- Department of Molecular Medicine and Surgery, Karolinska Institute
- 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
- Neurosciences Section, 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, School of Medicine & University Hospital Bonn
- 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
- Andrea Pfennig
- Department of Psychiatry and Psychotherapy, Medical Faculty, University Hospital Carl Gustav Carus, Technische Universität Dresden
- 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
- 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
- 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, Medical Faculty, Sigmund Freud University
- Claire M. Slaney
- Department of Psychiatry, Dalhousie University
- Claudia Pisanu
- Department of Biomedical Sciences, University of Cagliari
- Alessio Squassina
- Department of Biomedical Sciences, University of Cagliari
- Thomas Stamm
- Department of Psychiatry and Psychotherapy, Charité - Universitätsmedizin Berlin
- Pavla Stopkova
- National Institute of Mental Health
- Mario Maj
- Department of Psychiatry, University of Campania ‘Luigi Vanvitelli’
- Gustavo Turecki
- Douglas Mental Health University Institute, McGill University
- Eduard Vieta
- Bipolar Disorder Program, Institute of Neuroscience, Hospital Clinic, University of Barcelona, IDIBAPS, CIBERSAM
- Julia Veeh
- Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt
- Stephanie H. Witt
- Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg
- Adam Wright
- School of Psychiatry, University of New South Wales
- Peter P. Zandi
- Department of Mental Health, Johns Hopkins Bloomberg School of Public Health
- Philip B. Mitchell
- School of Psychiatry, University of New South Wales
- Michael Bauer
- Department of Psychiatry and Psychotherapy, Medical Faculty, University Hospital Carl Gustav Carus, Technische Universität Dresden
- Martin Alda
- Department of Psychiatry, Dalhousie University
- Marcella Rietschel
- Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg
- Francis J. McMahon
- Intramural Research Program, National Institute of Mental Health, National Institutes of Health, US Department of Health & Human Services
- Thomas G. Schulze
- Intramural Research Program, National Institute of Mental Health, National Institutes of Health, US Department of Health & Human Services
- Jean-Louis Spadoni
- Laboratoire Génomique, Bio-Informatique et Chimie Moléculaire (EA7528), Conservatoire National des Arts et Métiers, HESAM Université
- Wahid Boukouaci
- INSERM U955, IMRB, Laboratoire Neuro-Psychiatrie Translationnelle, Université Paris Est Créteil
- Jean-Romain Richard
- INSERM U955, IMRB, Laboratoire Neuro-Psychiatrie Translationnelle, Université Paris Est Créteil
- Philippe Le Corvoisier
- Centre Investigation Clinique, CIC Henri Mondor, Université Paris Est Créteil
- Caroline Barrau
- Plateforme de Ressources Biologiques, HU Henri Mondor
- Jean-François Zagury
- Laboratoire Génomique, Bio-Informatique et Chimie Moléculaire (EA7528), Conservatoire National des Arts et Métiers, HESAM Université
- Marion Leboyer
- AP-HP, Hôpital Henri Mondor, Département Médico-Universitaire de Psychiatrie et D’Addictologie (DMU IMPACT), Fédération Hospitalo-Universitaire de Médecine de Précision (FHU ADAPT)
- Ryad Tamouza
- AP-HP, Hôpital Henri Mondor, Département Médico-Universitaire de Psychiatrie et D’Addictologie (DMU IMPACT), Fédération Hospitalo-Universitaire de Médecine de Précision (FHU ADAPT)
- DOI
- https://doi.org/10.1038/s41598-021-97140-7
- Journal volume & issue
-
Vol. 11,
no. 1
pp. 1 – 12
Abstract
Abstract Bipolar affective disorder (BD) is a severe psychiatric illness, for which lithium (Li) is the gold standard for acute and maintenance therapies. The therapeutic response to Li in BD is heterogeneous and reliable biomarkers allowing patients stratification are still needed. A GWAS performed by the International Consortium on Lithium Genetics (ConLiGen) has recently identified genetic markers associated with treatment responses to Li in the human leukocyte antigens (HLA) region. To better understand the molecular mechanisms underlying this association, we have genetically imputed the classical alleles of the HLA region in the European patients of the ConLiGen cohort. We found our best signal for amino-acid variants belonging to the HLA-DRB1*11:01 classical allele, associated with a better response to Li (p < 1 × 10−3; FDR < 0.09 in the recessive model). Alanine or Leucine at position 74 of the HLA-DRB1 heavy chain was associated with a good response while Arginine or Glutamic acid with a poor response. As these variants have been implicated in common inflammatory/autoimmune processes, our findings strongly suggest that HLA-mediated low inflammatory background may contribute to the efficient response to Li in BD patients, while an inflammatory status overriding Li anti-inflammatory properties would favor a weak response.
