HLA-DRB1 and HLA-DQB1 genetic diversity modulates response to lithium in bipolar affective disorders

Sigrid Le Clerc^#¹, Laura Lombardi^#^{2

3

4}, Bernhard T Baune^{5

6

7}, Azmeraw T Amare^{8

9}, Klaus Oliver Schubert^{8

10}, Liping Hou¹¹, Scott R Clark⁸, Sergi Papiol^{12

13}, Micah Cearns⁸, Urs Heilbronner¹², Franziska Degenhardt¹⁴, Fasil Tekola-Ayele¹⁵, Yi-Hsiang Hsu^{16

17}, Tatyana Shekhtman¹⁸, Mazda Adli¹⁹, Nirmala Akula¹¹, Kazufumi Akiyama²⁰, Raffaella Ardau²¹, Bárbara Arias²², Jean-Michel Aubry²³, Lena Backlund^{24

25}, Abesh Kumar Bhattacharjee¹⁸, Frank Bellivier²⁶, Antonio Benabarre²⁷, Susanne Bengesser²⁸, Joanna M Biernacka^{29

30}, Armin Birner²⁸, Clara Brichant-Petitjean²⁶, Pablo Cervantes³¹, Hsi-Chung Chen³², Caterina Chillotti²¹, Sven Cichon^{33

34

35}, Cristiana Cruceanu³⁶, Piotr M Czerski³⁷, Nina Dalkner²⁸, Alexandre Dayer²³, Maria Del Zompo³⁸, J Raymond DePaulo³⁹, Bruno Étain²⁶, Stephane Jamain⁴⁰, Peter Falkai¹³, Andreas J Forstner^{14

34

41}, Louise Frisen^{24

25}, Mark A Frye³⁰, Janice M Fullerton^{42

43}, Sébastien Gard⁴⁴, Julie S Garnham⁴⁵, Fernando S Goes³⁹, Maria Grigoroiu-Serbanescu⁴⁶, Paul Grof⁴⁷, Ryota Hashimoto^{48

49}, Joanna Hauser³⁷, Stefan Herms^{14

35}, Per Hoffmann^{14

35}, Esther Jiménez²⁷, Jean-Pierre Kahn⁵⁰, Layla Kassem¹¹, Po-Hsiu Kuo⁵¹, Tadafumi Kato⁵², John R Kelsoe¹⁸, Sarah Kittel-Schneider⁵³, Ewa Ferensztajn-Rochowiak⁵⁴, Barbara König⁵⁵, Ichiro Kusumi⁵⁶, Gonzalo Laje¹¹, Mikael Landén^{57

58}, Catharina Lavebratt^{24

25}, Susan G Leckband⁵⁹, Alfonso Tortorella⁶⁰, Mirko Manchia^{61

62}, Lina Martinsson⁶³, Michael J McCarthy^{18

64}, Susan L McElroy⁶⁵, Francesc Colom^{66

67}, Vincent Millischer^{24

25}, Marina Mitjans^{68

69

70}, Francis M Mondimore³⁹, Palmiero Monteleone^{71

72}, Caroline M Nievergelt¹⁸, Markus M Nöthen¹⁴, Tomas Novák⁷³, Claire O'Donovan⁴⁵, Norio Ozaki⁷⁴, Urban Ösby⁷⁵, Andrea Pfennig⁷⁶, James B Potash³⁹, Andreas Reif⁵³, Eva Reininghaus²⁸, Guy A Rouleau⁷⁷, Janusz K Rybakowski⁵⁴, Martin Schalling^{24

25}, Peter R Schofield^{42

43}, Barbara W Schweizer³⁹, Giovanni Severino³⁸, Paul D Shilling¹⁸, Katzutaka Shimoda⁷⁸, Christian Simhandl⁷⁹, Claire M Slaney⁴⁵, Claudia Pisanu³⁸, Alessio Squassina³⁸, Thomas Stamm¹⁹, Pavla Stopkova⁷³, Mario Maj⁷², Gustavo Turecki³⁶, Eduard Vieta²⁷, Julia Veeh⁵³, Stephanie H Witt⁸⁰, Adam Wright⁸¹, Peter P Zandi⁸², Philip B Mitchell⁸¹, Michael Bauer⁷⁶, Martin Alda⁴⁵, Marcella Rietschel⁸⁰, Francis J McMahon¹¹, Thomas G Schulze^{11

12

39

80

83}, Jean-Louis Spadoni¹, Wahid Boukouaci^{3

4}, Jean-Romain Richard³, Philippe Le Corvoisier⁸⁴, Caroline Barrau⁸⁵, Jean-François Zagury^#¹, Marion Leboyer^{2

3

4}, Ryad Tamouza^#^{86

87

88}

Affiliations

¹ Laboratoire Génomique, Bio-Informatique et Chimie Moléculaire (EA7528), Conservatoire National des Arts et Métiers, HESAM Université, 292, rue Saint Martin, 75003, Paris, France.
² AP-HP, Hôpital Henri Mondor, Département Médico-Universitaire de Psychiatrie et D'Addictologie (DMU IMPACT), Fédération Hospitalo-Universitaire de Médecine de Précision (FHU ADAPT), 94010, Créteil, France.
³ INSERM U955, IMRB, Laboratoire Neuro-Psychiatrie Translationnelle, Université Paris Est Créteil, 94010, Créteil, France.
⁴ Fondation FondaMental, Créteil, France.
⁵ Department of Psychiatry, University of Münster, Münster, Germany.
⁶ Department of Psychiatry, Melbourne Medical School, The University of Melbourne, Melbourne, Australia.
⁷ The Florey Institute of Neuroscience and Mental Health, The University of Melbourne Parkville, Parkville, VIC, Australia.
⁸ Discipline of Psychiatry, School of Medicine, University of Adelaide, Adelaide, SA, Australia.
⁹ South Australian Academic Health Science and Translation Centre, South Australian Health and Medical Research Institute (SAHMRI), Adelaide, SA, Australia.
¹⁰ Mental Health Services, Northern Adelaide Local Health Network, Adelaide, SA, Australia.
¹¹ Intramural Research Program, National Institute of Mental Health, National Institutes of Health, US Department of Health & Human Services, Bethesda, MD, USA.
¹² Institute of Psychiatric Phenomics and Genomics (IPPG), University Hospital, LMU Munich, Nußbaumstr. 7, 80336, Munich, Germany.
¹³ Department of Psychiatry and Psychotherapy, Ludwig-Maximilian-University Munich, Munich, Germany.
¹⁴ Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany.
¹⁵ Epidemiology Branch, Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.
¹⁶ HSL Institute for Aging Research, Harvard Medical School, Boston, MA, USA.
¹⁷ Program for Quantitative Genomics, Harvard School of Public Health, Boston, MA, USA.
¹⁸ Department of Psychiatry, University of California San Diego, La Jolla, CA, USA.
¹⁹ Department of Psychiatry and Psychotherapy, Charité - Universitätsmedizin Berlin, Campus Charité Mitte, Berlin, Germany.
²⁰ Department of Biological Psychiatry and Neuroscience, Dokkyo Medical University School of Medicine, Mibu, Tochigi, Japan.
²¹ Unit of Clinical Pharmacology, Hospital University Agency of Cagliari, Cagliari, Italy.
²² Unitat de Zoologia I Antropologia Biològica (Dpt. Biologia Evolutiva, Ecologia I Ciències Ambientals), Facultat de Biologia and Institut de Biomedicina (IBUB), University of Barcelona, CIBERSAM, Barcelona, Spain.
²³ Department of Psychiatry, Mood Disorders Unit, HUG - Geneva University Hospitals, Geneva, Switzerland.
²⁴ Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden.
²⁵ Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden.
²⁶ INSERM UMR-S 1144, Département de Psychiatrie et de Médecine Addictologique, AP-HP, Groupe Hospitalier Saint-Louis-Lariboisière-F.Widal, Université Paris Diderot, Paris, France.
²⁷ Bipolar Disorder Program, Institute of Neuroscience, Hospital Clinic, University of Barcelona, IDIBAPS, CIBERSAM, Barcelona, Catalonia, Spain.
²⁸ Department of Psychiatry and Psychotherapeutic Medicine, Research Unit for Bipolar Affective Disorder, Medical University of Graz, Graz, Austria.
²⁹ Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
³⁰ Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN, USA.
³¹ The Neuromodulation Unit, McGill University Health Centre, Montreal, QC, Canada.
³² Department of Psychiatry & Center of Sleep Disorders, National Taiwan University Hospital, Taipei, Taiwan.
³³ Institute of Medical Genetics and Pathology, University Hospital Basel, Basel, Switzerland.
³⁴ Institute of Neuroscience and Medicine (INM-1), Research Center Jülich, Jülich, Germany.
³⁵ Human Genomics Research Group, Department of Biomedicine, University Hospital Basel, Basel, Switzerland.
³⁶ Douglas Mental Health University Institute, McGill University, Montreal, QC, Canada.
³⁷ Psychiatric Genetic Unit, Poznan University of Medical Sciences, Poznan, Poland.
³⁸ Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy.
³⁹ Department of Psychiatry and Behavioral Sciences, Johns Hopkins University, Baltimore, MD, USA.
⁴⁰ Univ Paris Est Créteil, INSERM, IMRB, Translational Neuropsychiatry, Fondation FondaMental, Créteil, France.
⁴¹ Centre for Human Genetics, University of Marburg, Marburg, Germany.
⁴² Neuroscience Research Australia, Sydney, NSW, Australia.
⁴³ School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia.
⁴⁴ Service de Psychiatrie, Hôpital Charles Perrens, Bordeaux, France.
⁴⁵ Department of Psychiatry, Dalhousie University, Halifax, NS, Canada.
⁴⁶ Biometric Psychiatric Genetics Research Unit, Alexandru Obregia Clinical Psychiatric Hospital, Bucharest, Romania.
⁴⁷ Mood Disorders Center of Ottawa, Ottawa, ON, Canada.
⁴⁸ Department of Pathology of Mental Diseases, National Institute of Mental Health, National Center of Neurology and Psychiatry, Tokyo, Japan.
⁴⁹ Department of Psychiatry, Osaka University Graduate School of Medicine, Osaka, Japan.
⁵⁰ Service de Psychiatrie Et Psychologie Clinique, Centre Psychothérapique de Nancy - Université de Lorraine, Nancy, France.
⁵¹ Department of Public Health & Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan.
⁵² Department of Psychiatry and Behavioral Science, Juntendo University Graduate School of Medicine, Tokyo, Japan.
⁵³ Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt, Frankfurt, Germany.
⁵⁴ Department of Adult Psychiatry, Poznan University of Medical Sciences, Poznan, Poland.
⁵⁵ Department of Psychiatry and Psychotherapeutic Medicine, Landesklinikum Neunkirchen, Neunkirchen, Austria.
⁵⁶ Department of Psychiatry, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
⁵⁷ Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the Gothenburg University, Gothenburg, Sweden.
⁵⁸ Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
⁵⁹ Office of Mental Health, VA San Diego Healthcare System, San Diego, CA, USA.
⁶⁰ Department of Psychiatry, University of Perugia, Perugia, Italy.
⁶¹ Section of Psychiatry, Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy.
⁶² Department of Pharmacology, Dalhousie University, Halifax, NS, Canada.
⁶³ Department of Clinical Neurosciences, Karolinska Institutet, Stockholm, Sweden.
⁶⁴ Department of Psychiatry, VA San Diego Healthcare System, San Diego, CA, USA.
⁶⁵ Department of Psychiatry, Lindner Center of Hope/University of Cincinnati, Mason, OH, USA.
⁶⁶ Mental Health Research Group, IMIM-Hospital del Mar, Barcelona, Catalonia, Spain.
⁶⁷ Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Instituto de Salud Carlos III, Madrid, Spain.
⁶⁸ Departament de Genètica, Microbiologia i Estadística, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain.
⁶⁹ Institut de Biomedicina de la Universitat de Barcelona (IBUB), Barcelona, Spain.
⁷⁰ Centro de Investigación Biomédica en Salud Mental (CIBERSAM), Madrid, Spain.
⁷¹ Neurosciences Section, Department of Medicine, Surgery and Dentistry 'Scuola Medica Salernitana', University of Salerno, Salerno, Italy.
⁷² Department of Psychiatry, University of Campania 'Luigi Vanvitelli', Naples, Italy.
⁷³ National Institute of Mental Health, Klecany, Czech Republic.
⁷⁴ Department of Psychiatry & Department of Child and Adolescent Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Japan.
⁷⁵ Department of Neurobiology, Care Sciences, and Society, Karolinska Institutet and Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden.
⁷⁶ Department of Psychiatry and Psychotherapy, Medical Faculty, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
⁷⁷ Montreal Neurological Institute and Hospital, McGill University, Montreal, QC, Canada.
⁷⁸ Department of Psychiatry, Dokkyo Medical University School of Medicine, Mibu, Tochigi, Japan.
⁷⁹ Bipolar Center Wiener Neustadt, Medical Faculty, Sigmund Freud University, Vienna, Austria.
⁸⁰ Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
⁸¹ School of Psychiatry, University of New South Wales, Sydney, NSW, Australia.
⁸² Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
⁸³ Department of Psychiatry and Psychotherapy, University Medical Center (UMG), Georg-August University Göttingen, Göttingen, Germany.
⁸⁴ Centre Investigation Clinique, CIC Henri Mondor, Université Paris Est Créteil, 94010, Créteil, France.
⁸⁵ Plateforme de Ressources Biologiques, HU Henri Mondor, 94010, Créteil, France.
⁸⁶ AP-HP, Hôpital Henri Mondor, Département Médico-Universitaire de Psychiatrie et D'Addictologie (DMU IMPACT), Fédération Hospitalo-Universitaire de Médecine de Précision (FHU ADAPT), 94010, Créteil, France. tamouza.ryad@gmail.com.
⁸⁷ INSERM U955, IMRB, Laboratoire Neuro-Psychiatrie Translationnelle, Université Paris Est Créteil, 94010, Créteil, France. tamouza.ryad@gmail.com.
⁸⁸ Fondation FondaMental, Créteil, France. tamouza.ryad@gmail.com.

^# Contributed equally.

PMID: 34497278
PMCID: PMC8426488
DOI: 10.1038/s41598-021-97140-7

HLA-DRB1 and HLA-DQB1 genetic diversity modulates response to lithium in bipolar affective disorders

Sigrid Le Clerc et al. Sci Rep. 2021.

. 2021 Sep 8;11(1):17823.

doi: 10.1038/s41598-021-97140-7.

Authors

Affiliations

¹ Laboratoire Génomique, Bio-Informatique et Chimie Moléculaire (EA7528), Conservatoire National des Arts et Métiers, HESAM Université, 292, rue Saint Martin, 75003, Paris, France.
² AP-HP, Hôpital Henri Mondor, Département Médico-Universitaire de Psychiatrie et D'Addictologie (DMU IMPACT), Fédération Hospitalo-Universitaire de Médecine de Précision (FHU ADAPT), 94010, Créteil, France.
³ INSERM U955, IMRB, Laboratoire Neuro-Psychiatrie Translationnelle, Université Paris Est Créteil, 94010, Créteil, France.
⁴ Fondation FondaMental, Créteil, France.
⁵ Department of Psychiatry, University of Münster, Münster, Germany.
⁶ Department of Psychiatry, Melbourne Medical School, The University of Melbourne, Melbourne, Australia.
⁷ The Florey Institute of Neuroscience and Mental Health, The University of Melbourne Parkville, Parkville, VIC, Australia.
⁸ Discipline of Psychiatry, School of Medicine, University of Adelaide, Adelaide, SA, Australia.
⁹ South Australian Academic Health Science and Translation Centre, South Australian Health and Medical Research Institute (SAHMRI), Adelaide, SA, Australia.
¹⁰ Mental Health Services, Northern Adelaide Local Health Network, Adelaide, SA, Australia.
¹¹ Intramural Research Program, National Institute of Mental Health, National Institutes of Health, US Department of Health & Human Services, Bethesda, MD, USA.
¹² Institute of Psychiatric Phenomics and Genomics (IPPG), University Hospital, LMU Munich, Nußbaumstr. 7, 80336, Munich, Germany.
¹³ Department of Psychiatry and Psychotherapy, Ludwig-Maximilian-University Munich, Munich, Germany.
¹⁴ Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany.
¹⁵ Epidemiology Branch, Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.
¹⁶ HSL Institute for Aging Research, Harvard Medical School, Boston, MA, USA.
¹⁷ Program for Quantitative Genomics, Harvard School of Public Health, Boston, MA, USA.
¹⁸ Department of Psychiatry, University of California San Diego, La Jolla, CA, USA.
¹⁹ Department of Psychiatry and Psychotherapy, Charité - Universitätsmedizin Berlin, Campus Charité Mitte, Berlin, Germany.
²⁰ Department of Biological Psychiatry and Neuroscience, Dokkyo Medical University School of Medicine, Mibu, Tochigi, Japan.
²¹ Unit of Clinical Pharmacology, Hospital University Agency of Cagliari, Cagliari, Italy.
²² Unitat de Zoologia I Antropologia Biològica (Dpt. Biologia Evolutiva, Ecologia I Ciències Ambientals), Facultat de Biologia and Institut de Biomedicina (IBUB), University of Barcelona, CIBERSAM, Barcelona, Spain.
²³ Department of Psychiatry, Mood Disorders Unit, HUG - Geneva University Hospitals, Geneva, Switzerland.
²⁴ Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden.
²⁵ Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden.
²⁶ INSERM UMR-S 1144, Département de Psychiatrie et de Médecine Addictologique, AP-HP, Groupe Hospitalier Saint-Louis-Lariboisière-F.Widal, Université Paris Diderot, Paris, France.
²⁷ Bipolar Disorder Program, Institute of Neuroscience, Hospital Clinic, University of Barcelona, IDIBAPS, CIBERSAM, Barcelona, Catalonia, Spain.
²⁸ Department of Psychiatry and Psychotherapeutic Medicine, Research Unit for Bipolar Affective Disorder, Medical University of Graz, Graz, Austria.
²⁹ Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
³⁰ Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN, USA.
³¹ The Neuromodulation Unit, McGill University Health Centre, Montreal, QC, Canada.
³² Department of Psychiatry & Center of Sleep Disorders, National Taiwan University Hospital, Taipei, Taiwan.
³³ Institute of Medical Genetics and Pathology, University Hospital Basel, Basel, Switzerland.
³⁴ Institute of Neuroscience and Medicine (INM-1), Research Center Jülich, Jülich, Germany.
³⁵ Human Genomics Research Group, Department of Biomedicine, University Hospital Basel, Basel, Switzerland.
³⁶ Douglas Mental Health University Institute, McGill University, Montreal, QC, Canada.
³⁷ Psychiatric Genetic Unit, Poznan University of Medical Sciences, Poznan, Poland.
³⁸ Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy.
³⁹ Department of Psychiatry and Behavioral Sciences, Johns Hopkins University, Baltimore, MD, USA.
⁴⁰ Univ Paris Est Créteil, INSERM, IMRB, Translational Neuropsychiatry, Fondation FondaMental, Créteil, France.
⁴¹ Centre for Human Genetics, University of Marburg, Marburg, Germany.
⁴² Neuroscience Research Australia, Sydney, NSW, Australia.
⁴³ School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia.
⁴⁴ Service de Psychiatrie, Hôpital Charles Perrens, Bordeaux, France.
⁴⁵ Department of Psychiatry, Dalhousie University, Halifax, NS, Canada.
⁴⁶ Biometric Psychiatric Genetics Research Unit, Alexandru Obregia Clinical Psychiatric Hospital, Bucharest, Romania.
⁴⁷ Mood Disorders Center of Ottawa, Ottawa, ON, Canada.
⁴⁸ Department of Pathology of Mental Diseases, National Institute of Mental Health, National Center of Neurology and Psychiatry, Tokyo, Japan.
⁴⁹ Department of Psychiatry, Osaka University Graduate School of Medicine, Osaka, Japan.
⁵⁰ Service de Psychiatrie Et Psychologie Clinique, Centre Psychothérapique de Nancy - Université de Lorraine, Nancy, France.
⁵¹ Department of Public Health & Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan.
⁵² Department of Psychiatry and Behavioral Science, Juntendo University Graduate School of Medicine, Tokyo, Japan.
⁵³ Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt, Frankfurt, Germany.
⁵⁴ Department of Adult Psychiatry, Poznan University of Medical Sciences, Poznan, Poland.
⁵⁵ Department of Psychiatry and Psychotherapeutic Medicine, Landesklinikum Neunkirchen, Neunkirchen, Austria.
⁵⁶ Department of Psychiatry, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
⁵⁷ Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the Gothenburg University, Gothenburg, Sweden.
⁵⁸ Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
⁵⁹ Office of Mental Health, VA San Diego Healthcare System, San Diego, CA, USA.
⁶⁰ Department of Psychiatry, University of Perugia, Perugia, Italy.
⁶¹ Section of Psychiatry, Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy.
⁶² Department of Pharmacology, Dalhousie University, Halifax, NS, Canada.
⁶³ Department of Clinical Neurosciences, Karolinska Institutet, Stockholm, Sweden.
⁶⁴ Department of Psychiatry, VA San Diego Healthcare System, San Diego, CA, USA.
⁶⁵ Department of Psychiatry, Lindner Center of Hope/University of Cincinnati, Mason, OH, USA.
⁶⁶ Mental Health Research Group, IMIM-Hospital del Mar, Barcelona, Catalonia, Spain.
⁶⁷ Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Instituto de Salud Carlos III, Madrid, Spain.
⁶⁸ Departament de Genètica, Microbiologia i Estadística, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain.
⁶⁹ Institut de Biomedicina de la Universitat de Barcelona (IBUB), Barcelona, Spain.
⁷⁰ Centro de Investigación Biomédica en Salud Mental (CIBERSAM), Madrid, Spain.
⁷¹ Neurosciences Section, Department of Medicine, Surgery and Dentistry 'Scuola Medica Salernitana', University of Salerno, Salerno, Italy.
⁷² Department of Psychiatry, University of Campania 'Luigi Vanvitelli', Naples, Italy.
⁷³ National Institute of Mental Health, Klecany, Czech Republic.
⁷⁴ Department of Psychiatry & Department of Child and Adolescent Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Japan.
⁷⁵ Department of Neurobiology, Care Sciences, and Society, Karolinska Institutet and Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden.
⁷⁶ Department of Psychiatry and Psychotherapy, Medical Faculty, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
⁷⁷ Montreal Neurological Institute and Hospital, McGill University, Montreal, QC, Canada.
⁷⁸ Department of Psychiatry, Dokkyo Medical University School of Medicine, Mibu, Tochigi, Japan.
⁷⁹ Bipolar Center Wiener Neustadt, Medical Faculty, Sigmund Freud University, Vienna, Austria.
⁸⁰ Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
⁸¹ School of Psychiatry, University of New South Wales, Sydney, NSW, Australia.
⁸² Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
⁸³ Department of Psychiatry and Psychotherapy, University Medical Center (UMG), Georg-August University Göttingen, Göttingen, Germany.
⁸⁴ Centre Investigation Clinique, CIC Henri Mondor, Université Paris Est Créteil, 94010, Créteil, France.
⁸⁵ Plateforme de Ressources Biologiques, HU Henri Mondor, 94010, Créteil, France.
⁸⁶ AP-HP, Hôpital Henri Mondor, Département Médico-Universitaire de Psychiatrie et D'Addictologie (DMU IMPACT), Fédération Hospitalo-Universitaire de Médecine de Précision (FHU ADAPT), 94010, Créteil, France. tamouza.ryad@gmail.com.
⁸⁷ INSERM U955, IMRB, Laboratoire Neuro-Psychiatrie Translationnelle, Université Paris Est Créteil, 94010, Créteil, France. tamouza.ryad@gmail.com.
⁸⁸ Fondation FondaMental, Créteil, France. tamouza.ryad@gmail.com.

^# Contributed equally.

PMID: 34497278
PMCID: PMC8426488
DOI: 10.1038/s41598-021-97140-7

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.

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Conflict of interest statement

The authors declare that they have no competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. MAd has received a grant from Servier, speaker’s fees from Servier, Lundbeck, Aristo, Parexel, Gilead, ViiV, Deutsche Bank, MSD, and MyTomorrows, plus a non-fi nancial support from Lundbeck. KA has received speaker’s fees from Taisho Toyama Pharmaceutical. MAl is funded by a grant of the Canadian Institutes of Health Research. MB has received speaker’s fees from AstraZeneca, Pfi zer, Lilly, Lundbeck, GlaxoSmithKline, Servier, and Ferrer Internacional. BÉ received non-financial support from Labex Biopsy and Fondation Fondamental. RH received grants and speaker honoraria from Dainippon Sumitomo Pharma and Novartis plus speaker honoraria from Eli Lilly Japan, GlaxoSmithKline, Hisamitsu Pharmaceutical, Janssen Pharmaceutical, Nippon Zoki Pharmaceutical, Otsuka Pharmaceutical, Astellas Pharma, Pfi zer, and the Yoshitomiyakuhin Corporation. TK received a grant from Takeda Pharmaceutical and fees from Kyowa Hakko Kirin, Eli Lilly Japan, Otsuka Pharmaceutical, GlaxoSmithKline, Taisho Toyama Pharmaceutical, Dainippon Sumitomo Pharma, Meiji Seika Pharma, Pfi zer Japan, Mochida Pharmaceutical, Shionogi & Co, Janssen Pharmaceutical, Yoshitomiyakuhin Corporation, Agilent Technologies, Astellas Pharma, and Wako Pure Chemical Industries. IK received grants and fees from Dainippon Sumitomo Pharma, Eisai, Eli Lilly, GlaxoSmithKline, Kyowa Hakko Kirin, Meiji Seika Pharma, MSD, Novartis, Otsuka, Ono Pharmaceutical, Pfi zer, Tanabe Mitsubishi Pharma, Takeda Pharmaceutical, Shionogi, and Yoshitomi Pharmaceutical; he received grants from AbbVie GK, Asahi Kasei Pharma, Boehringer Ingelheim, Chugai Pharmaceutical, and Daiichi Sankyo and fees from Astellas Pharma and Janssen Pharmaceutical. MJM served as unpaid consultant for Pathway Genomic (San Diego, USA). SLM received a grant and fees from Naurex and Shire, further grants from Alkermes, Cephalon, Forest, Marriott Foundation, Orexigen Therapeutics, and Takeda Pharmaceutical, he further has served on the advisory boards for Bracket, Hoff mann-La Roche, MedAvante, Sunovion and received fees from Novo Nordisk. PRS received a grant from NHMRC. TGS received a grant and fees from Roche Pharmaceuticals. TSt received personal fees from Servier, Lundbeck, and Bristol-Myers Squibb. EV has received grants and served as consultant, advisor or CME speaker for the following entities (unrelated to the present work): AB-Biotics, Abbott, Allergan, Angelini, Dainippon Sumitomo Pharma, Ferrer, Gedeon Richter, GH Research, Janssen, Lundbeck, Otsuka, Sage, Sanofi-Aventis, and Takeda. FC In the last two years he has served as a speaker or in the advisory board of the following companies: Abott, Sandoz and Sanofi and he receives unrestricted research support from Telefónica Alpha. JRDP was an unpaid consultant for Assurex Health on behalf of the National Network of Depression Centers and he owns stock in CVS. All above listed interests are outside of the submitted work. All other authors declare no competing interests.

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HLA-DRB1 and HLA-DQB1 genetic diversity modulates response to lithium in bipolar affective disorders

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HLA-DRB1 and HLA-DQB1 genetic diversity modulates response to lithium in bipolar affective disorders

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