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.

AP HP Hôpital Henri Mondor Département Médico Universitaire de Psychiatrie et D'Addictologie 94010 Créteil France

Biometric Psychiatric Genetics Research Unit Alexandru Obregia Clinical Psychiatric Hospital Bucharest Romania

Bipolar Center Wiener Neustadt Medical Faculty Sigmund Freud University Vienna Austria

Bipolar Disorder Program Institute of Neuroscience Hospital Clinic University of Barcelona IDIBAPS CIBERSAM Barcelona Catalonia Spain

Center for Molecular Medicine Karolinska University Hospital Stockholm Sweden

Centre for Human Genetics University of Marburg Marburg Germany

Centre Investigation Clinique CIC Henri Mondor Université Paris Est Créteil 94010 Créteil France

Centro de Investigación Biomédica en Red de Salud Mental Instituto de Salud Carlos 3 Madrid Spain

Centro de Investigación Biomédica en Salud Mental Madrid Spain

Departament de Genètica Microbiologia i Estadística Facultat de Biologia Universitat de Barcelona Barcelona Spain

Department of Adult Psychiatry Poznan University of Medical Sciences Poznan Poland

Department of Biological Psychiatry and Neuroscience Dokkyo Medical University School of Medicine Mibu Tochigi Japan

Department of Biomedical Sciences University of Cagliari Cagliari Italy

Department of Clinical Neurosciences Karolinska Institutet Stockholm Sweden

Department of Genetic Epidemiology in Psychiatry Central Institute of Mental Health Medical Faculty Mannheim University of Heidelberg Mannheim Germany

Department of Health Sciences Research Mayo Clinic Rochester MN USA

Department of Medical Epidemiology and Biostatistics Karolinska Institutet Stockholm Sweden

Department of Mental Health Johns Hopkins Bloomberg School of Public Health Baltimore MD USA

Department of Molecular Medicine and Surgery Karolinska Institute Stockholm Sweden

Department of Neurobiology Care Sciences and Society Karolinska Institutet and Center for Molecular Medicine Karolinska University Hospital Stockholm Sweden

Department of Pathology of Mental Diseases National Institute of Mental Health National Center of Neurology and Psychiatry Tokyo Japan

Department of Pharmacology Dalhousie University Halifax NS Canada

Department of Psychiatry and Behavioral Science Juntendo University Graduate School of Medicine Tokyo Japan

Department of Psychiatry and Behavioral Sciences Johns Hopkins University Baltimore MD USA

Department of Psychiatry and Center of Sleep Disorders National Taiwan University Hospital Taipei Taiwan

Department of Psychiatry and Department of Child and Adolescent Psychiatry Nagoya University Graduate School of Medicine Nagoya Japan

Department of Psychiatry and Psychology Mayo Clinic Rochester MN USA

Department of Psychiatry and Psychotherapeutic Medicine Landesklinikum Neunkirchen Neunkirchen Austria

Department of Psychiatry and Psychotherapeutic Medicine Research Unit for Bipolar Affective Disorder Medical University of Graz Graz Austria

Department of Psychiatry and Psychotherapy Charité Universitätsmedizin Berlin Campus Charité Mitte Berlin Germany

Department of Psychiatry and Psychotherapy Ludwig Maximilian University Munich Munich Germany

Department of Psychiatry and Psychotherapy Medical Faculty University Hospital Carl Gustav Carus Technische Universität Dresden Dresden Germany

Department of Psychiatry and Psychotherapy University Medical Center Georg August University Göttingen Göttingen Germany

Department of Psychiatry Dalhousie University Halifax NS Canada

Department of Psychiatry Dokkyo Medical University School of Medicine Mibu Tochigi Japan

Department of Psychiatry Hokkaido University Graduate School of Medicine Sapporo Japan

Department of Psychiatry Lindner Center of Hope University of Cincinnati Mason OH USA

Department of Psychiatry Melbourne Medical School The University of Melbourne Melbourne Australia

Department of Psychiatry Mood Disorders Unit HUG Geneva University Hospitals Geneva Switzerland

Department of Psychiatry Osaka University Graduate School of Medicine Osaka Japan

Department of Psychiatry Psychosomatic Medicine and Psychotherapy University Hospital Frankfurt Frankfurt Germany

Department of Psychiatry University of California San Diego La Jolla CA USA

Department of Psychiatry University of Campania 'Luigi Vanvitelli' Naples Italy

Department of Psychiatry University of Münster Münster Germany

Department of Psychiatry University of Perugia Perugia Italy

Department of Psychiatry VA San Diego Healthcare System San Diego CA USA

Department of Public Health and Institute of Epidemiology and Preventive Medicine College of Public Health National Taiwan University Taipei Taiwan

Discipline of Psychiatry School of Medicine University of Adelaide Adelaide SA Australia

Douglas Mental Health University Institute McGill University Montreal QC Canada

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

Fondation FondaMental Créteil France

HSL Institute for Aging Research Harvard Medical School Boston MA USA

Human Genomics Research Group Department of Biomedicine University Hospital Basel Basel Switzerland

INSERM U955 IMRB Laboratoire Neuro Psychiatrie Translationnelle Université Paris Est Créteil 94010 Créteil France

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

Institut de Biomedicina de la Universitat de Barcelona Barcelona Spain

Institute of Human Genetics University of Bonn School of Medicine and University Hospital Bonn Bonn Germany

Institute of Medical Genetics and Pathology University Hospital Basel Basel Switzerland

Institute of Neuroscience and Medicine Research Center Jülich Jülich Germany

Institute of Neuroscience and Physiology The Sahlgrenska Academy at the Gothenburg University Gothenburg Sweden

Institute of Psychiatric Phenomics and Genomics University Hospital LMU Munich Nußbaumstr 7 80336 Munich Germany

Intramural Research Program National Institute of Mental Health National Institutes of Health US Department of Health and Human Services Bethesda MD USA

Laboratoire Génomique Bio Informatique et Chimie Moléculaire Conservatoire National des Arts et Métiers HESAM Université 292 rue Saint Martin 75003 Paris France

Mental Health Research Group IMIM Hospital del Mar Barcelona Catalonia Spain

Mental Health Services Northern Adelaide Local Health Network Adelaide SA Australia

Montreal Neurological Institute and Hospital McGill University Montreal QC Canada

Mood Disorders Center of Ottawa Ottawa ON Canada

National Institute of Mental Health Klecany Czech Republic

Neuroscience Research Australia Sydney NSW Australia

Neurosciences Section Department of Medicine Surgery and Dentistry 'Scuola Medica Salernitana' University of Salerno Salerno Italy

Office of Mental Health VA San Diego Healthcare System San Diego CA USA

Plateforme de Ressources Biologiques HU Henri Mondor 94010 Créteil France

Program for Quantitative Genomics Harvard School of Public Health Boston MA USA

Psychiatric Genetic Unit Poznan University of Medical Sciences Poznan Poland

School of Medical Sciences University of New South Wales Sydney NSW Australia

School of Psychiatry University of New South Wales Sydney NSW Australia

Section of Psychiatry Department of Medical Sciences and Public Health University of Cagliari Cagliari Italy

Service de Psychiatrie Et Psychologie Clinique Centre Psychothérapique de Nancy Université de Lorraine Nancy France

Service de Psychiatrie Hôpital Charles Perrens Bordeaux France

South Australian Academic Health Science and Translation Centre South Australian Health and Medical Research Institute Adelaide SA Australia

The Florey Institute of Neuroscience and Mental Health The University of Melbourne Parkville Parkville VIC Australia

The Neuromodulation Unit McGill University Health Centre Montreal QC Canada

Unit of Clinical Pharmacology Hospital University Agency of Cagliari Cagliari Italy

Unitat de Zoologia 1 Antropologia Biològica University of Barcelona CIBERSAM Barcelona Spain

Univ Paris Est Créteil INSERM IMRB Translational Neuropsychiatry Fondation FondaMental Créteil France

Zobrazit více v PubMed

Ferrari AJ, et al. The prevalence and burden of bipolar disorder: findings from the Global Burden of Disease Study 2013. Bipolar Disord. 2016;18:440–450. doi: 10.1111/bdi.12423. PubMed DOI

Chesney E, Goodwin GM, Fazel S. Risks of all-cause and suicide mortality in mental disorders: a meta-review. World Psychiatry. 2014;13:153–160. doi: 10.1002/wps.20128. PubMed DOI PMC

Grande I, Berk M, Birmaher B, Vieta E. Bipolar disorder. The Lancet. 2016;387:1561–1572. doi: 10.1016/S0140-6736(15)00241-X. PubMed DOI

Miura T, et al. Comparative efficacy and tolerability of pharmacological treatments in the maintenance treatment of bipolar disorder: A systematic review and network meta-analysis. The Lancet Psychiatry. 2014;1:351–359. doi: 10.1016/S2215-0366(14)70314-1. PubMed DOI

Malhi GS, Tanious M, Das P, Berk M. The science and practice of lithium therapy. Aust. N. Z. J. Psychiatry. 2012;46:192–211. doi: 10.1177/0004867412437346. PubMed DOI

Malhi GS, Adams D, Berk M. Is lithium in a class of its own? A brief profile of its clinical use. Aust. N. Z. J. Psychiatry. 2009;43:1096–1104. doi: 10.3109/00048670903279937. PubMed DOI

Yildiz A, Vieta E, Leucht S, Baldessarini RJ. Efficacy of antimanic treatments: meta-analysis of randomized, controlled trials. Neuropsychopharmacology. 2011;36:375–389. doi: 10.1038/npp.2010.192. PubMed DOI PMC

Cipriani A, et al. Comparative efficacy and acceptability of antimanic drugs in acute mania: A multiple-treatments meta-analysis. The Lancet. 2011;378:1306–1315. doi: 10.1016/S0140-6736(11)60873-8. PubMed DOI

Joas E, et al. Pharmacological treatment and risk of psychiatric hospital admission in bipolar disorder. Br. J. Psychiatry. 2017;210:197–202. doi: 10.1192/bjp.bp.116.187989. PubMed DOI

National Collaborating Centre for Mental Health (UK) Bipolar Disorder: The Management of Bipolar Disorder in Adults, Children and Adolescents, in Primary and Secondary Care. British Psychological Society; 2006. PubMed

Yatham LN, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) collaborative update of CANMAT guidelines for the management of patients with bipolar disorder: Update 2013: CANMAT guidelines for bipolar disorder. Bipolar Disord. 2013;15:1–44. doi: 10.1111/bdi.12025. PubMed DOI

Malhi GS, et al. Royal Australian and New Zealand College of Psychiatrists clinical practice guidelines for mood disorders. Aust. N. Z. J. Psychiatry. 2015;49:1087–1206. doi: 10.1177/0004867415617657. PubMed DOI

Goodwin G, et al. Evidence-based guidelines for treating bipolar disorder: Revised third edition recommendations from the British Association for Psychopharmacology. J. Psychopharmacol. 2016;30:495–553. doi: 10.1177/0269881116636545. PubMed DOI PMC

Miller F, Tanenbaum JH, Griffin A, Ritvo E. Prediction of treatment response in bipolar, manic disorder. J. Affect. Disord. 1991;21:75–77. doi: 10.1016/0165-0327(91)90052-T. PubMed DOI

Machado-Vieira R, et al. Early improvement with lithium in classic mania and its association with later response. J. Affect. Disord. 2013;144:160–164. doi: 10.1016/j.jad.2012.05.039. PubMed DOI PMC

Hou L, et al. Genetic variants associated with response to lithium treatment in bipolar disorder: A genome-wide association study. The Lancet. 2016;387:1085–1093. doi: 10.1016/S0140-6736(16)00143-4. PubMed DOI PMC

Schubert KO, Wisdom A. Should the Australian Therapeutic Goods Administration recommend rapid dosing of lithium carbonate in acute mania? Aust. N. Z. J. Psychiatry. 2018;52:387–387. doi: 10.1177/0004867417746000. PubMed DOI

Chen C-H, et al. Variant GADL1 and response to lithium therapy in bipolar I disorder. N. Engl. J. Med. 2014;370:119–128. doi: 10.1056/NEJMoa1212444. PubMed DOI

International Consortium on Lithium Genetics (ConLi+Gen) et al. Association of polygenic score for Schizophrenia and HLA antigen and inflammation genes with response to lithium in bipolar affective disorder: A genome-wide association study. JAMA Psychiat. 2017 doi: 10.1001/jamapsychiatry.2017.3433. PubMed DOI PMC

Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium et al. Association of polygenic score for major depression with response to lithium in patients with bipolar disorder. Mol. Psychiatry. 2020 doi: 10.1038/s41380-020-0689-5. PubMed DOI

Schizophrenia Working Group of the Psychiatric Genomics Consortium et al. Schizophrenia risk from complex variation of complement component 4. Nature. 2016;530:177–183. doi: 10.1038/nature16549. PubMed DOI PMC

Del Vecchio M, et al. Cell membrane predictors of response to lithium prophylaxis of affective disorders. Neuropsychobiology. 1981;7:243–247. doi: 10.1159/000117856. PubMed DOI

Maj M, Vecchio M, Starace F, Pirozzi R, Kemali D. Prediction of affective psychoses response to lithium prophylaxis: The role of socio-demographic, clinical, psychological and biological variables. Acta Psychiatr. Scand. 1984;69:37–44. doi: 10.1111/j.1600-0447.1984.tb04514.x. PubMed DOI

Perris C, Strandman E, Wählby L. HL-A antigens and the response to prophylactic lithium. Neuropsychobiology. 1979;5:114–118. doi: 10.1159/000117671. PubMed DOI

Gonzalez-Galarza FF, et al. Allele frequency net database (AFND) 2020 update: Gold-standard data classification, open access genotype data and new query tools. Nucleic Acids Res. 2019 doi: 10.1093/nar/gkz1029. PubMed DOI PMC

Thomson, G. et al. Sequence feature variant type (SFVT) analysis of the HLA genetic association in juvenile idiopathic arthritis, in Pacific Symposium on Biocomputing, 359–370 (2010). 10.1142/9789814295291_0038. PubMed PMC

Barrett JC, Fry B, Maller J, Daly MJ. Haploview: Analysis and visualization of LD and haplotype maps. Bioinformatics. 2005;21:263–265. doi: 10.1093/bioinformatics/bth457. PubMed DOI

Rybakowski JK. Recent advances in the understanding and management of bipolar disorder in adults. F1000Res. 2017;6:2033. doi: 10.12688/f1000research.12329.1. PubMed DOI PMC

Beurel E, Jope RS. Inflammation and lithium: Clues to mechanisms contributing to suicide-linked traits. Transl. Psychiatry. 2014;4:e488. doi: 10.1038/tp.2014.129. PubMed DOI PMC

Beurel E, Michalek SM, Jope RS. Innate and adaptive immune responses regulated by glycogen synthase kinase-3 (GSK3) Trends Immunol. 2010;31:24–31. doi: 10.1016/j.it.2009.09.007. PubMed DOI PMC

Nassar A, Azab AN. Effects of lithium on inflammation. ACS Chem. Neurosci. 2014;5:451–458. doi: 10.1021/cn500038f. PubMed DOI PMC

Rybakowski JK. Lithium treatment in the era of personalized medicine. Drug Dev. Res. 2020 doi: 10.1002/ddr.21660. PubMed DOI

Reinsmoen NL, Bach FH. Structural model for T-cell recognition of HLA class II-associated alloepitopes. Hum Immunol. 1990;27:51–72. doi: 10.1016/0198-8859(90)90095-7. PubMed DOI

Yin L, Maben ZJ, Becerra A, Stern LJ. Evaluating the role of HLA-DM in MHC class II-peptide association reactions. J. Immunol. 2015;195:706–716. doi: 10.4049/jimmunol.1403190. PubMed DOI PMC

Ling SF, et al. HLA-DRB1 amino acid positions 11/13, 71, and 74 are associated with inflammation level, disease activity, and the health assessment questionnaire score in patients with inflammatory polyarthritis. Arthritis Rheumatol. (Hoboken, N.J.) 2016;68:2618–2628. doi: 10.1002/art.39780. PubMed DOI PMC

Weyand CM, McCarthy TG, Goronzy JJ. Correlation between disease phenotype and genetic heterogeneity in rheumatoid arthritis. J. Clin. Invest. 1995;95:2120–2126. doi: 10.1172/JCI117900. PubMed DOI PMC

Kaimen-Maciel DR, et al. HLA-DRB1* allele-associated genetic susceptibility and protection against multiple sclerosis in Brazilian patients. Mol. Med. Rep. 2009;2:993–998. PubMed

Ramagopalan SV, Ebers GC. Multiple sclerosis: major histocompatibility complexity and antigen presentation. Genome Med. 2009;1:105. doi: 10.1186/gm105. PubMed DOI PMC

Mamedov A, et al. Protective allele for multiple sclerosis HLA-DRB1*01:01 provides kinetic discrimination of myelin and exogenous antigenic peptides. Front. Immunol. 2020;10:3088. doi: 10.3389/fimmu.2019.03088. PubMed DOI PMC

Marangon AV, et al. Protective effect of HLA-DRB1*11 and predisposition of HLA-C*04 in the development of severe liver damage in Brazilian patients with chronic hepatitis C virus infection: HLA-DRB1*11 and C*04 on liver damage. Scand. J. Immunol. 2012;76:440–447. doi: 10.1111/j.1365-3083.2012.02755.x. PubMed DOI

Ban Y, et al. Analysis of immune regulatory genes in familial and sporadic Graves’ disease. J. Clin. Endocrinol. Metab. 2004;89:4562–4568. doi: 10.1210/jc.2003-031693. PubMed DOI

Crespi BJ, Go MC. Diametrical diseases reflect evolutionary-genetic tradeoffs: Evidence from psychiatry, neurology, rheumatology, oncology and immunology. Evol. Med. Public Health. 2015;2015:216–253. doi: 10.1093/emph/eov021. PubMed DOI PMC

Khakoo SI, et al. HLA and NK cell inhibitory receptor genes in resolving hepatitis C virus infection. Science. 2004;305:872–874. doi: 10.1126/science.1097670. PubMed DOI

Lenz TL, et al. Widespread non-additive and interaction effects within HLA loci modulate the risk of autoimmune diseases. Nat. Genet. 2015;47:1085–1090. doi: 10.1038/ng.3379. PubMed DOI PMC

Jia X, et al. Imputing amino acid polymorphisms in human leukocyte antigens. PLoS ONE. 2013;8:e64683. doi: 10.1371/journal.pone.0064683. PubMed DOI PMC

Purcell S, et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am. J. Hum. Genet. 2007;81:559–575. doi: 10.1086/519795. PubMed DOI PMC

Association of polygenic score and the involvement of cholinergic and glutamatergic pathways with lithium treatment response in patients with bipolar disorder