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

Le Clerc S, Lombardi L, Baune BT, Amare AT, Schubert KO, Hou L, Clark SR, Papiol S, Cearns M, Heilbronner U, Degenhardt F, Tekola-Ayele F, Hsu YH, Shekhtman T, Adli M, Akula N, Akiyama K, Ardau R, Arias B, Aubry JM, Backlund L, Bhattacharjee AK, Bellivier F, Benabarre A, Bengesser S, Biernacka JM, Birner A, Brichant-Petitjean C, Cervantes P, Chen HC, Chillotti C, Cichon S, Cruceanu C, Czerski PM, Dalkner N, Dayer A, Del Zompo M, DePaulo JR, Étain B, Jamain S, Falkai P, Forstner AJ, Frisen L, Frye MA, Fullerton JM, Gard S, Garnham JS, Goes FS, Grigoroiu-Serbanescu M, Grof P, Hashimoto R, Hauser J, Herms S, Hoffmann P, Jiménez E, Kahn JP, Kassem L, Kuo PH, Kato T, Kelsoe JR, Kittel-Schneider S, Ferensztajn-Rochowiak E, König B, Kusumi I, Laje G, Landén M, Lavebratt C, Leckband SG, Tortorella A, Manchia M, Martinsson L, McCarthy MJ, McElroy SL, Colom F, Millischer V, Mitjans M, Mondimore FM, Monteleone P, Nievergelt CM, Nöthen MM, Novák T, O’Donovan C, Ozaki N, Ösby U, Pfennig A, Potash JB, Reif A, Reininghaus E, Rouleau GA, Rybakowski JK, Schalling M, Schofield PR, Schweizer BW, Severino G, Shilling PD, Shimoda K, Simhandl C, Slaney CM, Pisanu C, Squassina A, Stamm T, Stopkova P, Maj M, Turecki G, Vieta E, Veeh J, Witt SH, Wright A, Zandi PP, Mitchell PB, Bauer M, Alda M, Rietschel M, McMahon FJ, Schulze TG, Spadoni JL, Boukouaci W, Richard JR, Le Corvoisier P, Barrau C, Zagury JF, Leboyer M, Tamouza R (2021)

Publication Type: Journal article

Publication year: 2021

Journal

Book Volume: 11

Article Number: 17823

Journal Issue: 1

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.

Involved external institutions

Karolinska Institute Sweden (SE) Universitat de Barcelona (UB) / University of Barcelona Spain (ES) Johns Hopkins University (JHU) United States (USA) (US) National Institute of Mental Health Information Resource Center United States (USA) (US) Università degli Studi di Salerno Italy (IT) Neuroscience Research Australia NeuRA Australia (AU) Poznan University of Medical Sciences / Uniwersytet Medyczny im. Karola Marcinkowskiego w Poznaniu Poland (PL) Universitätsklinikum Bonn Germany (DE) University of California, San Diego (UC San Diego, UCSD) United States (USA) (US) Sahlgrenska University Hospital / Sahlgrenska Universitetssjukhuset Sweden (SE) VA San Diego Healthcare System United States (USA) (US) Università degli Studi di Perugia Italy (IT) Università degli Studi di Cagliari Italy (IT) Mayo Clinic United States (USA) (US) Centre Hospitalier Charles Perrens (CHCP) France (FR) Dalhousie University Canada (CA) Mood Disorders Ottawa Canada (CA) Juntendo University Japan (JP) Universitätsklinikum Frankfurt am Main (KGU) Germany (DE) Städtisches Klinikum Neunkirchen Germany (DE) Dokkyo Medical University Japan (JP) Mondor Institute of Biomedical Research (IMRB) France (FR) Centre hospitalier universitaire Henri-Mondor (CHU Henri-Mondor) France (FR) National Conservatory of Arts and Crafts / Conservatoire National des Arts et Métiers (CNAM) France (FR) University of New South Wales (UNSW) Australia (AU) University of Cincinnati United States (USA) (US) Hospital del Mar Spain (ES) National Institute of Mental Health (NIMH) / Národní ústav duševního zdraví (NUDZ) Czech Republic (CZ) Nagoya University / 名古屋大学 Japan (JP) Karolinska University Hospital / Karolinska Universitetssjukhuset Sweden (SE) Universitätsklinikum Carl Gustav Carus Dresden Germany (DE) Medizinische Universität Graz Austria (AT) Université de Lorraine France (FR) Montreal Neurological Institute and Hospital (MNI, The Neuro) Canada (CA) National Taiwan University (NTU) Taiwan (TW) Sigmund-Freud-Privatuniversität Wien (SFU) / Sigmund Freud University Austria (AT) Douglas Mental Health University Institute Canada (CA) Ruprecht-Karls-Universität Heidelberg Germany (DE) Westfälische Wilhelms-Universität (WWU) Münster Germany (DE) University of Adelaide Australia (AU) Klinikum der Universität München (LMU Klinikum) Germany (DE) Charité - Universitätsmedizin Berlin Germany (DE) Università degli studi della Campania Luigi Vanvitelli Italy (IT) US National Institutes of Health (NIH) United States (USA) (US) Harvard University United States (USA) (US) Geneva University Hospitals / Hôpitaux universitaires de Genève (HUG) Switzerland (CH) Université Paris Cité France (FR) McGill University Health Centre (MUHC) / Centre universitaire de santé McGill Canada (CA) National Taiwan University Hospital (NTUH) / 國立台灣大學醫學院附設醫院 Taiwan (TW) Universitätsspital Basel Switzerland (CH) Paris-Est Créteil University / Université Paris-Est Créteil Val-de-Marne (UPEC) / Université Paris XII-Val-de-Marne / University Paris 12 Marne la Vallée France (FR)

How to cite

APA:

Le Clerc, S., Lombardi, L., Baune, B.T., Amare, A.T., Schubert, K.O., Hou, L.,... Tamouza, R. (2021). HLA-DRB1 and HLA-DQB1 genetic diversity modulates response to lithium in bipolar affective disorders. Scientific Reports, 11(1). https://doi.org/10.1038/s41598-021-97140-7

MLA:

Le Clerc, Sigrid, et al. "HLA-DRB1 and HLA-DQB1 genetic diversity modulates response to lithium in bipolar affective disorders." Scientific Reports 11.1 (2021).

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