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

Le Clerc, Sigrid;Lombardi, Laura;Baune, Bernhard T;Amare, Azmeraw T;Schubert, Klaus Oliver;Hou, Liping;Clark, Scott R;Papiol, Sergi;Cearns, Micah;Heilbronner, Urs;Degenhardt, Franziska;Tekola-Ayele, Fasil;Hsu, Yi-Hsiang;Shekhtman, Tatyana;Adli, Mazda;Akula, Nirmala;Akiyama, Kazufumi;Ardau, Raffaella;Arias, Bárbara;Aubry, Jean-Michel;Backlund, Lena;Bhattacharjee, Abesh Kumar;Bellivier, Frank;Benabarre, Antonio;Bengesser, Susanne;Biernacka, Joanna M;Birner, Armin;Brichant-Petitjean, Clara;Cervantes, Pablo;Chen, Hsi-Chung;Chillotti, Caterina;Cichon, Sven;Cruceanu, Cristiana;Czerski, Piotr M;Dalkner, Nina;Dayer, Alexandre;Del Zompo, Maria;DePaulo, J Raymond;Étain, Bruno;Jamain, Stephane;Falkai, Peter;Forstner, Andreas J;Frisen, Louise;Frye, Mark A;Fullerton, Janice M;Gard, Sébastien;Garnham, Julie S;Goes, Fernando S;Grigoroiu-Serbanescu, Maria;Grof, Paul;Hashimoto, Ryota;Hauser, Joanna;Herms, Stefan;Hoffmann, Per;Jiménez, Esther;Kahn, Jean-Pierre;Kassem, Layla;Kuo, Po-Hsiu;Kato, Tadafumi;Kelsoe, John R;Kittel-Schneider, Sarah;Ferensztajn-Rochowiak, Ewa;König, Barbara;Kusumi, Ichiro;Laje, Gonzalo;Landén, Mikael;Lavebratt, Catharina;Leckband, Susan G;Tortorella, Alfonso;Manchia, Mirko;Martinsson, Lina;McCarthy, Michael J;McElroy, Susan L;Colom, Francesc;Millischer, Vincent;Mitjans, Marina;Mondimore, Francis M;Monteleone, Palmiero;Nievergelt, Caroline M;Nöthen, Markus M;Novák, Tomas;O'Donovan, Claire;Ozaki, Norio;Ösby, Urban;Pfennig, Andrea;Potash, James B;Reif, Andreas;Reininghaus, Eva;Rouleau, Guy A;Rybakowski, Janusz K;Schalling, Martin;Schofield, Peter R;Schweizer, Barbara W;Severino, Giovanni;Shilling, Paul D;Shimoda, Katzutaka;Simhandl, Christian;Slaney, Claire M;Pisanu, Claudia;Squassina, Alessio;Stamm, Thomas;Stopkova, Pavla;Maj, Mario;Turecki, Gustavo;Vieta, Eduard;Veeh, Julia;Witt, Stephanie H;Wright, Adam;Zandi, Peter P;Mitchell, Philip B;Bauer, Michael;Alda, Martin;Rietschel, Marcella;McMahon, Francis J;Schulze, Thomas G;Spadoni, Jean-Louis;Boukouaci, Wahid;Richard, Jean-Romain;Le Corvoisier, Philippe;Barrau, Caroline;Zagury, Jean-François;Leboyer, Marion;Tamouza, Ryad

2021-01-01

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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.