HLA-DRB1 and HLA-DQB1 genetic diversity modulates response to lithium in bipolar affective disorders
Authors: 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 
Published: September 2021

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.