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

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 I...

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Main Authors: Le Clerc, Sigrid (Author) , Lombardi, Laura (Author) , Baune, Bernhard T. (Author) , Amare, Azmeraw T. (Author) , Schubert, Klaus Oliver (Author) , Hou, Liping (Author) , Clark, Scott R. (Author) , Papiol, Sergi (Author) , Cearns, Micah (Author) , Heilbronner, Urs (Author) , Degenhardt, Franziska (Author) , Tekola-Ayele, Fasil (Author) , Hsu, Yi-Hsiang (Author) , Shekhtman, Tatyana (Author) , Adli, Mazda (Author) , Akula, Nirmala (Author) , Akiyama, Kazufumi (Author) , Ardau, Raffaella (Author) , Arias, Bárbara (Author) , Aubry, Jean-Michel (Author) , Backlund, Lena (Author) , Bhattacharjee, Abesh Kumar (Author) , Bellivier, Frank (Author) , Benabarre, Antonio (Author) , Bengesser, Susanne (Author) , Biernacka, Joanna M. (Author) , Birner, Armin (Author) , Brichant-Petitjean, Clara (Author) , Cervantes, Pablo (Author) , Chen, Hsi-Chung (Author) , Chillotti, Caterina (Author) , Cichon, Sven (Author) , Cruceanu, Cristiana (Author) , Czerski, Piotr M. (Author) , Dalkner, Nina (Author) , Dayer, Alexandre (Author) , Del Zompo, Maria (Author) , DePaulo, J. Raymond (Author) , Étain, Bruno (Author) , Jamain, Stephane (Author) , Falkai, Peter (Author) , Forstner, Andreas J. (Author) , Frisen, Louise (Author) , Frye, Mark A. (Author) , Fullerton, Janice M. (Author) , Gard, Sébastien (Author) , Garnham, Julie S. (Author) , Goes, Fernando S. (Author) , Grigoroiu-Serbanescu, Maria (Author) , Grof, Paul (Author) , Hashimoto, Ryota (Author) , Hauser, Joanna (Author) , Herms, Stefan (Author) , Hoffmann, Per (Author) , Jiménez, Esther (Author) , Kahn, Jean-Pierre (Author) , Kassem, Layla (Author) , Kuo, Po-Hsiu (Author) , Kato, Tadafumi (Author) , Kelsoe, John R. (Author) , Kittel-Schneider, Sarah (Author) , Ferensztajn-Rochowiak, Ewa (Author) , König, Barbara (Author) , Kusumi, Ichiro (Author) , Laje, Gonzalo (Author) , Landén, Mikael (Author) , Lavebratt, Catharina (Author) , Leckband, Susan G. (Author) , Tortorella, Alfonso (Author) , Manchia, Mirko (Author) , Martinsson, Lina (Author) , McCarthy, Michael J. (Author) , McElroy, Susan L. (Author) , Colom, Francesc (Author) , Millischer, Vincent (Author) , Mitjans, Marina (Author) , Mondimore, Francis M. (Author) , Monteleone, Palmiero (Author) , Nievergelt, Caroline M. (Author) , Nöthen, Markus M. (Author) , Novák, Tomas (Author) , O’Donovan, Claire (Author) , Ozaki, Norio (Author) , Ösby, Urban (Author) , Pfennig, Andrea (Author) , Potash, James B. (Author) , Reif, Andreas (Author) , Reininghaus, Eva (Author) , Rouleau, Guy A. (Author) , Rybakowski, Janusz K. (Author) , Schalling, Martin (Author) , Schofield, Peter R. (Author) , Schweizer, Barbara W. (Author) , Severino, Giovanni (Author) , Shilling, Paul D. (Author) , Shimoda, Katzutaka (Author) , Simhandl, Christian (Author) , Slaney, Claire M. (Author) , Pisanu, Claudia (Author) , Squassina, Alessio (Author) , Stamm, Thomas (Author) , Stopkova, Pavla (Author) , Maj, Mario (Author) , Turecki, Gustavo (Author) , Vieta, Eduard (Author) , Veeh, Julia (Author) , Witt, Stephanie (Author) , Wright, Adam (Author) , Zandi, Peter P. (Author) , Mitchell, Philip B. (Author) , Bauer, Michael (Author) , Alda, Martin (Author) , Rietschel, Marcella (Author) , McMahon, Francis J. (Author) , Schulze, Thomas G. (Author) , Spadoni, Jean-Louis (Author) , Boukouaci, Wahid (Author) , Richard, Jean-Romain (Author) , Le Corvoisier, Philippe (Author) , Barrau, Caroline (Author) , Zagury, Jean-François (Author) , Leboyer, Marion (Author) , Tamouza, Ryad (Author)
Format: Article (Journal)
Language:English
Published: 08 September 2021
In: Scientific reports
Year: 2021, Volume: 11, Pages: 1-12
ISSN:2045-2322
DOI:10.1038/s41598-021-97140-7
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1038/s41598-021-97140-7
Verlag, lizenzpflichtig, Volltext: https://www.nature.com/articles/s41598-021-97140-7
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Author Notes:Sigrid Le Clerc, Laura Lombardi, Bernhard T. Baune, Azmeraw T. Amare, Klaus Oliver Schubert, Liping Hou, Scott R. Clark, Sergi Papiol, Micah Cearns, Urs Heilbronner, Franziska Degenhardt, Fasil Tekola-Ayele, Yi-Hsiang Hsu, Tatyana Shekhtman, Mazda Adli, Nirmala Akula, Kazufumi Akiyama, Raffaella Ardau, Bárbara Arias, Jean-Michel Aubry, Lena Backlund, Abesh Kumar Bhattacharjee, Frank Bellivier, Antonio Benabarre, Susanne Bengesser, Joanna M. Biernacka, Armin Birner, Clara Brichant-Petitjean, Pablo Cervantes, Hsi-Chung Chen, Caterina Chillotti, Sven Cichon, Cristiana Cruceanu, Piotr M. Czerski, Nina Dalkner, Alexandre Dayer, Maria Del Zompo, J. Raymond DePaulo, Bruno Étain, Stephane Jamain, Peter Falkai, Andreas J. Forstner, Louise Frisen, Mark A. Frye, Janice M. Fullerton, Sébastien Gard, Julie S. Garnham, Fernando S. Goes, Maria Grigoroiu-Serbanescu, Paul Grof, Ryota Hashimoto, Joanna Hauser, Stefan Herms, Per Hoffmann, Esther Jiménez, Jean-Pierre Kahn, Layla Kassem, Po-Hsiu Kuo, Tadafumi Kato, John R. Kelsoe, Sarah Kittel-Schneider, Ewa Ferensztajn-Rochowiak, Barbara König, Ichiro Kusumi, Gonzalo Laje, Mikael Landén, Catharina Lavebratt, Susan G. Leckband, Alfonso Tortorella, Mirko Manchia, Lina Martinsson, Michael J. McCarthy, Susan L. McElroy, Francesc Colom, Vincent Millischer, Marina Mitjans, Francis M. Mondimore, Palmiero Monteleone, Caroline M. Nievergelt, Markus M. Nöthen, Tomas Novák, Claire O’Donovan, Norio Ozaki, Urban Ösby, Andrea Pfennig, James B. Potash, Andreas Reif, Eva Reininghaus, Guy A. Rouleau, Janusz K. Rybakowski, Martin Schalling, Peter R. Schofield, Barbara W. Schweizer, Giovanni Severino, Paul D. Shilling, Katzutaka Shimoda, Christian Simhandl, Claire M. Slaney, Claudia Pisanu, Alessio Squassina, Thomas Stamm, Pavla Stopkova, Mario Maj, Gustavo Turecki, Eduard Vieta, Julia Veeh, Stephanie H. Witt, Adam Wright, Peter P. Zandi, Philip B. Mitchell, Michael Bauer, Martin Alda, Marcella Rietschel, Francis J. McMahon, Thomas G. Schulze, Jean-Louis Spadoni, Wahid Boukouaci, Jean-Romain Richard, Philippe Le Corvoisier, Caroline Barrau, Jean-François Zagury, Marion Leboyer, Ryad Tamouza

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245 1 0 |a HLA-DRB1 and HLA-DQB1 genetic diversity modulates response to lithium in bipolar affective disorders  |c Sigrid Le Clerc, Laura Lombardi, Bernhard T. Baune, Azmeraw T. Amare, Klaus Oliver Schubert, Liping Hou, Scott R. Clark, Sergi Papiol, Micah Cearns, Urs Heilbronner, Franziska Degenhardt, Fasil Tekola-Ayele, Yi-Hsiang Hsu, Tatyana Shekhtman, Mazda Adli, Nirmala Akula, Kazufumi Akiyama, Raffaella Ardau, Bárbara Arias, Jean-Michel Aubry, Lena Backlund, Abesh Kumar Bhattacharjee, Frank Bellivier, Antonio Benabarre, Susanne Bengesser, Joanna M. Biernacka, Armin Birner, Clara Brichant-Petitjean, Pablo Cervantes, Hsi-Chung Chen, Caterina Chillotti, Sven Cichon, Cristiana Cruceanu, Piotr M. Czerski, Nina Dalkner, Alexandre Dayer, Maria Del Zompo, J. Raymond DePaulo, Bruno Étain, Stephane Jamain, Peter Falkai, Andreas J. Forstner, Louise Frisen, Mark A. Frye, Janice M. Fullerton, Sébastien Gard, Julie S. Garnham, Fernando S. Goes, Maria Grigoroiu-Serbanescu, Paul Grof, Ryota Hashimoto, Joanna Hauser, Stefan Herms, Per Hoffmann, Esther Jiménez, Jean-Pierre Kahn, Layla Kassem, Po-Hsiu Kuo, Tadafumi Kato, John R. Kelsoe, Sarah Kittel-Schneider, Ewa Ferensztajn-Rochowiak, Barbara König, Ichiro Kusumi, Gonzalo Laje, Mikael Landén, Catharina Lavebratt, Susan G. Leckband, Alfonso Tortorella, Mirko Manchia, Lina Martinsson, Michael J. McCarthy, Susan L. McElroy, Francesc Colom, Vincent Millischer, Marina Mitjans, Francis M. Mondimore, Palmiero Monteleone, Caroline M. Nievergelt, Markus M. Nöthen, Tomas Novák, Claire O’Donovan, Norio Ozaki, Urban Ösby, Andrea Pfennig, James B. Potash, Andreas Reif, Eva Reininghaus, Guy A. Rouleau, Janusz K. Rybakowski, Martin Schalling, Peter R. Schofield, Barbara W. Schweizer, Giovanni Severino, Paul D. Shilling, Katzutaka Shimoda, Christian Simhandl, Claire M. Slaney, Claudia Pisanu, Alessio Squassina, Thomas Stamm, Pavla Stopkova, Mario Maj, Gustavo Turecki, Eduard Vieta, Julia Veeh, Stephanie H. Witt, Adam Wright, Peter P. Zandi, Philip B. Mitchell, Michael Bauer, Martin Alda, Marcella Rietschel, Francis J. McMahon, Thomas G. Schulze, Jean-Louis Spadoni, Wahid Boukouaci, Jean-Romain Richard, Philippe Le Corvoisier, Caroline Barrau, Jean-François Zagury, Marion Leboyer, Ryad Tamouza 
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520 |a 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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