HLA-DRB1 and HLA-DQB1 genetic diversity modulates response to lithium in bipolar affective disorders
Sigrid Le Clerc
(1)
,
Laura Lombardi
(2, 3, 4)
,
Bernhard T Baune
(5, 6, 7)
,
Azmeraw T Amare
(8)
,
Klaus Oliver Schubert
(8)
,
Liping Hou
(9)
,
Scott R Clark
(8)
,
Sergi Papiol
(10)
,
Micah Cearns
(8)
,
Urs Heilbronner
(10)
,
Franziska Degenhardt
(11)
,
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
(12)
,
Antonio Benabarre
,
Susanne Bengesser
,
Joanna M Biernacka
,
Armin Birner
,
Clara Brichant-Petitjean
(12)
,
Pablo Cervantes
,
Hsi-Chung Chen
,
Caterina Chillotti
,
Sven Cichon
,
Cristiana Cruceanu
,
Piotr M Czerski
,
Nina Dalkner
,
Alexandre Dayer
,
Maria del Zompo
,
J. Raymond Raymond Depaulo
,
Bruno Étain
(12)
,
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
(1)
,
Wahid Boukouaci
,
Jean-Romain Richard
,
Philippe Le Corvoisier
,
Caroline Barrau
,
Jean-François Zagury
(1)
,
Marion Leboyer
,
Ryad Tamouza
(3, 2, 4)
1
GBCM -
Laboratoire Génomique, bioinformatique et chimie moléculaire
2 CHU Henri Mondor [Créteil]
3 U955 Inserm - UPEC - IMRB - "Neuropsychiatrie translationnelle" [Créteil]
4 Fondation FondaMental [Créteil]
5 WWU - Westfälische Wilhelms-Universität Münster = University of Münster
6 Melbourne Medical School [Melbourne]
7 The Florey Institute of Neuroscience and Mental Health
8 University of Adelaide
9 NIH - National Institutes of Health [Bethesda, MD, USA]
10 LMU - Ludwig Maximilian University [Munich] = Ludwig Maximilians Universität München
11 Institut für Genetik - Universität Bonn / Institute of Genetics - University of Bonn
12 OPTeN (UMR_S 1144 / U1144) - Optimisation thérapeutique en Neuropsychopharmacologie
2 CHU Henri Mondor [Créteil]
3 U955 Inserm - UPEC - IMRB - "Neuropsychiatrie translationnelle" [Créteil]
4 Fondation FondaMental [Créteil]
5 WWU - Westfälische Wilhelms-Universität Münster = University of Münster
6 Melbourne Medical School [Melbourne]
7 The Florey Institute of Neuroscience and Mental Health
8 University of Adelaide
9 NIH - National Institutes of Health [Bethesda, MD, USA]
10 LMU - Ludwig Maximilian University [Munich] = Ludwig Maximilians Universität München
11 Institut für Genetik - Universität Bonn / Institute of Genetics - University of Bonn
12 OPTeN (UMR_S 1144 / U1144) - Optimisation thérapeutique en Neuropsychopharmacologie
Klaus Oliver Schubert
- Function : Author
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Liping Hou
- Function : Author
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- ORCID : 0000-0003-3972-245X
Sergi Papiol
- Function : Author
- PersonId : 779325
- ORCID : 0000-0001-9366-8728
Urs Heilbronner
- Function : Author
- PersonId : 769347
- ORCID : 0000-0001-7135-762X
Fasil Tekola-Ayele
- Function : Author
Yi-Hsiang Hsu
- Function : Author
Tatyana Shekhtman
- Function : Author
Mazda Adli
- Function : Author
Nirmala Akula
- Function : Author
Kazufumi Akiyama
- Function : Author
Raffaella Ardau
- Function : Author
Bárbara Arias
- Function : Author
Jean-Michel Aubry
- Function : Author
Lena Backlund
- Function : Author
Abesh Kumar Bhattacharjee
- Function : Author
Frank Bellivier
- Function : Author
- PersonId : 757742
- ORCID : 0000-0002-3660-6640
- IdRef : 070265062
Antonio Benabarre
- Function : Author
Susanne Bengesser
- Function : Author
Joanna M Biernacka
- Function : Author
Armin Birner
- Function : Author
Pablo Cervantes
- Function : Author
Hsi-Chung Chen
- Function : Author
Caterina Chillotti
- Function : Author
Sven Cichon
- Function : Author
Cristiana Cruceanu
- Function : Author
- PersonId : 791547
- ORCID : 0000-0002-7799-5531
Piotr M Czerski
- Function : Author
Nina Dalkner
- Function : Author
Alexandre Dayer
- Function : Author
Maria del Zompo
- Function : Author
- PersonId : 792984
- ORCID : 0000-0001-9491-5938
J. Raymond Raymond Depaulo
- Function : Author
Bruno Étain
- Function : Author
- PersonId : 757741
- IdHAL : bruno-etain
- ORCID : 0000-0002-5377-1488
- IdRef : 074181106
Stephane Jamain
- Function : Author
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- IdHAL : stephane-jamain
- ORCID : 0000-0002-4321-4100
- IdRef : 07777146X
Peter Falkai
- Function : Author
Andreas J Forstner
- Function : Author
Louise Frisen
- Function : Author
Mark A Frye
- Function : Author
Janice M Fullerton
- Function : Author
Sébastien Gard
- Function : Author
Julie S Garnham
- Function : Author
Fernando S Goes
- Function : Author
Maria Grigoroiu-Serbanescu
- Function : Author
- PersonId : 769351
- ORCID : 0000-0002-1304-6687
Paul Grof
- Function : Author
Ryota Hashimoto
- Function : Author
Joanna Hauser
- Function : Author
- PersonId : 765438
- ORCID : 0000-0002-6621-3493
Stefan Herms
- Function : Author
- PersonId : 764718
- ORCID : 0000-0002-2786-8200
Per Hoffmann
- Function : Author
Esther Jiménez
- Function : Author
Jean-Pierre Kahn
- Function : Author
Layla Kassem
- Function : Author
Po-Hsiu Kuo
- Function : Author
Tadafumi Kato
- Function : Author
John R Kelsoe
- Function : Author
Sarah Kittel-Schneider
- Function : Author
Ewa Ferensztajn-Rochowiak
- Function : Author
Barbara König
- Function : Author
Ichiro Kusumi
- Function : Author
- PersonId : 769349
- ORCID : 0000-0002-8747-5070
Gonzalo Laje
- Function : Author
Mikael Landén
- Function : Author
- PersonId : 761273
- ORCID : 0000-0002-4496-6451
Catharina Lavebratt
- Function : Author
- PersonId : 769121
- ORCID : 0000-0003-4987-2718
Susan G Leckband
- Function : Author
Alfonso Tortorella
- Function : Author
Mirko Manchia
- Function : Author
Lina Martinsson
- Function : Author
Michael J Mccarthy
- Function : Author
Susan L Mcelroy
- Function : Author
Francesc Colom
- Function : Author
Vincent Millischer
- Function : Author
Marina Mitjans
- Function : Author
Francis M Mondimore
- Function : Author
Palmiero Monteleone
- Function : Author
Caroline M Nievergelt
- Function : Author
Markus M Nöthen
- Function : Author
Tomas Novák
- Function : Author
- PersonId : 805591
- ORCID : 0000-0001-9156-9654
Claire O’donovan
- Function : Author
Norio Ozaki
- Function : Author
- PersonId : 769350
- ORCID : 0000-0002-7360-4898
Urban Ösby
- Function : Author
Andrea Pfennig
- Function : Author
James B Potash
- Function : Author
Andreas Reif
- Function : Author
- PersonId : 763135
- ORCID : 0000-0002-0992-634X
Eva Reininghaus
- Function : Author
Guy A Rouleau
- Function : Author
- PersonId : 764544
- ORCID : 0000-0001-8403-1418
Janusz K Rybakowski
- Function : Author
Martin Schalling
- Function : Author
Peter R Schofield
- Function : Author
Barbara W Schweizer
- Function : Author
Giovanni Severino
- Function : Author
- PersonId : 769352
- ORCID : 0000-0002-6354-2662
Paul D Shilling
- Function : Author
Katzutaka Shimoda
- Function : Author
- PersonId : 805593
- ORCID : 0000-0002-9663-6243
Christian Simhandl
- Function : Author
Claire M Slaney
- Function : Author
Claudia Pisanu
- Function : Author
- PersonId : 808123
- ORCID : 0000-0002-9151-4319
Alessio Squassina
- Function : Author
- PersonId : 769353
- ORCID : 0000-0001-7415-7607
Thomas Stamm
- Function : Author
Pavla Stopkova
- Function : Author
Mario Maj
- Function : Author
Gustavo Turecki
- Function : Author
- PersonId : 769354
- ORCID : 0000-0003-4075-2736
Eduard Vieta
- Function : Author
Julia Veeh
- Function : Author
Stephanie H Witt
- Function : Author
Adam Wright
- Function : Author
Peter P Zandi
- Function : Author
Philip B Mitchell
- Function : Author
Michael Bauer
- Function : Author
- PersonId : 765030
- ORCID : 0000-0002-2666-859X
Martin Alda
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Marcella Rietschel
- Function : Author
- PersonId : 757743
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Francis J Mcmahon
- Function : Author
Thomas G Schulze
- Function : Author
Wahid Boukouaci
- Function : Author
Jean-Romain Richard
- Function : Author
Philippe Le Corvoisier
- Function : Author
- PersonId : 754020
- IdHAL : lecorvoisier-philippe
- ORCID : 0000-0003-0402-9591
Caroline Barrau
- Function : Author
Jean-François Zagury
- Function : Author
- PersonId : 964657
Marion Leboyer
- Function : Author
- PersonId : 756830
- ORCID : 0000-0001-5473-3697
- IdRef : 089352475
Ryad Tamouza
Connectez-vous pour contacter l'auteur
- Function : Correspondent author
- PersonId : 761185
- ORCID : 0000-0003-3992-9565
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Abstract
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.
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