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

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...

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Autores principales: 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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spelling oai:doaj.org-article:cd2b00abcda74c64ac98ae9090e728982021-12-02T17:41:12ZHLA-DRB1 and HLA-DQB1 genetic diversity modulates response to lithium in bipolar affective disorders10.1038/s41598-021-97140-72045-2322https://doaj.org/article/cd2b00abcda74c64ac98ae9090e728982021-09-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-97140-7https://doaj.org/toc/2045-2322Abstract 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.Sigrid Le ClercLaura LombardiBernhard T. BauneAzmeraw T. AmareKlaus Oliver SchubertLiping HouScott R. ClarkSergi PapiolMicah CearnsUrs HeilbronnerFranziska DegenhardtFasil Tekola-AyeleYi-Hsiang HsuTatyana ShekhtmanMazda AdliNirmala AkulaKazufumi AkiyamaRaffaella ArdauBárbara AriasJean-Michel AubryLena BacklundAbesh Kumar BhattacharjeeFrank BellivierAntonio BenabarreSusanne BengesserJoanna M. BiernackaArmin BirnerClara Brichant-PetitjeanPablo CervantesHsi-Chung ChenCaterina ChillottiSven CichonCristiana CruceanuPiotr M. CzerskiNina DalknerAlexandre DayerMaria Del ZompoJ. Raymond DePauloBruno ÉtainStephane JamainPeter FalkaiAndreas J. ForstnerLouise FrisenMark A. FryeJanice M. FullertonSébastien GardJulie S. GarnhamFernando S. GoesMaria Grigoroiu-SerbanescuPaul GrofRyota HashimotoJoanna HauserStefan HermsPer HoffmannEsther JiménezJean-Pierre KahnLayla KassemPo-Hsiu KuoTadafumi KatoJohn R. KelsoeSarah Kittel-SchneiderEwa Ferensztajn-RochowiakBarbara KönigIchiro KusumiGonzalo LajeMikael LandénCatharina LavebrattSusan G. LeckbandAlfonso TortorellaMirko ManchiaLina MartinssonMichael J. McCarthySusan L. McElroyFrancesc ColomVincent MillischerMarina MitjansFrancis M. MondimorePalmiero MonteleoneCaroline M. NievergeltMarkus M. NöthenTomas NovákClaire O’DonovanNorio OzakiUrban ÖsbyAndrea PfennigJames B. PotashAndreas ReifEva ReininghausGuy A. RouleauJanusz K. RybakowskiMartin SchallingPeter R. SchofieldBarbara W. SchweizerGiovanni SeverinoPaul D. ShillingKatzutaka ShimodaChristian SimhandlClaire M. SlaneyClaudia PisanuAlessio SquassinaThomas StammPavla StopkovaMario MajGustavo TureckiEduard VietaJulia VeehStephanie H. WittAdam WrightPeter P. ZandiPhilip B. MitchellMichael BauerMartin AldaMarcella RietschelFrancis J. McMahonThomas G. SchulzeJean-Louis SpadoniWahid BoukouaciJean-Romain RichardPhilippe Le CorvoisierCaroline BarrauJean-François ZaguryMarion LeboyerRyad TamouzaNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-12 (2021)
institution DOAJ
collection DOAJ
language EN
topic Medicine
R
Science
Q
spellingShingle Medicine
R
Science
Q
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
HLA-DRB1 and HLA-DQB1 genetic diversity modulates response to lithium in bipolar affective disorders
description 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.
format article
author 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
author_facet 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
author_sort Sigrid Le Clerc
title HLA-DRB1 and HLA-DQB1 genetic diversity modulates response to lithium in bipolar affective disorders
title_short HLA-DRB1 and HLA-DQB1 genetic diversity modulates response to lithium in bipolar affective disorders
title_full HLA-DRB1 and HLA-DQB1 genetic diversity modulates response to lithium in bipolar affective disorders
title_fullStr HLA-DRB1 and HLA-DQB1 genetic diversity modulates response to lithium in bipolar affective disorders
title_full_unstemmed HLA-DRB1 and HLA-DQB1 genetic diversity modulates response to lithium in bipolar affective disorders
title_sort hla-drb1 and hla-dqb1 genetic diversity modulates response to lithium in bipolar affective disorders
publisher Nature Portfolio
publishDate 2021
url https://doaj.org/article/cd2b00abcda74c64ac98ae9090e72898
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