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

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

doi:10.1038/s41598-021-97140-7

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

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 AubryLena 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

Research output: Contribution to journal › Article › peer-review

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.

Original language	English (US)
Article number	17823
Journal	Scientific reports
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41598-021-97140-7
State	Published - Dec 2021

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Le Clerc, S., Lombardi, L., Baune, B. T., Amare, A. T., Schubert, K. O., Hou, L., Clark, S. R., Papiol, S., Cearns, M., Heilbronner, U., Degenhardt, F., Tekola-Ayele, F., Hsu, Y. H., Shekhtman, T., Adli, M., Akula, N., Akiyama, K., Ardau, R., Arias, B., ... Tamouza, R. (2021). HLA-DRB1 and HLA-DQB1 genetic diversity modulates response to lithium in bipolar affective disorders. Scientific reports, 11(1), Article 17823. https://doi.org/10.1038/s41598-021-97140-7

Le Clerc, S, Lombardi, L, Baune, BT, Amare, AT, Schubert, KO, Hou, L, Clark, SR, Papiol, S, Cearns, M, Heilbronner, U, Degenhardt, F, Tekola-Ayele, F, Hsu, YH, Shekhtman, T, Adli, M, Akula, N, Akiyama, K, Ardau, R, Arias, B, Aubry, JM, Backlund, L, Bhattacharjee, AK, Bellivier, F, Benabarre, A, Bengesser, S, Biernacka, JM, Birner, A, Brichant-Petitjean, C, Cervantes, P, Chen, HC, Chillotti, C, Cichon, S, Cruceanu, C, Czerski, PM, Dalkner, N, Dayer, A, Del Zompo, M, DePaulo, JR, Étain, B, Jamain, S, Falkai, P, Forstner, AJ, Frisen, L, Frye, MA, Fullerton, JM, Gard, S, Garnham, JS, Goes, FS, Grigoroiu-Serbanescu, M, Grof, P, Hashimoto, R, Hauser, J, Herms, S, Hoffmann, P, Jiménez, E, Kahn, JP, Kassem, L, Kuo, PH, Kato, T, Kelsoe, JR, Kittel-Schneider, S, Ferensztajn-Rochowiak, E, König, B, Kusumi, I, Laje, G, Landén, M, Lavebratt, C, Leckband, SG, Tortorella, A, Manchia, M, Martinsson, L, McCarthy, MJ, McElroy, SL, Colom, F, Millischer, V, Mitjans, M, Mondimore, FM, Monteleone, P, Nievergelt, CM, Nöthen, MM, Novák, T, O’Donovan, C, Ozaki, N, Ösby, U, Pfennig, A, Potash, JB, Reif, A, Reininghaus, E, Rouleau, GA, Rybakowski, JK, Schalling, M, Schofield, PR, Schweizer, BW, Severino, G, Shilling, PD, Shimoda, K, Simhandl, C, Slaney, CM, Pisanu, C, Squassina, A, Stamm, T, Stopkova, P, Maj, M, Turecki, G, Vieta, E, Veeh, J, Witt, SH, Wright, A, Zandi, PP, Mitchell, PB, Bauer, M, Alda, M, Rietschel, M, McMahon, FJ, Schulze, TG, Spadoni, JL, Boukouaci, W, Richard, JR, Le Corvoisier, P, Barrau, C, Zagury, JF, Leboyer, M & Tamouza, R 2021, 'HLA-DRB1 and HLA-DQB1 genetic diversity modulates response to lithium in bipolar affective disorders', Scientific reports, vol. 11, no. 1, 17823. https://doi.org/10.1038/s41598-021-97140-7

@article{0582c5bd01074860851739d41c1102a1,

title = "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 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.",

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

note = "Publisher Copyright: {\textcopyright} 2021, The Author(s).",

year = "2021",

month = dec,

doi = "10.1038/s41598-021-97140-7",

language = "English (US)",

volume = "11",

journal = "Scientific reports",

issn = "2045-2322",

publisher = "Nature Publishing Group",

number = "1",

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TY - JOUR

T1 - HLA-DRB1 and HLA-DQB1 genetic diversity modulates response to lithium in bipolar affective disorders

AU - Le Clerc, Sigrid

AU - Lombardi, Laura

AU - Baune, Bernhard T.

AU - Amare, Azmeraw T.

AU - Schubert, Klaus Oliver

AU - Hou, Liping

AU - Clark, Scott R.

AU - Papiol, Sergi

AU - Cearns, Micah

AU - Heilbronner, Urs

AU - Degenhardt, Franziska

AU - Tekola-Ayele, Fasil

AU - Hsu, Yi Hsiang

AU - Shekhtman, Tatyana

AU - Adli, Mazda

AU - Akula, Nirmala

AU - Akiyama, Kazufumi

AU - Ardau, Raffaella

AU - Arias, Bárbara

AU - Aubry, Jean Michel

AU - Backlund, Lena

AU - Bhattacharjee, Abesh Kumar

AU - Bellivier, Frank

AU - Benabarre, Antonio

AU - Bengesser, Susanne

AU - Biernacka, Joanna M.

AU - Birner, Armin

AU - Brichant-Petitjean, Clara

AU - Cervantes, Pablo

AU - Chen, Hsi Chung

AU - Chillotti, Caterina

AU - Cichon, Sven

AU - Cruceanu, Cristiana

AU - Czerski, Piotr M.

AU - Dalkner, Nina

AU - Dayer, Alexandre

AU - Del Zompo, Maria

AU - DePaulo, J. Raymond

AU - Étain, Bruno

AU - Jamain, Stephane

AU - Falkai, Peter

AU - Forstner, Andreas J.

AU - Frisen, Louise

AU - Frye, Mark A.

AU - Fullerton, Janice M.

AU - Gard, Sébastien

AU - Garnham, Julie S.

AU - Goes, Fernando S.

AU - Grigoroiu-Serbanescu, Maria

AU - Grof, Paul

AU - Hashimoto, Ryota

AU - Hauser, Joanna

AU - Herms, Stefan

AU - Hoffmann, Per

AU - Jiménez, Esther

AU - Kahn, Jean Pierre

AU - Kassem, Layla

AU - Kuo, Po Hsiu

AU - Kato, Tadafumi

AU - Kelsoe, John R.

AU - Kittel-Schneider, Sarah

AU - Ferensztajn-Rochowiak, Ewa

AU - König, Barbara

AU - Kusumi, Ichiro

AU - Laje, Gonzalo

AU - Landén, Mikael

AU - Lavebratt, Catharina

AU - Leckband, Susan G.

AU - Tortorella, Alfonso

AU - Manchia, Mirko

AU - Martinsson, Lina

AU - McCarthy, Michael J.

AU - McElroy, Susan L.

AU - Colom, Francesc

AU - Millischer, Vincent

AU - Mitjans, Marina

AU - Mondimore, Francis M.

AU - Monteleone, Palmiero

AU - Nievergelt, Caroline M.

AU - Nöthen, Markus M.

AU - Novák, Tomas

AU - O’Donovan, Claire

AU - Ozaki, Norio

AU - Ösby, Urban

AU - Pfennig, Andrea

AU - Potash, James B.

AU - Reif, Andreas

AU - Reininghaus, Eva

AU - Rouleau, Guy A.

AU - Rybakowski, Janusz K.

AU - Schalling, Martin

AU - Schofield, Peter R.

AU - Schweizer, Barbara W.

AU - Severino, Giovanni

AU - Shilling, Paul D.

AU - Shimoda, Katzutaka

AU - Simhandl, Christian

AU - Slaney, Claire M.

AU - Pisanu, Claudia

AU - Squassina, Alessio

AU - Stamm, Thomas

AU - Stopkova, Pavla

AU - Maj, Mario

AU - Turecki, Gustavo

AU - Vieta, Eduard

AU - Veeh, Julia

AU - Witt, Stephanie H.

AU - Wright, Adam

AU - Zandi, Peter P.

AU - Mitchell, Philip B.

AU - Bauer, Michael

AU - Alda, Martin

AU - Rietschel, Marcella

AU - McMahon, Francis J.

AU - Schulze, Thomas G.

AU - Spadoni, Jean Louis

AU - Boukouaci, Wahid

AU - Richard, Jean Romain

AU - Le Corvoisier, Philippe

AU - Barrau, Caroline

AU - Zagury, Jean François

AU - Leboyer, Marion

AU - Tamouza, Ryad

PY - 2021/12

Y1 - 2021/12

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85114641975&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85114641975&partnerID=8YFLogxK

U2 - 10.1038/s41598-021-97140-7

DO - 10.1038/s41598-021-97140-7

M3 - Article

C2 - 34497278

AN - SCOPUS:85114641975

SN - 2045-2322

VL - 11

JO - Scientific reports

JF - Scientific reports

IS - 1

M1 - 17823

ER -

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

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