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 | |
| State | Published - Dec 2021 |
ASJC Scopus subject areas
- General
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HLA-DRB1 and HLA-DQB1 genetic diversity modulates response to lithium in bipolar affective disorders. / Le Clerc, Sigrid; Lombardi, Laura; Baune, Bernhard T. et al.
In: Scientific reports, Vol. 11, No. 1, 17823, 12.2021.Research output: Contribution to journal › Article › peer-review
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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
N1 - Funding Information: This manuscript was written under the framework of Agence Nationale de la Recherche (I-GIVE ANR-13-SAMA-0004-01), INSERM (Institut National de la Santé et de la Recherche Médicale) and Fondation FondaMen-tal. Laura Lombardi benefits from a fellowship n° FDM202006011305 from Fondation de la Recherche Médicale (FRM). Sven Cichon. and Andreas J Forstner received support from the Swiss National Science Foundation / German Research Foundation (SNSF 310030L_182731/1). This work was in part funded by the Deutsche Forschun-gsgemeinschaft (DFG; grant no RI 908/7-1; grant FOR2107, RI 908/11-1 to Marcella Rietschel, Michael Bauer, and Thomas G Schulze, NO 246/10-1 to MMN) and the Intramural Research Program of the National Institute of Mental Health (ZIA-MH00284311; NCT00001174). The genotyping was in part funded by the German Federal Ministry of Education and Research (BMBF) through the Integrated Network IntegraMent (Integrated Understanding of Causes and Mechanisms in Mental Disorders), under the auspices of the e:Med. This work was supported by the NIH grants P50CA89392 from the National Cancer Institute and 5K02DA021237 from the National Institute of Drug Abuse. The Canadian part of the study was supported by a grant #64410 from the Canadian Institutes of Health Research to MAl. Collection and phenotyping of the Australian UNSW sample was funded by an Australian NHMRC Program Grant (No. 1037196).The collection of the Barcelona sample was supported by the Centro de Investigación en Red de Salud Mental (CIBERSAM) IDIBAPS (grant numbers PI080247, PI1200906, PI12/00018), and Secretaria d’Universitats i Recerca del Departament d’Economia i Coneixement (2014SGR1636 and 2014SGR398). Genotyping for part of the Swedish sample was funded by the Stanley Center for Psychiatric Research at the Broad Institute. The Swedish Research Council, the Stockholm County Council, Karolinska Institutet, and the Söderström-Königska Foundation supported this research through grants awarded to Drs Backlund, Frisen, Lavebratt, and Schalling. The collection of the Geneva sample was supported by grants Synapsy–The Synaptic Basis of Mental Diseases 51NF40-158776 and 32003B-125469 from the Swiss National Foundation. The work by the French group was supported by INSERM (Institut National de la Santé et de la Recherche Médicale), AP-HP (Assistance Publique des Hôpitaux de Paris), the Fondation FondaMental (RTRS Santé Mentale), and the labex Bio-PSY (Investissements d’Avenir program managed by the ANR under reference ANR-11-IDEX-0004-02). The collection of the Romanian sample was supported by a grant from Unitatea Execu-tiva pentru Finantarea Invatamantului Superior, a Cercetarii, Dezvoltarii si Inovarii (Dr Grigoroiu-Serbanescu). The collection of the Czech sample was supported by the project Nr. LO1611 with a financial support from the MEYS under the NPU I program and by the Czech Science Foundation, grant Nr. 17-07070S. Funding Information: The authors declare that they have no competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. MAd has received a grant from Servier, speaker’s fees from Servier, Lundbeck, Aristo, Parexel, Gilead, ViiV, Deutsche Bank, MSD, and MyTomorrows, plus a non-fi nancial support from Lundbeck. KA has received speaker’s fees from Taisho Toyama Pharmaceutical. MAl is funded by a grant of the Canadian Institutes of Health Research. MB has received speaker’s fees from AstraZeneca, Pfi zer, Lilly, Lundbeck, GlaxoSmithKline, Servier, and Ferrer Internacional. BÉ received non-financial support from Labex Biopsy and Fondation Fondamental. RH received grants and speaker honoraria from Dainippon Sumitomo Pharma and Novartis plus speaker honoraria from Eli Lilly Japan, GlaxoSmithKline, Hisamitsu Pharmaceutical, Janssen Pharmaceutical, Nippon Zoki Pharmaceutical, Otsuka Pharmaceutical, Astellas Pharma, Pfi zer, and the Yoshitomiyakuhin Corporation. TK received a grant from Takeda Pharmaceutical and fees from Kyowa Hakko Kirin, Eli Lilly Japan, Otsuka Pharmaceutical, GlaxoSmithKline, Taisho Toyama Pharmaceutical, Dainippon Sumitomo Pharma, Meiji Seika Pharma, Pfi zer Japan, Mochida Pharmaceutical, Shionogi & Co, Janssen Pharmaceutical, Yoshitomiyakuhin Corporation, Agilent Technologies, Astellas Pharma, and Wako Pure Chemical Industries. IK received grants and fees from Dainippon Sumitomo Pharma, Eisai, Eli Lilly, GlaxoSmithKline, Kyowa Hakko Kirin, Meiji Seika Pharma, MSD, Novartis, Otsuka, Ono Pharmaceutical, Pfi zer, Tanabe Mitsubishi Pharma, Takeda Pharmaceutical, Shionogi, and Yoshitomi Pharmaceutical; he received grants from AbbVie GK, Asahi Kasei Pharma, Boehringer Ingelheim, Chugai Pharmaceutical, and Daiichi Sankyo and fees from Astellas Pharma and Janssen Pharmaceutical. MJM served as unpaid consultant for Pathway Genomic (San Diego, USA). SLM received a grant and fees from Naurex and Shire, further grants from Alkermes, Cephalon, Forest, Marriott Foundation, Orexigen Therapeutics, and Takeda Pharmaceutical, he further has served on the advisory boards for Bracket, Hoff mann-La Roche, MedAvante, Sunovion and received fees from Novo Nordisk. PRS received a grant from NHMRC. TGS received a grant and fees from Roche Pharmaceuticals. TSt received personal fees from Servier, Lundbeck, and Bristol-Myers Squibb. EV has received grants and served as consultant, advisor or CME speaker for the following entities (unrelated to the present work): AB-Biotics, Abbott, Allergan, Angelini, Dainippon Sumitomo Pharma, Ferrer, Gedeon Richter, GH Research, Janssen, Lundbeck, Otsuka, Sage, Sanofi-Aventis, and Takeda. FC In the last two years he has served as a speaker or in the advisory board of the following companies: Abott, Sandoz and Sanofi and he receives unrestricted research support from Telefónica Alpha. Publisher Copyright: © 2021, The Author(s).
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 -