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Article Dans Une Revue Molecular Psychiatry Année : 2023

Association of polygenic score and the involvement of cholinergic and glutamatergic pathways with lithium treatment response in patients with bipolar disorder

Azmeraw T Amare (1) , Anbupalam Thalamuthu (2) , Klaus Oliver Schubert (1, 3) , Janice M Fullerton (4, 5) , Muktar Ahmed (1) , Simon Hartmann (1) , Sergi Papiol (6, 7) , Urs Heilbronner (6, 8) , Franziska Degenhardt (9, 10, 11) , Fasil Tekola-Ayele (12, 13) , Liping Hou (13) , Yi-Hsiang Hsu (14, 15) , Tatyana Shekhtman (16) , Mazda Adli (17) , Nirmala Akula (13) , Kazufumi Akiyama (18) , Raffaella Ardau (19) , Bárbara Arias (20, 21, 22) , Jean-Michel Aubry (23) , Roland Hasler (23) , Hélène Richard-Lepouriel (23) , Nader Perroud (23) , Lena Backlund (24, 25) , Abesh Kumar Bhattacharjee (16) , Frank Bellivier (26, 27) , Antonio Benabarre (21, 28, 22) , Susanne Bengesser (29) , Joanna M Biernacka (30) , Armin Birner (29) , Cynthia Marie-Claire (26, 27) , Pablo Cervantes (31) , Hsi-Chung Chen (32) , Caterina Chillotti (19) , Sven Cichon (9, 10, 33, 34) , Cristiana Cruceanu (35) , Piotr M Czerski (36) , Nina Dalkner (29) , Maria del Zompo (37) , J Raymond Depaulo (38) , Bruno Étain (26, 27) , Stephane Jamain (39, 40) , Peter Falkai (7, 41) , Andreas J Forstner (9, 10, 34) , Louise Frisen (42, 25) , Mark A Frye (30) , Sébastien Gard (43) , Julie S Garnham (44) , Fernando S Goes (38) , Maria Grigoroiu-Serbanescu (45) , Andreas J Fallgatter (46) , Sophia Stegmaier (47) , Thomas Ethofer (47) , Silvia Biere (48, 49) , Kristiyana Petrova (48, 49) , Ceylan Schuster (48, 49) , Kristina Adorjan (6, 7) , Monika Budde (6, 7) , Maria Heilbronner (6, 7) , Janos L Kalman (6, 7) , Mojtaba Oraki Kohshour (6, 7, 50) , Daniela Reich-Erkelenz (6, 7) , Sabrina K Schaupp (6, 7) , Eva C Schulte (6, 7) , Fanny Senner (6, 7) , Thomas Vogl (6, 7) , Ion-George Anghelescu (51) , Volker Arolt (52) , Udo Dannlowski (52) , Detlef Dietrich (53, 54) , Christian Figge (55) , Markus Jäger (56, 57) , Fabian U Lang (56, 57) , Georg Juckel (58, 59) , Carsten Konrad (60) , Jens Reimer (61, 62) , Max Schmauß (63) , Andrea Schmitt (7, 64) , Carsten Spitzer (65) , Martin von Hagen (66) , Jens Wiltfang (67, 68) , Jörg Zimmermann (69) , Till F M Andlauer (70, 71) , Andre Fischer (68) , Felix Bermpohl (17) , Philipp Ritter (72, 73) , Silke Matura (48, 49) , Anna Gryaznova (6, 7) , Irina Falkenberg (74) , Cüneyt Yildiz (74) , Tilo Kircher (74) , Julia Schmidt (67) , Marius Koch (67) , Kathrin Gade (67) , Sarah Trost (67) , Ida S Haussleiter (58, 59) , Martin Lambert (61) , Anja C Rohenkohl (61) , Vivien Kraft (61) , Paul Grof (75) , Ryota Hashimoto (76) , Joanna Hauser (36) , Stefan Herms (9, 10, 33) , Per Hoffmann (9, 10, 33) , Esther Jiménez (21, 28, 22) , Jean-Pierre Kahn (77, 78) , Layla Kassem (13) , Po-Hsiu Kuo (79) , Tadafumi Kato (80) , John Kelsoe (16) , Sarah Kittel-Schneider (48, 81) , Ewa Ferensztajn-Rochowiak (36) , Barbara König (82) , Ichiro Kusumi (83) , Gonzalo Laje (13) , Mikael Landén (84, 42) , Catharina Lavebratt (42, 25) , Marion Leboyer (40, 39, 85) , Susan G Leckband (86) , Alfonso Tortorella (87) , Mirko Manchia (19, 44) , Lina Martinsson (42) , Michael J Mccarthy (16, 86) , Susan Mcelroy (88) , Francesc Colom (89, 21) , Vincent Millischer (42, 25, 90) , Marina Mitjans (21, 20, 91) , Francis M Mondimore (38) , Palmiero Monteleone (92, 93) , Caroline M Nievergelt (16) , Markus M Nöthen (9, 10) , Tomas Novák (94) , Claire O’donovan (44) , Norio Ozaki (95) , Andrea Pfennig (72, 73) , Claudia Pisanu (37) , James B Potash (38) , Andreas Reif (48) , Eva Reininghaus (29) , Guy A Rouleau (35, 96) , Janusz K Rybakowski (36) , Martin Schalling (24, 25) , Peter R Schofield (4, 5) , Barbara W Schweizer (38) , Giovanni Severino (37) , Paul D Shilling (16) , Katzutaka Shimoda (18) , Christian Simhandl (97) , Claire M Slaney (44) , Alessio Squassina (37) , Thomas Stamm (17, 98) , Pavla Stopkova (94) , Mario Maj (93) , Gustavo Turecki (35) , Eduard Vieta (21, 28, 22) , Julia Veeh (48) , Stephanie H Witt (99) , Adam Wright (5, 100) , Peter P Zandi (101) , Philip B Mitchell (5, 100) , Michael Bauer (72, 73) , Martin Alda (44, 94) , Marcella Rietschel (99) , Francis J Mcmahon (13) , Thomas G Schulze (6, 7, 38, 102) , Scott R Clark (1) , Bernhard T Baune (52, 103, 104)
1 University of Adelaide
2 Centre for Healthy Brain Ageing (CHeBA), School of Psychiatry, UNSW Medicine, University of New South Wales, Sydney
3 Mental Health Services [Adelaide, SA, Australia]
4 NeuRA - Neuroscience Research Australia
5 UNSW - University of New South Wales [Sydney]
6 IPPG - Institute of Psychiatric Phenomics and Genomics
7 LMU - Ludwig Maximilian University [Munich] = Ludwig Maximilians Universität München
8 LMU - Institut für Informatik [München/Munich]
9 Universität Bonn = University of Bonn
10 University Hospital Bonn
11 Universität Duisburg-Essen = University of Duisburg-Essen [Essen]
12 NICHD - Eunice Kennedy Shriver National Institute of Child Health and Human Development
13 NIH - National Institutes of Health [Bethesda, MD, USA]
14 HMS - Harvard Medical School [Boston]
15 Harvard School of Public Health
16 UC San Diego - University of California [San Diego]
17 Charité - UniversitätsMedizin = Charité - University Hospital [Berlin]
18 Dokkyo Medical University
19 UniCa - Università degli Studi di Cagliari = University of Cagliari
20 Institute of Biomedicine - IBUB [Barcelona, Spain]
21 University of Barcelona
22 CIBERSAM - Centro de Investigación Biomédica en Red de Salud Mental [Barcelona, Spain]
23 HUG - Geneva University Hospital
24 Karolinska Institute
25 Karolinska University Hospital [Stockholm]
26 OPTeN (UMR_S 1144 / U1144) - Optimisation thérapeutique en Neuropsychopharmacologie
27 Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris]
28 IDIBAPS - Institut d'Investigacions Biomèdiques August Pi i Sunyer
29 Medical University of Graz
30 Mayo Clinic [Rochester]
31 RI-MUHC - Research Institute of the McGill University Health Centre
32 National Taiwan University Hospital [Taipei]
33 University Hospital Basel [Basel]
34 INM-1 - Institute of Neuroscience and Medicine [Jülich]
35 McGill University = Université McGill [Montréal, Canada]
36 PUMS - Poznan University of Medical Sciences [Poland]
37 University of Cagliari
38 JHU - Johns Hopkins University
39 Fondation FondaMental [Créteil]
40 IMRB - Institut Mondor de Recherche Biomédicale
41 Max Planck Institute of Psychiatry
42 Karolinska Institutet [Stockholm]
43 Centre hospitalier Charles Perrens [Bordeaux]
44 Dalhousie University [Halifax]
45 ERA-LEARN - Prof. Dr. Alexandru Obregia Psychiatry Hospital
46 University of Tübingen
47 Eberhard Karls Universität Tübingen = Eberhard Karls University of Tuebingen
48 Frankfurt University Hospital
49 Goethe University Frankfurt
50 AJUMS - Ahvaz Jundishapur University of Medical Sciences
51 MHI - Mental Health Institute Berlin [Berlin, Germany]
52 WWU - Westfälische Wilhelms-Universität Münster = University of Münster
53 AMEOS - AMEOS Clinical Center Hildesheim [Hildesheim, Germany]
54 ZSN - Center for Systems Neuroscience [Hannover, Germany]
55 EMS - European Medical School Oldenburg-Groningen [Oldenburg, Germany]
56 Universität Ulm - Ulm University [Ulm, Allemagne]
57 BKH - Bezirkskrankenhaus Günzburg [Günzburg, Germany]
58 RUB - Ruhr University Bochum = Ruhr-Universität Bochum
59 Universitätsklinikum Knappschaftskrankenhaus = University Hospital Knappschaftskrankenhaus [Bochum]
60 ADR - Agaplesion Diakonieklinikum [Rotenburg, Germany]
61 UKE - Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf [Hamburg]
62 HealthNorth [Bremen, Germany]
63 BKH - Bezirkskrankenhaus Augsburg [Augsburg, Germany]
64 USP - Universidade de São Paulo = University of São Paulo
65 University Medical Center Rostock
66 CCWM - Clinical Center Werra-Meißner [Eschwege, Germany]
67 UMG - University Medical Center Göttingen
68 Center for Neurodegenerative Diseases (DZNE), Goettingen
69 kJK - Karl Jaspers Klinik [Bad Zwischenahn, Germany]
70 MRI TUM - Klinikum rechts der Isar
71 TUM - Technische Universität Munchen - Technical University Munich - Université Technique de Munich
72 University Hospital Carl Gustav Carus [Dresden, Germany]
73 TU Dresden - Technische Universität Dresden = Dresden University of Technology
74 Philipps Universität Marburg = Philipps University of Marburg
75 MDCO - Mood Disorders Center of Ottawa
76 NIMH - National Institute of Mental Health
77 CPN - Centre Psychothérapique de Nancy [Laxou]
78 UL - Université de Lorraine
79 NTU - National Taiwan University [Taiwan]
80 RIKEN CBS - RIKEN Center for Brain Science [Wako]
81 University Hospital of Würzburg
82 LK Neunkirchen - Landesklinikum Neunkirchen
83 Hokkaido University Graduate School of Medicine [Sapporo, Japan]
84 Sahlgrenska Academy at University of Gothenburg [Göteborg]
85 Hôpital Henri Mondor
86 VASDHS - VA San Diego Healthcare System [San Diego, CA, USA]
87 UNIPG - Università degli Studi di Perugia = University of Perugia
88 UC - University of Cincinnati
89 IMIM-Hospital del Mar
90 Medizinische Universität Wien = Medical University of Vienna
91 CIBER-SAM - Centro de Investigación Biomédica en Red Salud Mental [Madrid]
92 UNISA - Università degli Studi di Salerno = University of Salerno
93 Università degli studi della Campania "Luigi Vanvitelli" = University of the Study of Campania Luigi Vanvitelli
94 NIMH - National Institute of Mental Health [Klecany, Czech Republic]
95 Nagoya University Graduate School of Medicine [Japon]
96 Montreal Neurological Institute and Hospital
97 SFU - Sigmund Freud University
98 MHB Theodor Fontane - Medizinische Hochschule Brandenburg Theodor Fontane / Brandenburg Medical School Theodor-Fontane
99 University of Heidelberg, Medical Faculty
100 Black Dog Institute [Sydney, Australia]
101 Johns Hopkins Bloomberg School of Public Health [Baltimore]
102 SUNY Upstate Medical University
103 University of Melbourne
104 The Florey Institute of Neuroscience and Mental Health
Azmeraw T Amare
Simon Hartmann
Joanna M Biernacka
Maria del Zompo
Mark A Frye
Julie S Garnham
Fernando S Goes
Julia Schmidt
Marius Koch
Kathrin Gade
Po-Hsiu Kuo
Claudia Pisanu
Andreas Reif
Eva Reininghaus
Giovanni Severino
Katzutaka Shimoda
Alessio Squassina
Scott R Clark

Résumé

Lithium is regarded as the first-line treatment for bipolar disorder (BD), a severe and disabling mental health disorder that affects about 1% of the population worldwide. Nevertheless, lithium is not consistently effective, with only 30% of patients showing a favorable response to treatment. To provide personalized treatment options for bipolar patients, it is essential to identify prediction biomarkers such as polygenic scores. In this study, we developed a polygenic score for lithium treatment response (Li + PGS) in patients with BD. To gain further insights into lithium's possible molecular mechanism of action, we performed a genome-wide gene-based analysis. Using polygenic score modeling, via methods incorporating Bayesian regression and continuous shrinkage priors, Li + PGS was developed in the International Consortium of Lithium Genetics cohort (ConLi + Gen: N = 2367) and replicated in the combined PsyCourse (N = 89) and BipoLife (N = 102) studies. The associations of Li + PGS and lithium treatment responsedefined in a continuous ALDA scale and a categorical outcome (good response vs. poor response) were tested using regression models, each adjusted for the covariates: age, sex, and the first four genetic principal components. Statistical significance was determined at P < 0.05. Li + PGS was positively associated with lithium treatment response in the ConLi + Gen cohort, in both the categorical (P = 9.8 × 10 −12 , R 2 = 1.9%) and continuous (P = 6.4 × 10 −9 , R 2 = 2.6%) outcomes. Compared to bipolar patients in the 1 st decile of the risk distribution, individuals in the 10 th decile had 3.47-fold (95%CI: 2.22-5.47) higher odds of responding favorably to lithium. The results were replicated in the independent cohorts for the categorical treatment outcome (P = 3.9 × 10 −4 , R 2 = 0.9%), but not for the continuous outcome (P = 0.13). Gene-based analyses revealed 36 candidate genes that are enriched in biological pathways controlled by glutamate and acetylcholine. Li + PGS may be useful in the development of pharmacogenomic testing strategies by enabling a classification of bipolar patients according to their response to treatment.
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Origine : Publication financée par une institution
Licence : CC BY - Paternité

Dates et versions

inserm-04165233 , version 1 (18-07-2023)

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Azmeraw T Amare, Anbupalam Thalamuthu, Klaus Oliver Schubert, Janice M Fullerton, Muktar Ahmed, et al.. Association of polygenic score and the involvement of cholinergic and glutamatergic pathways with lithium treatment response in patients with bipolar disorder. Molecular Psychiatry, 2023, ⟨10.1038/s41380-023-02149-1⟩. ⟨inserm-04165233⟩
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