Association of polygenic score and the involvement of cholinergic and glutamatergic pathways with lithium treatment response in patients with bipolar disorder - Inserm - Institut national de la santé et de la recherche médicale
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 (19) , J Raymond Depaulo (37) , Bruno Étain (26, 27) , Stephane Jamain (38, 39) , Peter Falkai (7, 40) , Andreas J Forstner (9, 10, 34) , Louise Frisen (41, 25) , Mark A Frye (30) , Sébastien Gard (42) , Julie S Garnham (43) , Fernando S Goes (37) , Maria Grigoroiu-Serbanescu (44) , Andreas J Fallgatter (45) , Sophia Stegmaier (45) , Thomas Ethofer (45) , Silvia Biere (46, 47) , Kristiyana Petrova (46, 47) , Ceylan Schuster (46, 47) , Kristina Adorjan (6, 7) , Monika Budde (6, 7) , Maria Heilbronner (6, 7) , Janos L Kalman (6, 7) , Mojtaba Oraki Kohshour (6, 7, 48) , 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 (49) , Volker Arolt (50) , Udo Dannlowski (50) , Detlef Dietrich (51, 52) , Christian Figge (53) , Markus Jäger (54, 55) , Fabian U Lang (54, 55) , Georg Juckel (56, 57) , Carsten Konrad (58) , Jens Reimer (59, 60) , Max Schmauß (61) , Andrea Schmitt (7, 62) , Carsten Spitzer (63) , Martin von Hagen (64) , Jens Wiltfang (65, 66) , Jörg Zimmermann (67) , Till F M Andlauer (68, 69) , Andre Fischer (66) , Felix Bermpohl (17) , Philipp Ritter (70, 71) , Silke Matura (46, 47) , Anna Gryaznova (6, 7) , Irina Falkenberg (72) , Cüneyt Yildiz (72) , Tilo Kircher (72) , Julia Schmidt (65) , Marius Koch (65) , Kathrin Gade (65) , Sarah Trost (65) , Ida S Haussleiter (56, 57) , Martin Lambert (59) , Anja C Rohenkohl (59) , Vivien Kraft (59) , Paul Grof (73) , Ryota Hashimoto (74) , Joanna Hauser (36) , Stefan Herms (9, 10, 33) , Per Hoffmann (9, 10, 33) , Esther Jiménez (21, 28, 22) , Jean-Pierre Kahn (75, 76) , Layla Kassem (13) , Po-Hsiu Kuo (77) , Tadafumi Kato (78) , John Kelsoe (16) , Sarah Kittel-Schneider (46, 79) , Ewa Ferensztajn-Rochowiak (36) , Barbara König (80) , Ichiro Kusumi (81) , Gonzalo Laje (13) , Mikael Landén (82, 41) , Catharina Lavebratt (41, 25) , Marion Leboyer (39, 38, 83) , Susan G Leckband (84) , Alfonso Tortorella (85) , Mirko Manchia (19, 43) , Lina Martinsson (41) , Michael J Mccarthy (16, 84) , Susan Mcelroy (86) , Francesc Colom (87, 21) , Vincent Millischer (41, 25, 88) , Marina Mitjans (21, 20, 89) , Francis M Mondimore (37) , Palmiero Monteleone (90, 91) , Caroline M Nievergelt (16) , Markus M Nöthen (9, 10) , Tomas Novák (92) , Claire O’donovan (43) , Norio Ozaki (93) , Andrea Pfennig (70, 71) , Claudia Pisanu (19) , James B Potash (37) , Andreas Reif (46) , Eva Reininghaus (29) , Guy A Rouleau (35, 94) , Janusz K Rybakowski (36) , Martin Schalling (24, 25) , Peter R Schofield (4, 5) , Barbara W Schweizer (37) , Giovanni Severino (19) , Paul D Shilling (16) , Katzutaka Shimoda (18) , Christian Simhandl (95) , Claire M Slaney (43) , Alessio Squassina (19) , Thomas Stamm (17, 96) , Pavla Stopkova (92) , Mario Maj (91) , Gustavo Turecki (35) , Eduard Vieta (21, 28, 22) , Julia Veeh (46) , Stephanie H Witt (97) , Adam Wright (5, 98) , Peter P Zandi (99) , Philip B Mitchell (5, 98) , Michael Bauer (70, 71) , Martin Alda (43, 92) , Marcella Rietschel (97) , Francis J Mcmahon (13) , Thomas G Schulze (6, 7, 37, 100) , Scott R Clark (1) , Bernhard T Baune (50, 101, 102)
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 = Berlin University Medicine
18 Dokkyo Medical University
19 UniCa - Università degli Studi di Cagliari = University of Cagliari = Université de Cagliari
20 Institute of Biomedicine - IBUB [Barcelona, Spain]
21 UB - Universitat de 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 = Medizinische Universität Graz
30 Mayo Clinic [Rochester]
31 RI-MUHC - Research Institute of the McGill University Health Centre
32 NTUH - 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 JHU - Johns Hopkins University
38 Fondation FondaMental [Créteil]
39 IMRB - Institut Mondor de Recherche Biomédicale
40 Max Planck Institute of Psychiatry
41 Karolinska Institutet [Stockholm]
42 Centre hospitalier Charles Perrens [Bordeaux]
43 Dalhousie University [Halifax]
44 ERA-LEARN - Prof. Dr. Alexandru Obregia Psychiatry Hospital
45 Eberhard Karls Universität Tübingen = University of Tübingen
46 Frankfurt University Hospital
47 Goethe University Frankfurt
48 AJUMS - Ahvaz Jundishapur University of Medical Sciences
49 MHI - Mental Health Institute Berlin [Berlin, Germany]
50 WWU - Westfälische Wilhelms-Universität Münster = University of Münster
51 AMEOS - AMEOS Clinical Center Hildesheim [Hildesheim, Germany]
52 ZSN - Center for Systems Neuroscience [Hannover, Germany]
53 EMS - European Medical School Oldenburg-Groningen [Oldenburg, Germany]
54 Universität Ulm - Ulm University [Ulm, Allemagne]
55 BKH - Bezirkskrankenhaus Günzburg [Günzburg, Germany]
56 RUB - Ruhr University Bochum = Ruhr-Universität Bochum
57 Universitätsklinikum Knappschaftskrankenhaus = University Hospital Knappschaftskrankenhaus [Bochum]
58 ADR - Agaplesion Diakonieklinikum [Rotenburg, Germany]
59 UKE - Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf [Hamburg]
60 HealthNorth [Bremen, Germany]
61 BKH - Bezirkskrankenhaus Augsburg [Augsburg, Germany]
62 USP - Universidade de São Paulo = University of São Paulo
63 University Medical Center Rostock
64 CCWM - Clinical Center Werra-Meißner [Eschwege, Germany]
65 UMG - University Medical Center Göttingen
66 Center for Neurodegenerative Diseases (DZNE), Goettingen
67 kJK - Karl Jaspers Klinik [Bad Zwischenahn, Germany]
68 MRI TUM - Klinikum rechts der Isar
69 TUM - Technische Universität Munchen - Technical University Munich - Université Technique de Munich
70 University Hospital Carl Gustav Carus [Dresden, Germany]
71 TU Dresden - Technische Universität Dresden = Dresden University of Technology
72 Philipps Universität Marburg = Philipps University of Marburg
73 MDCO - Mood Disorders Center of Ottawa
74 NIMH - National Institute of Mental Health
75 CPN - Centre Psychothérapique de Nancy [Laxou]
76 UL - Université de Lorraine
77 NTU - National Taiwan University [Taiwan]
78 RIKEN CBS - RIKEN Center for Brain Science [Wako]
79 University Hospital of Würzburg
80 LK Neunkirchen - Landesklinikum Neunkirchen
81 Hokkaido University Graduate School of Medicine [Sapporo, Japan]
82 Sahlgrenska Academy at University of Gothenburg [Göteborg]
83 Hôpital Henri Mondor
84 VASDHS - VA San Diego Healthcare System [San Diego, CA, USA]
85 UNIPG - Università degli Studi di Perugia = University of Perugia
86 UC - University of Cincinnati
87 IMIM-Hospital del Mar
88 Medizinische Universität Wien = Medical University of Vienna
89 CIBER-SAM - Centro de Investigación Biomédica en Red Salud Mental [Madrid]
90 UNISA - Università degli Studi di Salerno = University of Salerno
91 Università degli studi della Campania "Luigi Vanvitelli" = University of the Study of Campania Luigi Vanvitelli
92 NIMH - National Institute of Mental Health [Klecany, Czech Republic]
93 Nagoya University Graduate School of Medicine [Japon]
94 Montreal Neurological Institute and Hospital
95 SFU - Sigmund Freud University
96 MHB Theodor Fontane - Medizinische Hochschule Brandenburg Theodor Fontane / Brandenburg Medical School Theodor-Fontane
97 University of Heidelberg, Medical Faculty
98 Black Dog Institute [Sydney, Australia]
99 Johns Hopkins Bloomberg School of Public Health [Baltimore]
100 SUNY Upstate Medical University
101 University of Melbourne
102 The Florey Institute of Neuroscience and Mental Health
Azmeraw T Amare
Simon Hartmann
Joanna M Biernacka
Mark A Frye
Julie S Garnham
Fernando S Goes
Julia Schmidt
Marius Koch
Kathrin Gade
Po-Hsiu Kuo
Andreas Reif
Katzutaka Shimoda
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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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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