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Association of polygenic score for major depression with response to lithium in patients with bipolar disorder

Azmeraw Amare 1, 2 Klaus Oliver Schubert 1, 3 Liping Hou 4 Scott Clark 1 Sergi Papiol 5 Micah Cearns 1 Urs Heilbronner 5, 6 Franziska Degenhardt 7 Fasil Tekola-Ayele 4, 8 yi-Hsiang Hsu 9, 10 Tatyana Shekhtman 11 Mazda Adli 12 Nirmala Akula 4 Kazufumi Akiyama 13 Raffaella Ardau 14 Bárbara Arias 15, 16 Jean-Michel Aubry 17 Lena Backlund 18, 19 Abesh Kumar Bhattacharjee 11 Frank Bellivier 20 Antonio Benabarre 21, 16 Susanne Bengesser 22 Joanna Biernacka 23 Armin Birner 22 Clara Brichant-Petitjean 20 Pablo Cervantes 24 Hsi-Chung Chen 25 Caterina Chillotti 14 Sven Cichon 7, 26 Cristiana Cruceanu 24 Piotr Czerski 27 Nina Dalkner 22 Alexandre Dayer 17 Maria del Zompo 14 J. Raymond Depaulo 28 Bruno Étain 20 Stephane Jamain 29, 30, 31 Peter Falkai 5 Andreas Forstner 7, 26, 32 Louise Frisen 18, 19 Mark Frye 23 Janice Fullerton 33, 34 Sébastien Gard 35 Julie Garnham 36 Fernando Goes 28 Maria Grigoroiu-Serbanescu 37 Paul Grof 38 Ryota Hashimoto 39, 40 Joanna Hauser 27 Stefan Herms 7, 26 Per Hoffmann 7, 26 Andrea Hofmann 7 Esther Jiménez 21, 41 Jean-Pierre Kahn 42, 43 Layla Kassem 4, 44 Po-Hsiu Kuo 25 Tadafumi Kato 45 John Kelsoe 11 Sarah Kittel-Schneider 46 Sebastian Kliwicki 27 Barbara König 47 Ichiro Kusumi 48 Gonzalo Laje 4, 44 Mikael Landén 49, 18 Catharina Lavebratt 18, 19 Marion Leboyer 29, 30, 31 Susan Leckband 50 Alfonso Tortorella 51 Mirko Manchia 14, 36 Lina Martinsson 18 Michael Mccarthy 11, 50 Susan Mcelroy 52 Francesc Colom 53, 16 Marina Mitjans 16, 54 Francis Mondimore 28 Palmiero Monteleone 55, 56 Caroline Nievergelt 11 Markus Nöthen 7 Tomas Novák 57 Claire O’donovan 36 Norio Ozaki 58 Urban Ösby 19 Andrea Pfennig 59 James Potash 28 Andreas Reif 46 Eva Reininghaus 60 Guy Rouleau 61 Janusz Rybakowski 27 Martin Schalling 18, 19 Peter Schofield 33, 34 Barbara Schweizer 28 Giovanni Severino 14 Paul Shilling 11 Katzutaka Shimoda 13 Christian Simhandl 62 Claire Slaney 36 Alessio Squassina 14 Thomas Stamm 12 Pavla Stopkova 57 Mario Maj 14 Gustavo Turecki 63 Eduard Vieta 21, 16 Julia Veeh 46 Stephanie Witt 64 Adam Wright 34, 65 Peter Zandi 66 Philip Mitchell 34, 65 Michael Bauer 59 Martin Alda 36, 57 Marcella Rietschel 64 Francis Mcmahon 4, 44 Thomas Schulze 64, 4, 44, 6, 28 Bernhard Baune 67, 68, 69 
1 University of Adelaide
2 SAHMRI - South Australian Health and Medical Research Institute [ Adelaide]
3 Mental Health Services [Adelaide, SA, Australia]
4 NIMH - National Institute of Mental Health
5 LMU - Ludwig Maximilian University [Munich]
6 Georg-August-University [Göttingen]
7 Institut für Genetik - Universität Bonn / Institute of Genetics - University of Bonn
8 NICHD - Eunice Kennedy Shriver National Institute of Child Health and Human Development
9 HMS - Harvard Medical School [Boston]
10 Harvard School of Public Health
11 UC San Diego - University of California [San Diego]
12 Charité - UniversitätsMedizin = Charité - University Hospital [Berlin]
13 Dokkyo Medical University
14 Universita degli Studi di Cagliari [Cagliari]
15 UAB - Universitat Autònoma de Barcelona
16 CIBERSAM - Centro de Investigación Biomédica en Red de Salud Mental [Barcelona, Spain]
17 HUG - Geneva University Hospital
18 Karolinska Institutet [Stockholm]
19 Karolinska University Hospital [Stockholm]
20 OPTeN (UMR_S_1144 / U1144) - Optimisation thérapeutique en Neuropsychopharmacologie
21 IDIBAPS - Institut d'Investigacions Biomèdiques August Pi i Sunyer
22 Karl-Franzens-Universität [Graz, Autriche]
23 Mayo Clinic [Rochester]
24 MUHC - McGill University Health Center [Montreal]
25 NTU - National Taiwan University [Taiwan]
26 University Hospital Basel [Basel]
27 PUMS - Poznan University of Medical Sciences [Poland]
28 JHU - Johns Hopkins University
29 IMRB - Institut Mondor de Recherche Biomédicale
30 Fondation FondaMental [Créteil]
31 U955 Inserm - UPEC - IMRB - "Neuropsychiatrie translationnelle" [Créteil]
IMRB - Institut Mondor de Recherche Biomédicale
32 Unibas - University of Basel
33 NRA - Neuroscience Research Australia [Sydney, NSW, Australia]
34 UNSW - University of New South Wales [Sydney]
35 Psychiatrie de l'enfant et de l'adolescent [CH C. Perrens, Bordeaux]
36 Dalhousie University [Halifax]
37 "Prof. Dr. Alexandru Obregia" Clinical Hospital of Psychiatry [Bucharest, Romania]
38 MDCO - Mood Disorders Center of Ottawa
39 Osaka University [Osaka]
40 Graduate School of Medicine [Osaka]
41 CIBER-SAM - Centro de Investigación Biomédica en Red Salud Mental [Madrid]
42 Psychiatrie et Psychologie Clinique de Liaison [CHRU Nancy]
43 CPN - Centre Psychothérapique de Nancy
44 NIH - National Institutes of Health [Bethesda]
45 RIKEN - Environmental Molecular Biology Laboratory
46 Goethe-University Frankfurt am Main
47 LK Neunkirchen - Landesklinikum Neunkirchen
48 Hokkaido University Graduate School of Medicine [Sapporo, Japan]
49 Sahlgrenska Academy at University of Gothenburg [Göteborg]
50 Research Service VA San Diego Healthcare System
51 UNIPG - Università degli Studi di Perugia
52 UC - University of Cincinnati
53 IMIM-Hospital del Mar
54 MPI - Max Planck Institute of Experimental Medicine [Göttingen]
55 UNISA - University of Salerno
56 University of the Study of Campania Luigi Vanvitelli
57 NIMH - National Institute of Mental Health [Klecany, Czech Republic]
58 Nagoya University Graduate School of Medicine [Japon]
59 TU Dresden - Technische Universität Dresden = Dresden University of Technology
60 Medical University Graz
61 Montreal Neurological Institute and Hospital
62 SFU - Sigmund Freud University
63 Douglas Mental Health University Institute [Montréal]
64 University of Heidelberg, Medical Faculty
65 Black Dog Institute [Sydney, Australia]
66 Johns Hopkins Bloomberg School of Public Health [Baltimore]
67 WWU - Westfälische Wilhelms-Universität Münster = University of Münster
68 Melbourne Medical School [Melbourne]
69 The Florey Institute of Neuroscience and Mental Health [Parkville, VIC, Australie]
Abstract : Lithium is a first-line medication for bipolar disorder (BD), but only one in three patients respond optimally to the drug. Since evidence shows a strong clinical and genetic overlap between depression and bipolar disorder, we investigated whether a polygenic susceptibility to major depression is associated with response to lithium treatment in patients with BD. Weighted polygenic scores (PGSs) were computed for major depression (MD) at different GWAS p value thresholds using genetic data obtained from 2586 bipolar patients who received lithium treatment and took part in the Consortium on Lithium Genetics (ConLi+Gen) study. Summary statistics from genome-wide association studies in MD (135,458 cases and 344,901 controls) from the Psychiatric Genomics Consortium (PGC) were used for PGS weighting. Response to lithium treatment was defined by continuous scores and categorical outcome (responders versus non-responders) using measurements on the Alda scale. Associations between PGSs of MD and lithium treatment response were assessed using a linear and binary logistic regression modeling for the continuous and categorical outcomes, respectively. The analysis was performed for the entire cohort, and for European and Asian sub-samples. The PGSs for MD were significantly associated with lithium treatment response in multi-ethnic, European or Asian populations, at various p value thresholds. Bipolar patients with a low polygenic load for MD were more likely to respond well to lithium, compared to those patients with high polygenic load [lowest vs highest PGS quartiles, multi-ethnic sample: OR = 1.54 (95% CI: 1.18-2.01) and European sample: OR = 1.75 (95% CI: 1.30-2.36)]. While our analysis in the Asian sample found equivalent effect size in the same direction: OR = 1.71 (95% CI: 0.61-4.90), this was not statistically significant. Using PGS decile comparison, we found a similar trend of association between a high genetic loading for MD and lower response to lithium. Our findings underscore the genetic contribution to lithium response in BD and support the emerging concept of a lithium-responsive biotype in BD.
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https://www.hal.inserm.fr/inserm-03130374
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Submitted on : Wednesday, February 3, 2021 - 3:15:30 PM
Last modification on : Wednesday, June 29, 2022 - 1:42:25 PM

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INSERM | UPEC-UPEM | IMRB | UPEC | UNIV-PARIS | UP-SANTE

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Azmeraw Amare, Klaus Oliver Schubert, Liping Hou, Scott Clark, Sergi Papiol, et al.. Association of polygenic score for major depression with response to lithium in patients with bipolar disorder. Molecular Psychiatry, Nature Publishing Group, 2021, Online ahead of print. ⟨10.1038/s41380-020-0689-5⟩. ⟨inserm-03130374⟩

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