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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 Peter Falkai 5 Andreas Forstner 7, 26, 31 Louise Frisen 18, 19 Mark Frye 23 Janice Fullerton 32, 33 Sébastien Gard 34 Julie Garnham 35 Fernando Goes 28 Maria Grigoroiu-Serbanescu 36 Paul Grof 37 Ryota Hashimoto 38, 39 Joanna Hauser 27 Stefan Herms 7, 26 Per Hoffmann 7, 26 Andrea Hofmann 7 Esther Jiménez 21, 40 Jean-Pierre Kahn 41, 42 Layla Kassem 4, 43 Po-Hsiu Kuo 25 Tadafumi Kato 44 John Kelsoe 11 Sarah Kittel-Schneider 45 Sebastian Kliwicki 27 Barbara König 46 Ichiro Kusumi 47 Gonzalo Laje 4, 43 Mikael Landén 48, 18 Catharina Lavebratt 18, 19 Marion Leboyer 29, 30 Susan Leckband 49 Alfonso Tortorella 50 Mirko Manchia 14, 35 Lina Martinsson 18 Michael Mccarthy 11, 49 Susan Mcelroy 51 Francesc Colom 52, 16 Marina Mitjans 16, 53 Francis Mondimore 28 Palmiero Monteleone 54, 55 Caroline Nievergelt 11 Markus Nöthen 7 Tomas Novák 56 Claire O’donovan 35 Norio Ozaki 57 Urban Ösby 19 Andrea Pfennig 58 James Potash 28 Andreas Reif 45 Eva Reininghaus 59 Guy Rouleau 60 Janusz Rybakowski 27 Martin Schalling 18, 19 Peter Schofield 32, 33 Barbara Schweizer 28 Giovanni Severino 14 Paul Shilling 11 Katzutaka Shimoda 13 Christian Simhandl 61 Claire Slaney 35 Alessio Squassina 14 Thomas Stamm 12 Pavla Stopkova 56 Mario Maj 14 Gustavo Turecki 62 Eduard Vieta 21, 16 Julia Veeh 45 Stephanie Witt 63 Adam Wright 33, 64 Peter Zandi 65 Philip Mitchell 33, 64 Michael Bauer 58 Martin Alda 35, 56 Marcella Rietschel 63 Francis Mcmahon 4, 43 Thomas Schulze 63, 4, 43, 6, 28 Bernhard Baune 66, 67, 68
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 Berlin / Charite - University Medicine 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 VariaPsy - U1144 - Optimisation Thérapeutique en Neuropsychopharmacologie
21 IDIBAPS - Institut d'Investigacions Biomèdiques August Pi i Sunyer
22 University of Graz
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 Unibas - University of Basel
32 NRA - Neuroscience Research Australia [Sydney, NSW, Australia]
33 UNSW - University of New South Wales [Sydney]
34 Psychiatrie de l'enfant et de l'adolescent [CH C. Perrens, Bordeaux]
35 Dalhousie University [Halifax]
36 "Prof. Dr. Alexandru Obregia" Clinical Hospital of Psychiatry [Bucharest, Romania]
37 MDCO - Mood Disorders Center of Ottawa
38 Osaka University [Osaka]
39 Graduate School of Medicine [Osaka]
40 CIBER-SAM - Centro de Investigación Biomédica en Red Salud Mental [Madrid]
41 Psychiatrie et Psychologie Clinique de Liaison [CHRU Nancy]
42 CPN - Centre Psychothérapique de Nancy
43 NIH - National Institutes of Health [Bethesda]
44 RIKEN - Environmental Molecular Biology Laboratory
45 Goethe-University Frankfurt am Main
46 LK Neunkirchen - Landesklinikum Neunkirchen
47 Hokkaido University Graduate School of Medicine [Sapporo, Japan]
48 Sahlgrenska Academy at University of Gothenburg [Göteborg]
49 Research Service VA San Diego Healthcare System
50 UNIPG - Università degli Studi di Perugia
51 UC - University of Cincinnati
52 IMIM-Hospital del Mar
53 MPI - Max Planck Institute of Experimental Medicine [Göttingen]
54 UNISA - University of Salerno
55 University of the Study of Campania Luigi Vanvitelli
56 NIMH - National Institute of Mental Health [Klecany, Czech Republic]
57 Nagoya University Graduate School of Medicine [Japon]
58 TU Dresden - Technische Universität Dresden = Dresden University of Technology
59 Medical University Graz
60 Montreal Neurological Institute and Hospital
61 SFU - Sigmund Freud University
62 Douglas Mental Health University Institute [Montréal]
63 University of Heidelberg, Medical Faculty
64 Black Dog Institute [Sydney, Australia]
65 Johns Hopkins Bloomberg School of Public Health [Baltimore]
66 University of Münster
67 Melbourne Medical School [Melbourne]
68 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
Contributor : Stéphane Jamain <>
Submitted on : Wednesday, February 3, 2021 - 3:15:30 PM
Last modification on : Wednesday, June 2, 2021 - 4:26:42 PM

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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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