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
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
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Klaus Oliver Schubert
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Janice M Fullerton
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Simon Hartmann
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Sergi Papiol
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Urs Heilbronner
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Bárbara Arias
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Joanna M Biernacka
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Cynthia Marie-Claire
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Hsi-Chung Chen
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Sven Cichon
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Cristiana Cruceanu
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Piotr M Czerski
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Maria del Zompo
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Bruno Étain
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Stephane Jamain
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Andreas J Forstner
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Julie S Garnham
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Fernando S Goes
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Maria Grigoroiu-Serbanescu
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Janos L Kalman
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Eva C Schulte
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Jens Reimer
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Jens Wiltfang
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Till F M Andlauer
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Philipp Ritter
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Cüneyt Yildiz
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Julia Schmidt
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Marius Koch
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Kathrin Gade
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Joanna Hauser
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Po-Hsiu Kuo
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Sarah Kittel-Schneider
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Ichiro Kusumi
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Mikael Landén
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Catharina Lavebratt
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Marion Leboyer
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Alfonso Tortorella
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Michael J Mccarthy
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Francesc Colom
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Vincent Millischer
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Markus M Nöthen
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Tomas Novák
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Claudia Pisanu
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Andreas Reif
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Eva Reininghaus
- Fonction : Auteur
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Guy A Rouleau
- Fonction : Auteur
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Janusz K Rybakowski
- Fonction : Auteur
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Martin Schalling
- Fonction : Auteur
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Peter R Schofield
- Fonction : Auteur
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Giovanni Severino
- Fonction : Auteur
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Katzutaka Shimoda
- Fonction : Auteur
- PersonId : 805593
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Alessio Squassina
- Fonction : Auteur
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Pavla Stopkova
- Fonction : Auteur
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Gustavo Turecki
- Fonction : Auteur
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- ORCID : 0000-0003-4075-2736
Eduard Vieta
- Fonction : Auteur
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Stephanie H Witt
- Fonction : Auteur
- PersonId : 804383
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Peter P Zandi
- Fonction : Auteur
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Martin Alda
- Fonction : Auteur
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Marcella Rietschel
- Fonction : Auteur
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Francis J Mcmahon
- Fonction : Auteur
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Scott R Clark
- Fonction : Auteur
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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.
Domaines
Psychiatrie et santé mentale
Fichier principal
Association of polygenic score and the involvement of cholinergic and glutamatergic pathways with lithium treatment response in patients with bipolar disorder.pdf (3.57 Mo)
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Origine : Publication financée par une institution
Licence : CC BY - Paternité
Licence : CC BY - Paternité