Association of polygenic score for major depression with response to lithium in patients with bipolar disorder
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] = Ludwig Maximilians Universität München
6 Georg-August-University of Goettingen = Georg-August-Universität 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 University Medicine
13 Dokkyo Medical University
14 UniCa - Università degli Studi di Cagliari = University of Cagliari = Université de Cagliari
15 UAB - Universitat Autònoma de Barcelona = Autonomous University of Barcelona = Universidad Autónoma de Barcelona
16 CIBERSAM - Centro de Investigación Biomédica en Red de Salud Mental [Barcelona, Spain]
17 HUG - Hôpitaux Universitaires de Genève = University Hospital of Geneva [Genève]
18 Karolinska Institutet = Karolinska Institute [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 Universität Graz = University of Graz
23 Mayo Clinic [Rochester]
24 MUHC - McGill University Health Center [Montreal]
25 NTU - National Taiwan University
26 University Hospital Basel [Basel]
27 PUMS - Poznan University of Medical Sciences [Poland]
28 JHU - Johns Hopkins University [Baltimore]
29 IMRB - Institut Mondor de Recherche Biomédicale
30 Fondation FondaMental [Créteil]
31 U955 Inserm - UPEC - IMRB - "Neuropsychiatrie translationnelle" [Créteil]
32 Unibas - Université de Bâle = University of Basel = Basel Universität
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 ERA-LEARN - Prof. Dr. Alexandru Obregia Psychiatry Hospital
38 MDCO - Mood Disorders Center of Ottawa
39 UOsaka - The University of 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 [Laxou]
44 NIH - National Institutes of Health [Bethesda, MD, USA]
45 RIKEN - Environmental Molecular Biology Laboratory
46 Goethe University Frankfurt = Goethe-Universität Frankfurt am Main
47 LK Neunkirchen - Landesklinikum Neunkirchen/Neunkirchen Regional Hospital [Neunkirchen, Austria]
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 = University of Perugia
52 UC - University of Cincinnati
53 IMIM-Hospital del Mar
54 MPI - Max Planck Institute of Experimental Medicine [Göttingen]
55 UNISA - Università degli Studi di Salerno = University of Salerno
56 Università degli studi della Campania "Luigi Vanvitelli" = University of the Study of Campania Luigi Vanvitelli
57 NUDZ - 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 of Graz = Medizinische Universität 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 = Université de Münster [Münster, Allemagne]
68 Melbourne Medical School [Melbourne]
69 The Florey Institute of Neuroscience and Mental Health [Parkville, VIC, Australie]
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Résumé
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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