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Mol Psychiatry. 2020 Mar 16. doi: 10.1038/s41380-020-0689-5. [Epub ahead of print]

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

Amare AT1,2, Schubert KO1,3, Hou L4, Clark SR1, Papiol S5,6, Cearns M1, Heilbronner U5,7, Degenhardt F8, Tekola-Ayele F9, Hsu YH10,11, Shekhtman T12, Adli M13, Akula N4, Akiyama K14, Ardau R15, Arias B16, Aubry JM17, Backlund L18,19, Bhattacharjee AK12, Bellivier F20, Benabarre A21, Bengesser S22, Biernacka JM23,24, Birner A22, Brichant-Petitjean C20, Cervantes P25, Chen HC26, Chillotti C15, Cichon S8,27, Cruceanu C28, Czerski PM29, Dalkner N22, Dayer A17, Del Zompo M30, DePaulo JR31, Étain B20, Jamain S32, Falkai P6, Forstner AJ8,27,33, Frisen L18,19, Frye MA24, Fullerton JM34,35, Gard S36, Garnham JS37, Goes FS31, Grigoroiu-Serbanescu M38, Grof P39, Hashimoto R40,41, Hauser J29, Herms S8,27, Hoffmann P8,27, Hofmann A8, Jiménez E21, Kahn JP42, Kassem L4, Kuo PH43, Kato T44, Kelsoe JR12, Kittel-Schneider S45, Kliwicki S46, König B47, Kusumi I48, Laje G4, Landén M49,50, Lavebratt C18,19, Leboyer M51, Leckband SG52, Tortorella A53, Manchia M54,55, Martinsson L56, McCarthy MJ12,57, McElroy SL58, Colom F59,60, Mitjans M16,60,61, Mondimore FM31, Monteleone P62,63, Nievergelt CM12, Nöthen MM8, Novák T64, O'Donovan C37, Ozaki N65, Ösby U66, Pfennig A67, Potash JB31, Reif A45; Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, Reininghaus E22, Rouleau GA68, Rybakowski JK46, Schalling M18,19, Schofield PR34,35, Schweizer BW31, Severino G30, Shilling PD12, Shimoda K69, Simhandl C70, Slaney CM37, Squassina A30, Stamm T13, Stopkova P64, Maj M63, Turecki G28, Vieta E21, Veeh J45, Witt SH71, Wright A72, Zandi PP73, Mitchell PB72, Bauer M67, Alda M37,64, Rietschel M71, McMahon FJ4, Schulze TG4,5,7,31,71, Baune BT74,75,76.

Collaborators (197)

Wray NR, Ripke S, Mattheisen M, Trzaskowski M, Byrne EM, Abdellaoui A, Adams MJ, Agerbo E, Air TM, Andlauer TFM, Bacanu SA, Bækvad-Hansen M, Beekman ATF, Bigdeli TB, Binder EB, Blackwood DHR, Bryois J, Buttenschøn HN, Bybjerg-Grauholm J, Cai N, Castelao E, Christensen JV, Clarke TK, Coleman JRI, Colodro-Conde L, Couvy-Duchesne B, Craddock N, Crawford GE, Davies G, Deary IJ, Degenhardt F, Derks EM, Direk N, Dolan CV, Dunn EC, Eley TC, Escott-Price V, Kiadeh FFH, Finucane HK, Forstner AJ, Frank J, Gaspar HA, Gill M, Goes FS, Gordon SD, Grove J, Hall LS, Hansen CS, Hansen TF, Herms S, Hickie IB, Hoffmann P, Homuth G, Horn C, Hottenga JJ, Hougaard DM, Ising M, Jansen R, Jorgenson E, Knowles JA, Kohane IS, Kraft J, Kretzschmar WW, Krogh J, Kutalik Z, Li Y, Lind PA, MacIntyre DJ, MacKinnon DF, Maier RM, Maier W, Marchini J, Mbarek H, McGrath P, McGuffin P, Medland SE, Mehta D, Middeldorp CM, Mihailov E, Milaneschi Y, Milani L, Mondimore FM, Montgomery GW, Mostafavi S, Mullins N, Nauck M, Ng B, Nivard MG, Nyholt DR, O'Reilly PF, Oskarsson H, Owen MJ, Painter JN, Pedersen CB, Pedersen MG, Peterson RE, Pettersson E, Peyrot WJ, Pistis G, Posthuma D, Quiroz JA, Qvist P, Rice JP, Riley BP, Rivera M, Mirza SS, Schoevers R, Schulte EC, Shen L, Shi J, Shyn SI, Sigurdsson E, Sinnamon GCB, Smit JH, Smith DJ, Stefansson H, Steinberg S, Streit F, Strohmaier J, Tansey KE, Teismann H, Teumer A, Thompson W, Thomson PA, Thorgeirsson TE, Traylor M, Treutlein J, Trubetskoy V, Uitterlinden AG, Umbricht D, Van der Auwera S, van Hemert AM, Viktorin A, Visscher PM, Wang Y, Webb BT, Weinsheimer SM, Wellmann J, Willemsen G, Witt SH, Wu Y, Xi HS, Yang J, Zhang F, Arolt V, Baune BT, Berger K, Boomsma DI, Cichon S, Dannlowski U, de Geus EJC, DePaulo JR, Domenici E, Domschke K, Esko T, Grabe HJ, Hamilton SP, Hayward C, Heath AC, Kendler KS, Kloiber S, Lewis G, Li QS, Lucae S, Madden PAF, Magnusson PK, Martin NG, McIntosh AM, Metspalu A, Mors O, Mortensen PB, Müller-Myhsok B, Nordentoft M, Nöthen MM, O'Donovan MC, Paciga SA, Pedersen NL, Penninx BWJH, Perlis RH, Porteous DJ, Potash JB, Preisig M, Rietschel M, Schaefer C, Schulze TG, Smoller JW, Stefansson K, Tiemeier H, Uher R, Völzke H, Weissman MM, Werge T, Lewis CM, Levinson DF, Breen G, Børglum AD, Sullivan PF.

Author information

1
Discipline of Psychiatry, School of Medicine, University of Adelaide, Adelaide, SA, Australia.
2
South Australian Academic Health Science and Translation Centre, South Australian Health and Medical Research Institute (SAHMRI), Adelaide, SA, Australia.
3
Northern Adelaide Local Health Network, Mental Health Services, Adelaide, SA, Australia.
4
Intramural Research Program, National Institute of Mental Health, National Institutes of Health, US Department of Health & Human Services, Bethesda, MD, USA.
5
Institute of Psychiatric Phenomics and Genomics (IPPG), University Hospital, LMU Munich, Munich, Germany.
6
Department of Psychiatry and Psychotherapy, Ludwig-Maximilian-University Munich, Munich, Germany.
7
Department of Psychiatry and Psychotherapy, University Medical Center (UMG), Georg-August University Göttingen, Göttingen, Germany.
8
Institute of Human Genetics, University of Bonn and Department of Genomics, Life & Brain Center, Bonn, Germany.
9
Epidemiology Branch, Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.
10
HSL Institute for Aging Research, Harvard Medical School, Boston, MA, USA.
11
Program for Quantitative Genomics, Harvard School of Public Health, Boston, MA, USA.
12
Department of Psychiatry, University of California San Diego, San Diego, CA, USA.
13
Department of Psychiatry and Psychotherapy, Charité - Universitätsmedizin Berlin, Campus Charité Mitte, Berlin, Germany.
14
Department of Biological Psychiatry and Neuroscience, Dokkyo Medical University School of Medicine, Mibu, Tochigi, Japan.
15
Unit of Clinical Pharmacology, Hospital University Agency of Cagliari, Cagliari, Italy.
16
Unitat de Zoologia i Antropologia Biològica (Dpt. Biologia Evolutiva, Ecologia i Ciències Ambientals), Facultat de Biologia and Institut de Biomedicina (IBUB), University of Barcelona, CIBERSAM, Barcelona, Spain.
17
Department of Psychiatry, Mood Disorders Unit, HUG - Geneva University Hospitals, Geneva, Switzerland.
18
Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden.
19
Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden.
20
INSERM UMR-S 1144, Université Paris Diderot, Département de Psychiatrie et de Médecine Addictologique, AP-HP, Groupe Hospitalier Saint-Louis-Lariboisière-F.Widal, Paris, France.
21
Bipolar Disorder Program, Institute of Neuroscience, Hospital Clinic, University of Barcelona, IDIBAPS, CIBERSAM, Barcelona, Catalonia, Spain.
22
Department of Psychiatry and Psychotherapeutic Medicine, Research Unit for bipolar affective disorder, Medical University of Graz, Graz, Austria.
23
Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
24
Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN, USA.
25
The Neuromodulation Unit, McGill University Health Centre, Montreal, QC, Canada.
26
Department of Psychiatry & Center of Sleep Disorders, National Taiwan University Hospital, Taipei, Taiwan.
27
Human Genomics Research Group, Department of Biomedicine, University Hospital Basel, Basel, Switzerland.
28
Douglas Mental Health University Institute, McGill University, Montreal, QC, Canada.
29
Psychiatric Genetic Unit, Poznan University of Medical Sciences, Poznan, Poland.
30
Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy.
31
Department of Psychiatry and Behavioral Sciences, Johns Hopkins University, Baltimore, MD, USA.
32
Inserm U955, Translational Psychiatry laboratory, Fondation FondaMental, Créteil, France.
33
Department of Psychiatry (UPK), University of Basel, Basel, Switzerland.
34
Neuroscience Research Australia, Sydney, NSW, Australia.
35
School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia.
36
Service de psychiatrie, Hôpital Charles Perrens, Bordeaux, France.
37
Department of Psychiatry, Dalhousie University, Halifax, NS, Canada.
38
Biometric Psychiatric Genetics Research Unit, Alexandru Obregia Clinical Psychiatric Hospital, Bucharest, Romania.
39
Mood Disorders Center of Ottawa, Ottawa, ON, Canada.
40
Molecular Research Center for Children's Mental Development, United Graduate School of Child Development, Osaka University, Osaka, Japan.
41
Department of Psychiatry, Osaka University Graduate School of Medicine, Osaka, Japan.
42
Service de Psychiatrie et Psychologie Clinique, Centre Psychothérapique de Nancy - Université de Lorraine, Nancy, France.
43
Department of Public Health & Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan.
44
Laboratory for Molecular Dynamics of Mental Disorders, RIKEN Center for Brain Science, Saitama, Japan.
45
Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt, Frankfurt, Germany.
46
Department of Adult Psychiatry, Poznan University of Medical Sciences, Poznan, Poland.
47
Department of Psychiatry and Psychotherapeutic Medicine, Landesklinikum Neunkirchen, Neunkirchen, Austria.
48
Department of Psychiatry, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
49
Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the Gothenburg University, Gothenburg, Sweden.
50
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
51
Inserm U955, Translational Psychiatry laboratory, Université Paris-Est-Créteil, Department of Psychiatry and Addictology of Mondor University Hospital, AP-HP, Fondation FondaMental, Créteil, France.
52
Office of Mental Health, VA San Diego Healthcare System, San Diego, CA, USA.
53
Department of Psychiatry, University of Perugia, Perugia, Italy.
54
Section of Psychiatry, Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy.
55
Department of Pharmacology, Dalhousie University, Halifax, NS, Canada.
56
Department of Clinical Neurosciences, Karolinska Institutet, Stockholm, Sweden.
57
Department of Psychiatry, VA San Diego Healthcare System, San Diego, CA, USA.
58
Department of Psychiatry, Lindner Center of Hope / University of Cincinnati, Mason, OH, USA.
59
Mental Health Research Group, IMIM-Hospital del Mar, Barcelona, Catalonia, Spain.
60
Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Instituto de Salud Carlos III, Madrid, Spain.
61
Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Göttingen, Germany.
62
Neurosciences Section, Department of Medicine, Surgery and Dentistry "Scuola Medica Salernitana", University of Salerno, Salerno, Italy.
63
Department of Psychiatry, University of Campania "Luigi Vanvitelli", Naples, Italy.
64
National Institute of Mental Health, Klecany, Czech Republic.
65
Department of Psychiatry & Department of Child and Adolescent Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Japan.
66
Department of Neurobiology, Care Sciences, and Society, Karolinska Institutet and Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden.
67
Department of Psychiatry and Psychotherapy, University Hospital Carl Gustav Carus, Medical Faculty, Technische Universität Dresden, Dresden, Germany.
68
Montreal Neurological Institute and Hospital, McGill University, Montreal, QC, Canada.
69
Department of Psychiatry, Dokkyo Medical University School of Medicine, Mibu, Tochigi, Japan.
70
Bipolar Center Wiener Neustadt, Sigmund Freud University, Medical Faculty, Vienna, Austria.
71
Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
72
School of Psychiatry, University of New South Wales, and Black Dog Institute, Sydney, NSW, Australia.
73
Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
74
Department of Psychiatry and Psychotherapy, University of Münster, Münster, Germany. bernhard.baune@ukmuenster.de.
75
Department of Psychiatry, Melbourne Medical School, University of Melbourne, Parkville, VIC, Australia. bernhard.baune@ukmuenster.de.
76
The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, VIC, Australia. bernhard.baune@ukmuenster.de.

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.

PMID:
32203155
DOI:
10.1038/s41380-020-0689-5

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