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

Amare AT, Schubert KO, Hou L, Clark SR, Papiol S, Cearns M, Heilbronner U, Tekola-Ayele F, Hsu YH, Shekhtman T, Adli M, Akula N, Akiyama K, Ardau R, Arias B, Aubry JM, Backlund L, Bhattacharjee AK, Bellivier F, Benabarre A, Bengesser S, Biernacka JM, Birner A, Brichant-Petitjean C, Cervantes P, Chen HC, Chillotti C, Cruceanu C, Czerski PM, Dalkner N, Dayer A, Del Zompo M, DePaulo JR, Étain B, Jamain S, Falkai P, Forstner AJ, Frisen L, Frye MA, Fullerton JM, Gard S, Garnham JS, Goes FS, Grigoroiu-Serbanescu M, Grof P, Hashimoto R, Hauser J, Hofmann A, Jiménez E, Kahn JP, Kassem L, Kuo PH, Kato T, Kelsoe JR, Kittel-Schneider S, Kliwicki S, König B, Kusumi I, Laje G, Landén M, Lavebratt C, Leboyer M, Leckband SG, Tortorella A, Manchia M, Martinsson L, McCarthy MJ, McElroy SL, Colom F, Mitjans M, Mondimore FM, Monteleone P, Nievergelt CM, Nöthen MM, Novák T, O’Donovan C, Ozaki N, Ösby U, Pfennig A, Potash JB, Reif A, Wray NR, Ripke S, Mattheisen M, Trzaskowski M, Byrne EM, Abdellaoui A, Adams MJ, Agerbo E, Air TM, Andlauer TF, Bacanu SA, Bækvad-Hansen M, Beekman AT, Bigdeli TB, Binder EB, Blackwood DH, Bryois J, Buttenschøn HN, Bybjerg-Grauholm J, Cai N, Castelao E, Christensen Jv, Clarke TK, Coleman JR, 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, 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 GC, 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, Berger K, Boomsma DI, Cichon S, Dannlowski U, de Geus EJ, 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 PA, Magnusson PK, Martin NG, McIntosh AM, Metspalu A, Mors O, Mortensen PB, Müller-Myhsok B, Nordentoft M, O’Donovan MC, Paciga SA, Pedersen NL, Penninx BW, 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, Reininghaus E, Rouleau GA, Rybakowski JK, Schalling M, Schofield PR, Schweizer BW, Severino G, Shilling PD, Shimoda K, Simhandl C, Slaney CM, Squassina A, Stamm T, Stopkova P, Maj M, Turecki G, Vieta E, Veeh J, Wright A, Zandi PP, Mitchell PB, Bauer M, Alda M, McMahon FJ, Schulze TG, Baune BT (2021)

Publication Type: Journal article

Publication year: 2021

Journal

Book Volume: 26

Pages Range: 2457-2470

Journal Issue: 6

DOI: 10.1038/s41380-020-0689-5

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.

Involved external institutions

Charité - Universitätsmedizin Berlin Germany (DE) National Institute of Mental Health Information Resource Center United States (USA) (US) Università degli Studi di Cagliari Italy (IT) Universitat de Barcelona (UB) / University of Barcelona Spain (ES) Karolinska Institute Sweden (SE) Université Paris Cité France (FR) Medizinische Universität Graz Austria (AT) University of Adelaide Australia (AU) Università degli Studi di Perugia Italy (IT) University of Edinburgh United Kingdom (GB) University of Queensland Australia (AU) Cardiff University United Kingdom (GB) Rigshospitalet Denmark (DK) University of Glasgow United Kingdom (GB) deCODE genetics Iceland (IS) Rheinische Friedrich-Wilhelms-Universität Bonn Germany (DE) Universitätsklinikum Mannheim / University Medical Centre Mannheim (Universitätsmedizin Mannheim) Germany (DE) University of Oxford United Kingdom (GB) Westfälische Wilhelms-Universität (WWU) Münster Germany (DE) Universitätsmedizin Greifswald / Universitätsklinikum Greifswald Germany (DE) Virginia Commonwealth University (VCU) United States (USA) (US) Amsterdam University Medical Centers (Amsterdam UMC) / Amsterdam Universitair Medische Centra Netherlands (NL) University of Amsterdam Netherlands (NL) Massachusetts General Hospital United States (USA) (US) University of Tartu Estonia (EE) University of Iowa United States (USA) (US) Lausanne University Hospital / Centre hospitalier universitaire vaudois (CHUV) Switzerland (CH) Max-Planck-Institut für Psychiatrie (Deutsche Forschungsanstalt für Psychiatrie) Germany (DE) University College London (UCL) United Kingdom (GB) Kaiser Permanente United States (USA) (US) Janssen Global Services, LLC United States (USA) (US) Washington University in St. Louis United States (USA) (US) Johns Hopkins Hospital United States (USA) (US) QIMR Berghofer Medical Research Institute (früher: the Queensland Institute of Medical Research) Australia (AU) Erasmus University Medical Center (MC) Netherlands (NL) Dalhousie University Canada (CA) University of British Columbia Canada (CA) Columbia University Irving Medical Center (CUIMC) United States (USA) (US) King’s College London United Kingdom (GB) Aarhus University Denmark (DK) Deutsches Zentrum für Herz-Kreislauf-Forschung (DZHK e.V.) Germany (DE) Montreal Neurological Institute and Hospital (MNI, The Neuro) Canada (CA) Dokkyo Medical University Japan (JP) Sigmund-Freud-Privatuniversität Wien (SFU) / Sigmund Freud University Austria (AT) Università degli studi della Campania Luigi Vanvitelli Italy (IT) Douglas Mental Health University Institute Canada (CA) Universitätsklinikum Frankfurt am Main (KGU) Germany (DE) University of New South Wales (UNSW) Australia (AU) Johns Hopkins University (JHU) United States (USA) (US) Pfizer, Inc. United States (USA) (US) Stanford University United States (USA) (US) Poznan University of Medical Sciences / Uniwersytet Medyczny im. Karola Marcinkowskiego w Poznaniu Poland (PL) Università degli Studi di Trento Italy (IT) Neuroscience Research Australia NeuRA Australia (AU) Universitätsklinikum Freiburg Germany (DE) Eli and Edythe L. Broad Institute of MIT and Harvard United States (USA) (US) National Institute of Mental Health (NIMH) / Národní ústav duševního zdraví (NUDZ) Czech Republic (CZ) Universitätsklinikum Carl Gustav Carus Dresden Germany (DE) Kaiser Permanente United States (USA) (US) Osaka University / 大阪大学 Japan (JP) Université de Lorraine France (FR) National Taiwan University (NTU) Taiwan (TW) RIKEN Center for Brain Science (CBS) Japan (JP) Städtisches Klinikum Neunkirchen Germany (DE) Sahlgrenska University Hospital / Sahlgrenska Universitetssjukhuset Sweden (SE) VA San Diego Healthcare System United States (USA) (US) Mayo Clinic United States (USA) (US) Klinikum der Universität München (LMU Klinikum) Germany (DE) University of Cincinnati United States (USA) (US) US National Institutes of Health (NIH) United States (USA) (US) Hospital del Mar Spain (ES) Harvard University United States (USA) (US) National Taiwan University Hospital (NTUH) / 國立台灣大學醫學院附設醫院 Taiwan (TW) Università degli Studi di Salerno Italy (IT) Nagoya University / 名古屋大学 Japan (JP) Geneva University Hospitals / Hôpitaux universitaires de Genève (HUG) Switzerland (CH) Paris-Est Créteil University / Université Paris-Est Créteil Val-de-Marne (UPEC) / Université Paris XII-Val-de-Marne / University Paris 12 Marne la Vallée France (FR) Fondation FondaMental France (FR) University of Southern California (USC) United States (USA) (US) Centre Hospitalier Charles Perrens (CHCP) France (FR) Wellcome Centre for Human Genetics United Kingdom (GB) Gentofte Hospital Denmark (DK) Solid Biosciences Inc. United States (USA) (US) Institut universitaire de médecine sociale et préventive (IUMSP) Switzerland (CH) University Medical Center Groningen (UMCG) / Universitair Medisch Centrum Groningen Netherlands (NL) F. Hoffmann-La Roche Ltd Switzerland (CH) Trinity College Dublin Ireland (IE) Wellcome Trust Sanger Institute - Genome Research Limited United Kingdom (GB) Queensland University of Technology (QUT) Australia (AU) McGill University Health Centre (MUHC) / Centre universitaire de santé McGill Canada (CA) Karolinska University Hospital / Karolinska Universitetssjukhuset Sweden (SE) Mood Disorders Ottawa Canada (CA) Duke University United States (USA) (US) National Cancer Institute (NCI) United States (USA) (US) University of Iceland (UI) / Háskóli Íslands Iceland (IS) James Cook University Australia (AU) Harvard T.H. Chan School of Public Health United States (USA) (US) University of Sydney (USYD) Australia (AU) University of Cambridge United Kingdom (GB) Leiden University Medical Center Netherlands (NL)

How to cite

APA:

Amare, A.T., Schubert, K.O., Hou, L., Clark, S.R., Papiol, S., Cearns, M.,... Baune, B.T. (2021). Association of polygenic score for major depression with response to lithium in patients with bipolar disorder. Molecular Psychiatry, 26(6), 2457-2470. https://doi.org/10.1038/s41380-020-0689-5

MLA:

Amare, Azmeraw T., et al. "Association of polygenic score for major depression with response to lithium in patients with bipolar disorder." Molecular Psychiatry 26.6 (2021): 2457-2470.

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