Combining schizophrenia and depression polygenic risk scores improves the genetic prediction of lithium response in bipolar disorder patients

Schubert KO, Thalamuthu A, Amare AT, Frank J, Streit F, Adl 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, Marie-Claire C, Cearns M, Cervantes P, Chen HC, Chillotti C, Cichon S, Clark SR, Cruceanu C, Czerski PM, Dalkner N, Dayer A, Degenhardt F, Del Zompo M, DePaulo JR, Étain B, 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, Heilbronner U, Herms S, Hoffmann P, Hou L, Hsu YH, Jamain S, Jiménez E, Kahn JP, Kassem L, Kuo PH, Kato T, Kelsoe J, Kittel-Schneider S, Ferensztajn-Rochowiak E, König B, Kusumi I, Laje G, Landén M, Lavebratt C, Leboyer M, Leckband SG, Maj M, Manchia M, Martinsson L, McCarthy MJ, McElroy S, Colom F, Mitjans M, Mondimore FM, Monteleone P, Nievergelt CM, Nöthen MM, Novák T, O’Donovan C, Ozaki N, Ösby U, Papiol S, Pfennig A, Pisanu C, Potash JB, Reif A, Reininghaus E, Rouleau GA, Rybakowski JK, Schalling M, Schofield PR, Schweizer BW, Severino G, Shekhtman T, Shilling PD, Shimoda K, Simhandl C, Slaney CM, Squassina A, Stamm T, Stopkova P, Tekola-Ayele F, Tortorella A, Turecki G, Veeh J, Vieta E, Witt SH, Roberts G, Zandi PP, Alda M, Bauer M, McMahon FJ, Mitchell PB, Schulze TG, Rietschel M, Baune BT (2021)

Publication Type: Journal article

Publication year: 2021

Journal

Book Volume: 11

Article Number: 606

Journal Issue: 1

DOI: 10.1038/s41398-021-01702-2

Abstract

Lithium is the gold standard therapy for Bipolar Disorder (BD) but its effectiveness differs widely between individuals. The molecular mechanisms underlying treatment response heterogeneity are not well understood, and personalized treatment in BD remains elusive. Genetic analyses of the lithium treatment response phenotype may generate novel molecular insights into lithium’s therapeutic mechanisms and lead to testable hypotheses to improve BD management and outcomes. We used fixed effect meta-analysis techniques to develop meta-analytic polygenic risk scores (MET-PRS) from combinations of highly correlated psychiatric traits, namely schizophrenia (SCZ), major depression (MD) and bipolar disorder (BD). We compared the effects of cross-disorder MET-PRS and single genetic trait PRS on lithium response. For the PRS analyses, we included clinical data on lithium treatment response and genetic information for n = 2283 BD cases from the International Consortium on Lithium Genetics (ConLi⁺Gen; www.ConLiGen.org). Higher SCZ and MD PRSs were associated with poorer lithium treatment response whereas BD-PRS had no association with treatment outcome. The combined MET2-PRS comprising of SCZ and MD variants (MET2-PRS) and a model using SCZ and MD-PRS sequentially improved response prediction, compared to single-disorder PRS or to a combined score using all three traits (MET3-PRS). Patients in the highest decile for MET2-PRS loading had 2.5 times higher odds of being classified as poor responders than patients with the lowest decile MET2-PRS scores. An exploratory functional pathway analysis of top MET2-PRS variants was conducted. Findings may inform the development of future testing strategies for personalized lithium prescribing in BD.

Involved external institutions

Universitätsspital Basel Switzerland (CH) University of Adelaide Australia (AU) Douglas Mental Health University Institute Canada (CA) Universitätsklinikum Mannheim / University Medical Centre Mannheim (Universitätsmedizin Mannheim) Germany (DE) Charité - Universitätsmedizin Berlin Germany (DE) McGill University Health Centre (MUHC) / Centre universitaire de santé McGill Canada (CA) National Taiwan University Hospital (NTUH) / 國立台灣大學醫學院附設醫院 Taiwan (TW) Università degli Studi di Cagliari Italy (IT) Städtisches Klinikum Neunkirchen Germany (DE) National Institute of Mental Health Information Resource Center United States (USA) (US) Sahlgrenska University Hospital / Sahlgrenska Universitetssjukhuset Sweden (SE) 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) Hospital del Mar Spain (ES) Università degli Studi di Salerno Italy (IT) Rheinische Friedrich-Wilhelms-Universität Bonn Germany (DE) Dalhousie University Canada (CA) Johns Hopkins University (JHU) United States (USA) (US) Karolinska Institute Sweden (SE) National Institute of Mental Health (NIMH) / Národní ústav duševního zdraví (NUDZ) Czech Republic (CZ) Nagoya University / 名古屋大学 Japan (JP) Karolinska University Hospital / Karolinska Universitetssjukhuset Sweden (SE) University of New South Wales (UNSW) Australia (AU) Westfälische Wilhelms-Universität (WWU) Münster Germany (DE) Université Paris Cité France (FR) Università degli studi della Campania Luigi Vanvitelli Italy (IT) Universitat de Barcelona (UB) / University of Barcelona Spain (ES) Klinikum der Universität München (LMU Klinikum) Germany (DE) Universitätsklinikum Carl Gustav Carus Dresden Germany (DE) Universitätsklinikum Frankfurt am Main (KGU) Germany (DE) Medizinische Universität Graz Austria (AT) Montreal Neurological Institute and Hospital (MNI, The Neuro) Canada (CA) Dokkyo Medical University Japan (JP) Geneva University Hospitals / Hôpitaux universitaires de Genève (HUG) Switzerland (CH) Mayo Clinic United States (USA) (US) Osaka University / 大阪大学 Japan (JP) Poznan University of Medical Sciences / Uniwersytet Medyczny im. Karola Marcinkowskiego w Poznaniu Poland (PL) Harvard University United States (USA) (US) Université de Lorraine France (FR) VA San Diego Healthcare System United States (USA) (US) Università degli Studi di Perugia Italy (IT) Mood Disorders Ottawa Canada (CA) Neuroscience Research Australia NeuRA Australia (AU) Centre Hospitalier Charles Perrens (CHCP) France (FR) National Taiwan University (NTU) Taiwan (TW) Juntendo University Japan (JP) University of Cincinnati United States (USA) (US) Sigmund-Freud-Privatuniversität Wien (SFU) / Sigmund Freud University Austria (AT) US National Institutes of Health (NIH) United States (USA) (US)

How to cite

APA:

Schubert, K.O., Thalamuthu, A., Amare, A.T., Frank, J., Streit, F., Adl, M.,... Baune, B.T. (2021). Combining schizophrenia and depression polygenic risk scores improves the genetic prediction of lithium response in bipolar disorder patients. Translational Psychiatry, 11(1). https://doi.org/10.1038/s41398-021-01702-2

MLA:

Schubert, Klaus Oliver, et al. "Combining schizophrenia and depression polygenic risk scores improves the genetic prediction of lithium response in bipolar disorder patients." Translational Psychiatry 11.1 (2021).

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