Association of polygenic score and the involvement of cholinergic and glutamatergic pathways with lithium treatment response in patients with bipolar disorder

Amare AT, Thalamuthu A, Schubert KO, Fullerton JM, Ahmed M, Hartmann S, Papiol S, Heilbronner U, Degenhardt F, Tekola-Ayele F, Hou L, Hsu YH, Shekhtman T, Adli M, Akula N, Akiyama K, Ardau R, Arias B, Aubry JM, Hasler R, Richard-Lepouriel H, Perroud N, Backlund L, Bhattacharjee AK, Bellivier F, Benabarre A, Bengesser S, Biernacka JM, Birner A, Marie-Claire C, Cervantes P, Chen HC, Chillotti C, Cichon S, Cruceanu C, Czerski PM, Dalkner N, Del Zompo M, DePaulo JR, Étain B, Jamain S, Falkai P, Forstner AJ, Frisen L, Frye MA, Gard S, Garnham JS, Goes FS, Grigoroiu-Serbanescu M, Fallgatter AJ, Stegmaier S, Ethofer T, Biere S, Petrova K, Schuster C, Adorjan K, Budde M, Heilbronner M, Kalman JL, Kohshour MO, Reich-Erkelenz D, Schaupp SK, Schulte EC, Senner F, Vogl T, Anghelescu IG, Arolt V, Dannlowski U, Dietrich D, Figge C, Jäger M, Lang FU, Juckel G, Konrad C, Reimer J, Schmauß M, Schmitt A, Spitzer C, von Hagen M, Wiltfang J, Zimmermann J, Andlauer TF, Fischer A, Bermpohl F, Ritter P, Matura S, Gryaznova A, Falkenberg I, Yildiz C, Kircher T, Schmidt J, Koch M, Gade K, Trost S, Haussleiter IS, Lambert M, Rohenkohl AC, Kraft V, Grof P, Hashimoto R, Hauser J, Herms S, Hoffmann P, 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, Tortorella A, Manchia M, Martinsson L, McCarthy MJ, McElroy S, Colom F, Millischer V, Mitjans M, Mondimore FM, Monteleone P, Nievergelt CM, Nöthen MM, Novák T, O’Donovan C, Ozaki N, Pfennig A, Pisanu C, Potash JB, Reif A, 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, Witt SH, Wright A, Zandi PP, Mitchell PB, Bauer M, Alda M, Rietschel M, McMahon FJ, Schulze TG, Clark SR, Baune BT (2023)

Publication Type: Journal article

Publication year: 2023

Journal

Book Volume: 28

Pages Range: 5251-5261

Journal Issue: 12

DOI: 10.1038/s41380-023-02149-1

Abstract

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 response — defined 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, R² = 1.9%) and continuous (P = 6.4 × 10⁻⁹, R² = 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, R² = 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.

Involved external institutions

Klinikum der Universität München (LMU Klinikum) Germany (DE) Universitätsklinikum Bonn Germany (DE) National Institute of Mental Health Information Resource Center United States (USA) (US) Harvard University United States (USA) (US) Charité - Universitätsmedizin Berlin Germany (DE) Dokkyo Medical University Japan (JP) Universitätsklinikum Hamburg-Eppendorf (UKE) Germany (DE) Università degli Studi di Cagliari Italy (IT) Universitat de Barcelona (UB) / University of Barcelona Spain (ES) Johns Hopkins University (JHU) United States (USA) (US) Poznan University of Medical Sciences / Uniwersytet Medyczny im. Karola Marcinkowskiego w Poznaniu Poland (PL) Université Sorbonne Paris Cité France (FR) Fondation FondaMental France (FR) Karolinska Institute Sweden (SE) Mayo Clinic United States (USA) (US) Université de Lorraine France (FR) Centre Hospitalier Charles Perrens (CHCP) France (FR) Dalhousie University Canada (CA) Universitätsklinikum Tübingen Germany (DE) Eberhard Karls Universität Tübingen Germany (DE) Universitätsklinikum Frankfurt am Main (KGU) Germany (DE) RIKEN Center for Brain Science (CBS) Japan (JP) US National Institutes of Health (NIH) United States (USA) (US) Medizinische Universität Graz Austria (AT) Städtisches Klinikum Neunkirchen Germany (DE) Universitätsklinikum Mannheim / University Medical Centre Mannheim (Universitätsmedizin Mannheim) 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) Sahlgrenska University Hospital / Sahlgrenska Universitetssjukhuset Sweden (SE) University of Adelaide Australia (AU) Westfälische Wilhelms-Universität (WWU) Münster Germany (DE) Douglas Mental Health University Institute Canada (CA) Hospital del Mar Spain (ES) 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) VA San Diego Healthcare System United States (USA) (US) Università degli Studi di Perugia Italy (IT) Università degli Studi di Salerno Italy (IT) National Institute of Mental Health (NIMH) / Národní ústav duševního zdraví (NUDZ) Czech Republic (CZ) MHI Mental Health Institute Berlin Germany (DE) Nagoya University / 名古屋大学 Japan (JP) Philipps-Universität Marburg Germany (DE) Universitätsklinikum Göttingen Germany (DE) Montreal Neurological Institute and Hospital (MNI, The Neuro) Canada (CA) Neuroscience Research Australia NeuRA Australia (AU) Sigmund-Freud-Privatuniversität Wien (SFU) / Sigmund Freud University Austria (AT) University of New South Wales (UNSW) Australia (AU) Universitätsklinikum Carl Gustav Carus Dresden Germany (DE) Karl-Jaspers-Klinik Germany (DE) Klinikum rechts der Isar Germany (DE) Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE) Germany (DE) Geneva University Hospitals / Hôpitaux universitaires de Genève (HUG) Switzerland (CH) Mood Disorders Ottawa Canada (CA) National Taiwan University (NTU) Taiwan (TW) University of Cincinnati United States (USA) (US) AMEOS Klinikum Hildesheim Germany (DE) Universität Ulm Germany (DE) Agaplesion Diakonieklinikum Rotenburg Germany (DE) Bezirkskliniken Schwaben Germany (DE) Universitätsmedizin Rostock Germany (DE) Klinikum Werra-Meißner / Clinical Center Werra-Meißner Germany (DE) Università degli studi della Campania Luigi Vanvitelli Italy (IT)

How to cite

APA:

Amare, A.T., Thalamuthu, A., Schubert, K.O., Fullerton, J.M., Ahmed, M., Hartmann, S.,... Baune, B.T. (2023). Association of polygenic score and the involvement of cholinergic and glutamatergic pathways with lithium treatment response in patients with bipolar disorder. Molecular Psychiatry, 28(12), 5251-5261. https://doi.org/10.1038/s41380-023-02149-1

MLA:

Amare, Azmeraw T., et al. "Association of polygenic score and the involvement of cholinergic and glutamatergic pathways with lithium treatment response in patients with bipolar disorder." Molecular Psychiatry 28.12 (2023): 5251-5261.

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