Pathway-Specific Polygenic Scores for Predicting Clinical Lithium Treatment Response in Patients With Bipolar Disorder

Sharew NT, Clark SR, Papiol S, Heilbronner U, Degenhardt F, Fullerton JM, Hou L, Shekhtman T, Adli M, Akula N, Akiyama K, Ardau R, Arias B, 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 DE, 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, Viswanath B, Witt SH, Wright A, Zandi PP, Mitchell PB, Bauer M, Alda M, Rietschel M, McMahon FJ, Schulze TG, Baune BT, Schubert KO, Amare AT (2025)

Publication Type: Journal article

Publication year: 2025

Journal

Book Volume: 5

Article Number: 100558

Journal Issue: 5

DOI: 10.1016/j.bpsgos.2025.100558

Abstract

Background: Polygenic scores (PGSs) hold the potential to identify patients who respond favorably to specific psychiatric treatments. However, their biological interpretation remains unclear. In this study, we developed pathway-specific PGSs (PSPGSs) for lithium response and assessed their association with clinical lithium response in patients with bipolar disorder. Methods: Using sets of genes involved in pathways affected by lithium, we developed 9 PSPGSs and evaluated their associations with lithium response in the International Consortium on Lithium Genetics (ConLi⁺Gen) (N = 2367), with validation in combined PsyCourse (Pathomechanisms and Signatures in the Longitudinal Course of Psychosis) (N = 105) and BipoLife (N = 102) cohorts. The association between each PSPGS and lithium response—defined both as a continuous ALDA score and a categorical outcome (good vs. poor responses)—was evaluated using regression models, with adjustment for confounders. The cutoff for a significant association was p < .05 after multiple testing correction. Results: The PGSs for acetylcholine, GABA (gamma-aminobutyric acid), and mitochondria were associated with response to lithium in both categorical and continuous outcomes. However, the PGSs for calcium channel, circadian rhythm, and GSK (glycogen synthase kinase) were associated only with the continuous outcome. Each score explained 0.29% to 1.91% of the variance in the categorical and 0.30% to 1.54% of the variance in the continuous outcomes. A multivariate model combining PSPGSs that showed significant associations in the univariate analysis (combined PSPGS) increased the percentage of variance explained (R²) to 3.71% and 3.18% for the categorical and continuous outcomes, respectively. Associations for PGSs for GABA and circadian rhythm were replicated. Patients with the highest genetic loading (10th decile) for acetylcholine variants were 3.03 times more likely (95% CI, 1.95 to 4.69) to show a good lithium response (categorical outcome) than patients with the lowest genetic loading (1st decile). Conclusions: PSPGSs achieved predictive performance comparable to the conventional genome-wide PGSs, with the added advantage of biological interpretability using a smaller list of genetic variants.

Involved external institutions

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

How to cite

APA:

Sharew, N.T., Clark, S.R., Papiol, S., Heilbronner, U., Degenhardt, F., Fullerton, J.M.,... Amare, A.T. (2025). Pathway-Specific Polygenic Scores for Predicting Clinical Lithium Treatment Response in Patients With Bipolar Disorder. Biological Psychiatry Global Open Science, 5(5). https://doi.org/10.1016/j.bpsgos.2025.100558

MLA:

Sharew, Nigussie T., et al. "Pathway-Specific Polygenic Scores for Predicting Clinical Lithium Treatment Response in Patients With Bipolar Disorder." Biological Psychiatry Global Open Science 5.5 (2025).

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