Open Access

Nigussie T. Sharew, Scott R. Clark, Sergi Papiol, Urs Heilbronner, Franziska Degenhardt, Janice M. Fullerton, Liping Hou, Tatyana Shekhtman, Mazda Adli, Nirmala Akula, Kazufumi Akiyama, Raffaella Ardau, Bárbara Arias, Roland Hasler, Hélène Richard-Lepouriel, Nader Perroud, Lena Backlund, Abesh Kumar Bhattacharjee, Frank Bellivier, Antonio Benabarre, Susanne Bengesser, Joanna M. Biernacka, Armin Birner, Cynthia Marie-Claire, Pablo Cervantes, Hsi-Chung Chen, Caterina Chillotti, Sven Cichon, Cristiana Cruceanu, Piotr M. Czerski, Nina Dalkner, Maria Del Zompo, J. Raymond DePaulo, Bruno Étain, Stephane Jamain, Peter Falkai, Andreas J. Forstner, Louise Frisen, Mark A. Frye, Sébastien Gard, Julie S. Garnham, Fernando S. Goes, Maria Grigoroiu-Serbanescu, Andreas J. Fallgatter, Sophia Stegmaier, Thomas Ethofer, Silvia Biere, Kristiyana Petrova, Ceylan Schuster, Kristina Adorjan, Monika Budde, Maria Heilbronner, Janos L. Kalman, Mojtaba Oraki Kohshour, Daniela Reich-Erkelenz, Sabrina K. Schaupp, Eva C. Schulte, Fanny Senner, Thomas Vogl, Ion-George Anghelescu, Volker Arolt, Udo Dannlowski, Detlef E. Dietrich, Christian Figge, Markus Jäger, Fabian U. Lang, Georg Juckel, Carsten Konrad, Jens Reimer, Max Schmauß, Andrea Schmitt, Carsten Spitzer, Martin von Hagen, Jens Wiltfang, Jörg Zimmermann, Till F. M. Andlauer, Andre Fischer, Felix Bermpohl, Philipp Ritter, Silke Matura, Anna Gryaznova, Irina Falkenberg, Cüneyt Yildiz, Tilo Kircher, Julia Schmidt, Marius Koch, Kathrin Gade, Sarah Trost, Ida S. Haussleiter, Martin Lambert, Anja C. Rohenkohl, Vivien Kraft, Paul Grof, Ryota Hashimoto, Joanna Hauser, Stefan Herms, Per Hoffmann, Esther Jiménez, Jean-Pierre Kahn, Layla Kassem, Po-Hsiu Kuo, Tadafumi Kato, John Kelsoe, Sarah Kittel-Schneider, Ewa Ferensztajn-Rochowiak, Barbara König, Ichiro Kusumi, Gonzalo Laje, Mikael Landén, Catharina Lavebratt, Marion Leboyer, Susan G. Leckband, Alfonso Tortorella, Mirko Manchia, Lina Martinsson, Michael J. McCarthy, Susan McElroy, Francesc Colom, Vincent Millischer, Marina Mitjans, Francis M. Mondimore, Caroline M. Nievergelt, Markus M. Nöthen, Tomas Novák, Claire O'Donovan, Norio Ozaki, Andrea Pfennig, Claudia Pisanu, James B. Potash, Andreas Reif, Eva Reininghaus, Guy A. Rouleau, Janusz K. Rybakowski, Martin Schalling, Peter R. Schofield, Barbara W. Schweizer, Giovanni Severino, Paul D. Shilling, Katzutaka Shimoda, Christian Simhandl, Claire M. Slaney, Alessio Squassina, Thomas Stamm, Pavla Stopkova, Mario Maj, Gustavo Turecki, Eduard Vieta, Julia Veeh, Biju Viswanath, Stephanie H. Witt, Adam Wright, Peter P. Zandi, Philip B. Mitchell, Michael Bauer, Martin Alda, Marcella Rietschel, Francis J. McMahon, Thomas G. Schulze, Bernhard T. Baune, Klaus Oliver Schubert, Azmeraw T. Amare

• 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 significantBackground 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.…