17 Amare, Azmeraw T Thalamuthu, Anbupalam Schubert, Klaus Oliver Fullerton, Janice M Ahmed, Muktar Hartmann, Simon Papiol, Sergi Heilbronner, Urs Degenhardt, Franziska Tekola-Ayele, Fasil Hou, Liping Hsu, Yi-Hsiang Shekhtman, Tatyana Adli, Mazda Akula, Nirmala Akiyama, Kazufumi Ardau, Raffaella Arias, Bárbara Aubry, Jean-Michel Hasler, Roland Richard-Lepouriel, Hélène Perroud, Nader Backlund, Lena Bhattacharjee, Abesh Kumar Bellivier, Frank Benabarre, Antonio Bengesser, Susanne Biernacka, Joanna M Birner, Armin Marie-Claire, Cynthia Cervantes, Pablo Chen, Hsi-Chung Chillotti, Caterina Cichon, Sven Cruceanu, Cristiana Czerski, Piotr M Dalkner, Nina Del Zompo, Maria DePaulo, J Raymond Étain, Bruno Jamain, Stephane Falkai, Peter Forstner, Andreas J Frisen, Louise Frye, Mark A Gard, Sébastien Garnham, Julie S Goes, Fernando S Grigoroiu-Serbanescu, Maria Fallgatter, Andreas Stegmaier, Sophia Ethofer, Thomas Biere, Silvia Petrova, Kristiyana Schuster, Ceylan Adorjan, Kristina Budde, Monika Heilbronner, Maria Kalman, Janos L Kohshour, Mojtaba Oraki Reich-Erkelenz, Daniela Schaupp, Sabrina K Schulte, Eva C Senner, Fanny Vogl, Thomas Anghelescu, Ion-George Arolt, Volker Dannlowski, Udo Dietrich, Detlef Figge, Christian Jäger, Markus Lang, Fabian U Juckel, Georg Konrad, Carsten Reimer, Jens Schmauß, Max Schmitt, Andrea Spitzer, Carsten von Hagen, Martin Wiltfang, Jens Zimmermann, Jörg Andlauer, Till F M Fischer, Andre Bermpohl, Felix Ritter, Philipp Matura, Silke Gryaznova, Anna Falkenberg, Irina Yildiz, Cüneyt Kircher, Tilo Schmidt, Julia Koch, Marius Gade, Kathrin Trost, Sarah Haussleiter, Ida S Lambert, Martin Rohenkohl, Anja C Kraft, Vivien Grof, Paul Hashimoto, Ryota Hauser, Joanna Herms, Stefan Hoffmann, Per Jiménez, Esther Kahn, Jean-Pierre Kassem, Layla Kuo, Po-Hsiu Kato, Tadafumi Kelsoe, John Kittel-Schneider, Sarah Ferensztajn-Rochowiak, Ewa König, Barbara Kusumi, Ichiro Laje, Gonzalo Landén, Mikael Lavebratt, Catharina Leboyer, Marion Leckband, Susan G Tortorella, Alfonso Manchia, Mirko Martinsson, Lina McCarthy, Michael J McElroy, Susan Colom, Francesc Millischer, Vincent Mitjans, Marina Mondimore, Francis M Monteleone, Palmiero Nievergelt, Caroline M Nöthen, Markus M. Novák, Tomas O'Donovan, Claire Ozaki, Norio Pfennig, Andrea Pisanu, Claudia Potash, James B Reif, Andreas Reininghaus, Eva Rouleau, Guy A Rybakowski, Janusz K Schalling, Martin Schofield, Peter R Schweizer, Barbara W Severino, Giovanni Shilling, Paul D Shimoda, Katzutaka Simhandl, Christian Slaney, Claire M Squassina, Alessio Stamm, Thomas Stopkova, Pavla Maj, Mario Turecki, Gustavo Vieta, Eduard Veeh, Julia Witt, Stephanie H Wright, Adam Zandi, Peter P Mitchell, Philip B Bauer, Michael Alda, Martin Rietschel, Marcella McMahon, Francis J Schulze, Thomas G Clark, Scott R Baune, Bernhard T AG Wiltfang AG Fischer Molecular psychiatry Molecular psychiatry Macmillan London 1359-4184 10.1038/s41380-023-02149-1 English 5251 - 5261 12 28 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 1st decile of the risk distribution, individuals in the 10th 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. PUB:(DE-HGF)16, ; 0, ; Bipolar Disorder: drug therapy Bipolar Disorder: genetics Humans Female Male Multifactorial Inheritance: genetics Adult Middle Aged Lithium: therapeutic use Lithium: pharmacology Treatment Outcome Bayes Theorem Genome-Wide Association Study: methods Glutamic Acid: metabolism Cohort Studies Lithium Compounds: therapeutic use Lithium Compounds: pharmacology Acetylcholine: metabolism Polymorphism, Single Nucleotide: genetics Antimanic Agents: therapeutic use Antimanic Agents: pharmacology Lithium Glutamic Acid Lithium Compounds Acetylcholine Antimanic Agents Journal Article 2023 DZNE-2024-00517 2023 pmc:PMC11041653 pmid:37433967 https://pub.dzne.de/record/269348 https://doi.org/10.1038/s41380-023-02149-1