Using multi-trait polygenic scores to predict lithium responsiveness in patients with bipolar disorder
Abstract
Background The predictive power of polygenic scores (PGSs) for lithium treatment response in bipolar disorder remains limited. Aims To enhance the prediction of lithium responsiveness by developing a multi-trait PGS (mt-PGS) combining genetic information from multiple phenotypes implicated in lithium response and/or bipolar disorder aetiology. Method We analysed data collected from bipolar disorder patients who had received lithium treatment for at least 6 months and participated in the International Consortium on Lithium Genetics study ( N = 2367). The Alda scale was used to assess lithium responsiveness, and treatment outcome was defined as continuous total Alda score (0–10) and categorical outcome (favourable ≥7 versus unfavourable response). PGSs were calculated for 60 phenotypes grouped into 5 clinical–biological clusters: psychiatric and behavioural (#23 phenotypes), cardiometabolic (#17), autoimmune/inflammatory (#5), neurocognitive (#8) and renal function (#7). We applied cross-validated machine learning regression approaches in both outcomes within each cluster, with the selected features from each cluster subsequently combined to construct the final mt-PGS models. Model performance was assessed using explained variance ( R 2 ) for the continuous outcome, and both McFadden’s pseudo- R 2 and standard classification model parameters for the categorical outcome. Results mt-PGS explained between 5.70% (continuous outcome) and 9.11% (categorical outcome) of the interindividual variability in lithium responsiveness. Classification accuracy (area under the curve) for the categorical outcome was 68.24% (95% CI: 64.98–71.66), with a Brier score of 0.257. Of the 5 clusters, the PGSs for psychiatric and behavioural phenotypes were most strongly associated with lithium responsiveness, accounting for 3.67–6.52% of its variability. Conclusions By integrating PGSs for multiple relevant phenotypes, predictive accuracy for lithium response improved substantially compared with single-trait methods. Future research incorporating larger, more diverse populations and combining genetic scores with clinical data holds promise for further enhancing prediction and advancing clinical implementation.
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Authors: Nigussie Tadesse Sharew, Scott Richard Clark, Simon Hartmann, Sergi Papiol, Urs Heilbronner, Franziska Degenhardt, Janice M. Fullerton, Liping Hou, Tatyana Shekhtman, Mazda Adli, Nirmala Akula, Kazufumi Akiyama, Raffaella Ardau, Bárbara Arias, Fasil Tekola Ayele, Carla Gallo, 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 Cruceana, Piotr M. Czerski, Nina Dalkner, Maria Del Zompo, J. Raymond DePaulo, Bruno Étain, Stéphane Jamain, Peter Falkai, Andreas J. Forstner, Louise Frisen, Mark A. Frye, Sébastien Gard, Julie S. Garnham, Fernando S. Goes, Maria Grigoroiu‐Serbânescu, 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 Christina Schulte, Fanny Senner, Thomas Vogl, Anghelescu Ion-George, 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, André Fischer, Felix Bermpohl, Philipp Ritter, Silke Matura, Anna Gryaznova, Irina Falkenberg, Cüneyt Yildiz, Tilo Kircher, Julia Schmidt, M. Koch, Katrin Gade, Sarah Trost, Ida S. Haussleiter, Martin Lambert, Anja Christine Rohenkohl, Vivien Kraft, Paul Grof, Ryota Hashimoto, J Hauser, Stefan Herms, Per Hoffman
Institutions: Eunice Kennedy Shriver National Institute of Child Health and Human Development, Karolinska Institutet, University of California San Diego, Johns Hopkins University, Charité - Universitätsmedizin Berlin, Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Dalhousie University, Universidade de São Paulo, The University of Melbourne, The University of Adelaide, University Hospital of Basel, McGill University Health Centre, Universitätsmedizin Göttingen, University of Göttingen, UNSW Sydney, Ludwig-Maximilians-Universität München, Debre Berhan University, Instituto de Salud Carlos III, University of Tübingen, Ahvaz Jundishapur University of Medical Sciences, Karolinska University Hospital, National Taiwan University, University of Bern, University of Bonn, University of Münster, University Medical Center Hamburg-Eppendorf, Philipps University of Marburg, Centro de Investigación Biomédica en Red de Salud Mental, Assistance Publique – Hôpitaux de Paris, Universitat de Barcelona, Goethe University Frankfurt, Consorci Institut D'Investigacions Biomediques August Pi I Sunyer, McGill University, Technical University of Munich, Ruhr University Bochum, Poznan University of Medical Sciences, Mayo Clinic, Medical University of Graz, University Hospital Frankfurt, University of Duisburg-Essen, National Institutes of Health, Universität Ulm, University of Cagliari, Technische Universität Dresden, Forschungszentrum Jülich, LWL-Universitätsklinikum Bochum, Max Planck Institute of Psychiatry, University of Hildesheim, Hôpital Lariboisière, University Hospital Bonn, Geneva College, National Center of Neurology and Psychiatry, Neuroscience Research Australia, Bezirkskrankenhaus Augsburg, Universidad Peruana Cayetano Heredia, Dokkyo Medical University, Institute of Mental Health, Agaplesion Diakonieklinikum Rotenburg, Fondation FondaMental, Orygen, Department of Health and Human Services, Adelaide University, Centre Hospitalier Charles Perrens, Azienda Ospedaliero-Universitaria Cagliari, Universitätsmedizin Rostock, Optimisation Thérapeutique en Neuropsychopharmacologie, Spitalul Clinic de Psihiatrie Alexandru Obregia, European Science Communication Institute