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

Molecular psychiatry

Authors: Azmeraw T Amare, Anbupalam Thalamuthu, Klaus Oliver Schubert, Janice M Fullerton, Muktar Ahmed, Simon Hartmann, Sergi Papiol, Urs Heilbronner, Franziska Degenhardt, Fasil Tekola-Ayele, Liping Hou, Yi-Hsiang Hsu, Tatyana Shekhtman, Mazda Adli, Nirmala Akula, Kazufumi Akiyama, Raffaella Ardau, Bárbara Arias, Jean-Michel Aubry, 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 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, Palmiero Monteleone, 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, Stephanie H Witt, Adam Wright, Peter P Zandi, Philip B Mitchell, Michael Bauer, Martin Alda, Marcella Rietschel, Francis J McMahon, Thomas G Schulze, Scott R Clark, Bernhard T Baune

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) 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 was developed in the International Consortium of Lithium Genetics cohort (ConLiGen: N = 2367) and replicated in the combined PsyCourse (N = 89) and BipoLife (N = 102) studies. The associations of Li 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 was positively associated with lithium treatment response in the ConLiGen cohort, in both the categorical (P = 9.8 × 10, R = 1.9%) and continuous (P = 6.4 × 10, R = 2.6%) outcomes. Compared to bipolar patients in the 1 decile of the risk distribution, individuals in the 10 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, R = 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 may be useful in the development of pharmacogenomic testing strategies by enabling a classification of bipolar patients according to their response to treatment.

© 2023. The Author(s).

PMID: 37433967

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