Association of polygenic score and the involvement of cholinergic and glutamatergic pathways with lithium treatment response in patients with bipolar disorder
Azmeraw T. Amare, Anbupalam Thalamuthu, Klaus Oliver Schubert, Janice M. Fullerton, Muktar Beshir 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, Stéphane Jamain, Peter Falkai, Andreas J. Forstner, Louise Frisén, Mark A. Frye, Sébastien Gard, Julie 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, János Kálmán, 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 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, Kathrin Gade, Sarah Trost, Ida S. Haussleiter, Martin Lambert, Anja Rohenkohl, Vivien Kraft, Paul Grof, Ryota Hashimoto
Abstract
Abstract 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 , R 2 = 1.9%) and continuous ( P = 6.4 × 10 − 9 , R 2 = 2.6%) outcomes. Compared to bipolar patients in the 1 st decile of the risk distribution, individuals in the 10 th 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 , R 2 = 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.