Association of polygenic score and the involvement of cholinergic and glutamatergic pathways with lithium treatment response in patients with bipolar disorder
Authors: 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 J. , 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. 
Published: July 2023

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.