Association of Polygenic Score and the involvement of Cholinergic and Glutamatergic Pathways with Lithium Treatment Response in Patients with Bipolar Disorder
Authors: Amare Azmeraw , Thalamuthu Anbupalam , Schubert Klaus Oliver , Fullerton Janice , 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 , Backlund Lena , Bhattacharjee Abesh Kumar , Bellivier Frank , Benabarre Antoni , Bengesser Susanne , Biernacka Joanna , Birner Armin , Marie-Claire Cynthia , Cervantes Pablo , Chen Hsi-Chung , Chillotti Caterina , Cichon Sven , Cruceanu Cristiana , Czerski Piotr , Dalkner Nina , Zompo Maria Del , DePaulo J. Raymond , Etain Bruno , Jamain Stéphane , Falkai Peter , Forstner Andreas J. , Frisén Louise , Frye Mark , Gard Sébastien , Garnham Julie , Goes Fernando , Grigoroiu-Serbanescu Maria , Fallgatter Andreas , Stegmaier Sophia , Ethofer Thomas , Biere Silvia , Petrova Kristiyana , Schuster Ceylan , Adorjan Kristina , Budde Monika , Heilbronner Maria , Kalman Janos , Kohshour Mojtaba Oraki , Reich-Erkelenz Daniela , Schaupp Sabrina , Schulte Eva , Senner Fanny , Vogl Thomas , Anghelescu Ion-George , Arolt Volker , Dannlowski Udo , Dietrich Detlef E. , Figge Christian , Jäger Markus , Lang Fabian , Juckel Georg , Spitzer Carsten , Reimer Jens , Schmauß Max , Schmitt Andrea , Konrad Carsten , von Hagen Martin , Wiltfang Jens , Zimmermann Jörg , Andlauer Till , Fischer Andre , Bermpohl Felix , Kraft Vivien , Matura Silke , Gryaznova Anna , Falkenberg Irina , Yildiz Cüneyt , Kircher Tilo , Schmidt Julia , Koch Marius , Gade Katrin , Trost Sarah , Haußleiter Ida , 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 , McElroy Susan L. , Colom Francesc , Mitjans Marina , Mondimore Francis , Monteleone Palmiero , Nievergelt Caroline , Nöthen Markus , Novak Tomas , O'Donovan Claire , Ozaki Norio , Pfennig Andrea , Pisanu Claudia , Potash James , Reif Andreas , Reininghaus Eva , Rouleau Guy , Rybakowski Janusz K. , Schalling Martin , Schofield Peter , Schweizer Barbara W. , Severino Giovanni , Shilling Paul D , Shimoda Kazutaka , Simhandl Christian , Slaney Claire , Squassina Alessio , Stamm Thomas , Stopkova Pavla , Maj Mario , Turecki Gustavo , Vieta Eduard , Veeh Julia , Witt Stephanie , Wright Adam , Zandi Peter , Mitchell Philip , Bauer Michael , Alda Martin , Rietschel Marcella , McMahon Francis , Schulze Thomas G. , Millischer Vincent , Clark Scott , Baune Bernhard 
Published: February 2023

Abstract
Lithium is regarded as the first-line treatment for bipolar disorder (BD), a severe and disabling mental 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=2,367) 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<����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������