Association of polygenic score and the involvement of cholinergic and glutamatergic pathways with lithium treatment response in patients with bipolar disorder
Journal
Molecular psychiatry
Date Issued
2023
Author(s)
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
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
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
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, 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.
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Type
journal article