Journal Article

DZNE-2024-00517

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Association of polygenic score and the involvement of cholinergic and glutamatergic pathways with lithium treatment response in patients with bipolar disorder.

Amare, A. T. ; Thalamuthu, A. ; Schubert, K. O. ; Fullerton, J. M. ; Ahmed, M. ; Hartmann, S. ; Papiol, S. ; Heilbronner, U. ; Degenhardt, F. ; Tekola-Ayele, F. ; Hou, L. ; Hsu, Y.-H. ; Shekhtman, T. ; Adli, M. ; Akula, N. ; Akiyama, K. ; Ardau, R. ; Arias, B. ; Aubry, J.-M. ; Hasler, R. ; Richard-Lepouriel, H. ; Perroud, N. ; Backlund, L. ; Bhattacharjee, A. K. ; Bellivier, F. ; Benabarre, A. ; Bengesser, S. ; Biernacka, J. M. ; Birner, A. ; Marie-Claire, C. ; Cervantes, P. ; Chen, H.-C. ; Chillotti, C. ; Cichon, S. ; Cruceanu, C. ; Czerski, P. M. ; Dalkner, N. ; Del Zompo, M. ; DePaulo, J. R. ; Étain, B. ; Jamain, S. ; Falkai, P. ; Forstner, A. J. ; Frisen, L. ; Frye, M. A. ; Gard, S. ; Garnham, J. S. ; Goes, F. S. ; Grigoroiu-Serbanescu, M. ; Fallgatter, A.Extern* ; Stegmaier, S. ; Ethofer, T. ; Biere, S. ; Petrova, K. ; Schuster, C. ; Adorjan, K. ; Budde, M. ; Heilbronner, M. ; Kalman, J. L. ; Kohshour, M. O. ; Reich-Erkelenz, D. ; Schaupp, S. K. ; Schulte, E. C. ; Senner, F. ; Vogl, T. ; Anghelescu, I.-G. ; Arolt, V. ; Dannlowski, U. ; Dietrich, D. ; Figge, C. ; Jäger, M. ; Lang, F. U. ; Juckel, G. ; Konrad, C. ; Reimer, J. ; Schmauß, M. ; Schmitt, A. ; Spitzer, C. ; von Hagen, M. ; Wiltfang, J.DZNE* ; Zimmermann, J. ; Andlauer, T. F. M. ; Fischer, A.DZNE* ; Bermpohl, F. ; Ritter, P. ; Matura, S. ; Gryaznova, A. ; Falkenberg, I. ; Yildiz, C. ; Kircher, T. ; Schmidt, J. ; Koch, M. ; Gade, K. ; Trost, S. ; Haussleiter, I. S. ; Lambert, M. ; Rohenkohl, A. C. ; Kraft, V. ; Grof, P. ; Hashimoto, R. ; Hauser, J. ; Herms, S. ; Hoffmann, P. ; Jiménez, E. ; Kahn, J.-P. ; Kassem, L. ; Kuo, P.-H. ; Kato, T. ; Kelsoe, J. ; Kittel-Schneider, S. ; Ferensztajn-Rochowiak, E. ; König, B. ; Kusumi, I. ; Laje, G. ; Landén, M. ; Lavebratt, C. ; Leboyer, M. ; Leckband, S. G. ; Tortorella, A. ; Manchia, M. ; Martinsson, L. ; McCarthy, M. J. ; McElroy, S. ; Colom, F. ; Millischer, V. ; Mitjans, M. ; Mondimore, F. M. ; Monteleone, P. ; Nievergelt, C. M. ; Nöthen, M. ; Novák, T. ; O'Donovan, C. ; Ozaki, N. ; Pfennig, A. ; Pisanu, C. ; Potash, J. B. ; Reif, A. ; Reininghaus, E. ; Rouleau, G. A. ; Rybakowski, J. K. ; Schalling, M. ; Schofield, P. R. ; Schweizer, B. W. ; Severino, G. ; Shilling, P. D. ; Shimoda, K. ; Simhandl, C. ; Slaney, C. M. ; Squassina, A. ; Stamm, T. ; Stopkova, P. ; Maj, M. ; Turecki, G. ; Vieta, E. ; Veeh, J. ; Witt, S. H. ; Wright, A. ; Zandi, P. P. ; Mitchell, P. B. ; Bauer, M. ; Alda, M. ; Rietschel, M. ; McMahon, F. J. ; Schulze, T. G. ; Clark, S. R. ; Baune, B. T.

2023
Macmillan London

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Please use a persistent id in citations: doi:10.1038/s41380-023-02149-1

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.

Keyword(s): Bipolar Disorder: drug therapy (MeSH) ; Bipolar Disorder: genetics (MeSH) ; Humans (MeSH) ; Female (MeSH) ; Male (MeSH) ; Multifactorial Inheritance: genetics (MeSH) ; Adult (MeSH) ; Middle Aged (MeSH) ; Lithium: therapeutic use (MeSH) ; Lithium: pharmacology (MeSH) ; Treatment Outcome (MeSH) ; Bayes Theorem (MeSH) ; Genome-Wide Association Study: methods (MeSH) ; Glutamic Acid: metabolism (MeSH) ; Cohort Studies (MeSH) ; Lithium Compounds: therapeutic use (MeSH) ; Lithium Compounds: pharmacology (MeSH) ; Acetylcholine: metabolism (MeSH) ; Polymorphism, Single Nucleotide: genetics (MeSH) ; Antimanic Agents: therapeutic use (MeSH) ; Antimanic Agents: pharmacology (MeSH) ; Lithium ; Glutamic Acid ; Lithium Compounds ; Acetylcholine ; Antimanic Agents

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Contributing Institute(s):

1. Molecular biomarkers for predictive diagnostics of neurodegenerative diseases (AG Wiltfang)
2. Epigenetics and Systems Medicine in Neurodegenerative Diseases (AG Fischer)

Research Program(s):

1. 353 - Clinical and Health Care Research (POF4-353) (POF4-353)
2. 352 - Disease Mechanisms (POF4-352) (POF4-352)

Appears in the scientific report 2023

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Database coverage:
; ; ; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; DEAL Springer ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 10 ; JCR ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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