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Association of polygenic score and the involvement of cholinergic and glutamatergic pathways with lithium treatment response in patients with bipolar disorder

ContributorsAmare, Azmeraw T.orcid; Thalamuthu, Anbupalam; Schubert, Klaus Oliverorcid; Fullerton, Janice M.orcid; Ahmed, Muktar; Hartmann, Simonorcid; Papiol, Sergiorcid; Heilbronner, Ursorcid; Degenhardt, Franziska; Tekola-Ayele, Fasil; Hou, Liping; Hsu, Yi-Hsiang; Shekhtman, Tatyana; Adli, Mazda; Akula, Nirmala; Akiyama, Kazufumi; Ardau, Raffaella; Arias, Bárbaraorcid; Aubry, Jean-Michel; Hasler, Roland; Richard Lepouriel, Hélèneorcid; Perroud, Nader Aliorcid; Backlund, Lena; Bhattacharjee, Abesh Kumar; Bellivier, Frank; Benabarre, Antonio; Bengesser, Susanne; Biernacka, Joanna M.orcid; Birner, Armin; Marie-Claire, Cynthiaorcid; Cervantes, Pablo; Chen, Hsi-Chungorcid; Chillotti, Caterina; Cichon, Svenorcid; Cruceanu, Cristianaorcid; Czerski, Piotr M.orcid; Dalkner, Nina; Del Zompo, Mariaorcid; DePaulo, J. Raymondorcid; Étain, Brunoorcid; Jamain, Stephaneorcid; Falkai, Peter; Forstner, Andreas J.orcid; Frisen, Louise; Frye, Mark A.orcid; Gard, Sébastien; Garnham, Julie S.orcid; Goes, Fernando S.orcid; Grigoroiu-Serbanescu, Mariaorcid; Fallgatter, Andreas J.; Stegmaier, Sophia; Ethofer, Thomas; Biere, Silvia; Petrova, Kristiyana; Schuster, Ceylan; Adorjan, Kristina; Budde, Monika; Heilbronner, Maria; Kalman, Janos L.orcid; Kohshour, Mojtaba Orakiorcid; Reich-Erkelenz, Daniela; Schaupp, Sabrina K.; Schulte, Eva C.orcid; 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, Jensorcid; Schmauß, Max; Schmitt, Andrea; Spitzer, Carsten; von Hagen, Martin; Wiltfang, Jensorcid; Zimmermann, Jörg; Andlauer, Till F. M.orcid; Fischer, Andre; Bermpohl, Felix; Ritter, Philipporcid; Matura, Silke; Gryaznova, Anna; Falkenberg, Irina; Yildiz, Cüneytorcid; Kircher, Tilo; Schmidt, Juliaorcid; Koch, Mariusorcid; Gade, Kathrinorcid; Trost, Sarah; Haussleiter, Ida S.; Lambert, Martin; Rohenkohl, Anja C.; Kraft, Vivien; Grof, Paul; Hashimoto, Ryota
Publication date2023-07-11
First online date2023-07-11
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.

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Citation (ISO format)
AMARE, Azmeraw T. et al. Association of polygenic score and the involvement of cholinergic and glutamatergic pathways with lithium treatment response in patients with bipolar disorder. In: Molecular psychiatry, 2023. doi: 10.1038/s41380-023-02149-1
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ISSN of the journal1359-4184
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