Scientific article
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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

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.

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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Article (Published version)
ISSN of the journal1359-4184

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