학술논문
Association of polygenic score and the involvement of cholinergic and glutamatergic pathways with lithium treatment response in patients with bipolar disorder
Document Type
Original Paper
Author
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; Chen, Hsi-Chung; 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; 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 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.
Source
Molecular Psychiatry. 28(12):5251-5261
Subject
Language
English
ISSN
1359-4184
1476-5578
1476-5578
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.