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
Discipline of Psychiatry, School of Medicine, University of Adelaide, Adelaide, SA, Australia.
Centre for Healthy Brain Ageing (CHeBA), Discipline of Psychiatry and Mental Health, UNSW Medicine & Health, University of New South Wales, Sydney, Australia.
Mol Psychiatry. 2023 Dec;28(12):5251-5261. doi: 10.1038/s41380-023-02149-1. Epub 2023 Jul 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) 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 was developed in the International Consortium of Lithium Genetics cohort (ConLiGen: N = 2367) and replicated in the combined PsyCourse (N = 89) and BipoLife (N = 102) studies. The associations of Li 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 was positively associated with lithium treatment response in the ConLiGen cohort, in both the categorical (P = 9.8 × 10, R = 1.9%) and continuous (P = 6.4 × 10, R = 2.6%) outcomes. Compared to bipolar patients in the 1 decile of the risk distribution, individuals in the 10 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, R = 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 may be useful in the development of pharmacogenomic testing strategies by enabling a classification of bipolar patients according to their response to treatment.
锂被视为双相情感障碍（BD）的一线治疗药物，双相情感障碍是一种严重且致残的心理健康障碍，全球约1%的人口受其影响。然而，锂并非始终有效，只有30%的患者对治疗表现出良好反应。为双相情感障碍患者提供个性化治疗方案，识别诸如多基因分数等预测生物标志物至关重要。在本研究中，我们开发了一种用于双相情感障碍患者锂治疗反应（Li）的多基因分数。为了进一步深入了解锂可能的分子作用机制，我们进行了全基因组基于基因的分析。通过使用结合贝叶斯回归和连续收缩先验的方法进行多基因分数建模，在国际锂遗传学联盟队列（ConLiGen：N = 2367）中开发了Li，并在PsyCourse（N = 89）和BipoLife（N = 102）联合研究中进行了复制。使用回归模型测试Li与锂治疗反应的关联——以连续的ALDA量表和分类结果（良好反应与不良反应）定义，每个模型均针对协变量进行了调整：年龄、性别和前四个遗传主成分。统计学显著性确定为P < 0.05。在ConLiGen队列中，Li与锂治疗反应呈正相关，在分类结果（P = 9.8×10，R = 1.9%）和连续结果（P = 6.4×10，R = 2.6%）中均如此。与处于风险分布第1十分位数的双相情感障碍患者相比，处于第10十分位数的个体对锂产生良好反应的几率高3.47倍（95%CI：2.22 - 5.47）。结果在独立队列中针对分类治疗结果进行了复制（P = 3.9×10，R = 0.9%），但针对连续结果未进行复制（P = 0.13）。基于基因的分析揭示了36个候选基因，这些基因在由谷氨酸和乙酰胆碱控制的生物途径中富集。Li可能有助于开发药物基因组学检测策略，通过根据双相情感障碍患者对治疗的反应进行分类。
