Sharew Nigussie T, Clark Scott R, Papiol Sergi, Heilbronner Urs, Degenhardt Franziska, Fullerton Janice M, Hou Liping, Shekhtman Tatyana, Adli Mazda, Akula Nirmala, Akiyama Kazufumi, Ardau Raffaella, Arias Bárbara, 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 E, 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, Viswanath Biju, Witt Stephanie H, Wright Adam, Zandi Peter P, Mitchell Philip B, Bauer Michael, Alda Martin, Rietschel Marcella, McMahon Francis J, Schulze Thomas G, Baune Bernhard T, Schubert Klaus Oliver, Amare Azmeraw T
medRxiv. 2025 Mar 24:2025.03.20.25324216. doi: 10.1101/2025.03.20.25324216.
Polygenic scores (PGSs) hold the potential to identify patients who respond favourably to specific psychiatric treatments. However, their biological interpretations remain unclear. In this study, we developed pathway-specific PGSs (PS ) for lithium response and assessed their association with clinical lithium response in patients with bipolar disorder (BD).
Using sets of genes involved in pathways affected by lithium, we developed nine PS and evaluated their associations with lithium response in the International Consortium on Lithium Genetics cohort (ConLi Gen: N = 2367), validated in the combined PsyCourse (N = 105) and BipoLife (N = 102) cohorts. Lithium responsiveness was assessed using the Retrospective Assessment of the Lithium Response Phenotype Scale (ALDA scale), for categorical outcome (good vs poor response) and continuous ALDA total score. Logistic and linear regressions, adjusting for age, sex, chip type, and the first four genetic principal components, were used to test associations, after multiple testing corrections ( <0.05).
Response to lithium was associated with PS for acetylcholine, GABA, calcium channel signalling, mitochondria, circadian rhythm, and GSK pathways, R² ranging from 0.29% to 1.91%, with R² of 3.71% for the combined PS Associations for GABA and CIR were replicated. In decile-based stratified analysis, patients with the highest genetic loading (10 decile) for acetylcholine pathway genetic variants were 3.03 times (95%CI: 1.95 - 4.69) more likely to have a good lithium response than the lowest decile (1 decile).
PS achieved predictive performance comparable with conventional genome-wide PGSs, with more biological interpretability and using a smaller list of genetic variants, facilitating further investigation into the interaction of variants and biological pathways underlying lithium response.
多基因分数（PGS）有潜力识别出对特定精神科治疗反应良好的患者。然而，它们的生物学解释仍不明确。在本研究中，我们开发了针对锂反应的通路特异性多基因分数（PS ），并评估了其与双相情感障碍（BD）患者临床锂反应的关联。
利用参与受锂影响通路的基因集，我们开发了9个PS ，并在国际锂遗传学联盟队列（ConLi Gen：N = 2367）中评估了它们与锂反应的关联，在联合的PsyCourse（N = 105）和BipoLife（N = 102）队列中进行了验证。使用锂反应表型回顾性评估量表（ALDA量表）评估锂反应性，用于分类结局（良好反应与不良反应）和连续的ALDA总分。在进行多重检验校正（ <0.05）后，使用逻辑回归和线性回归，并对年龄、性别、芯片类型和前四个遗传主成分进行调整，以检验关联。
对锂的反应与乙酰胆碱、γ-氨基丁酸（GABA）、钙通道信号传导、线粒体、昼夜节律和糖原合成酶激酶（GSK）通路的PS 相关，R²范围为0.29%至1.91%，联合PS 的R²为3.71%。GABA 和CIR 的关联得到了重复验证。在基于十分位数的分层分析中，乙酰胆碱通路基因变异的遗传负荷最高（第10十分位数）的患者比最低十分位数（第1十分位数）的患者有良好锂反应的可能性高3.03倍（95%置信区间：1.95 - 4.69）。
PS 实现了与传统全基因组PGS相当的预测性能，具有更强的生物学可解释性，且使用的基因变异列表更小，便于进一步研究锂反应背后的变异与生物学通路的相互作用。
