用于预测双相情感障碍患者临床锂盐治疗反应的特定通路多基因评分
Pathway-Specific Polygenic Scores for Predicting Clinical Lithium Treatment Response in Patients With Bipolar Disorder.
作者信息
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
机构信息
Discipline of Psychiatry, School of Medicine, University of Adelaide, Adelaide, South Australia, Australia.
Asrat Woldeyes Health Science Campus, Debre Berhan University, Debre Berhan, Ethiopia.
出版信息
Biol Psychiatry Glob Open Sci. 2025 Jun 25;5(5):100558. doi: 10.1016/j.bpsgos.2025.100558. eCollection 2025 Sep.
BACKGROUND
Polygenic scores (PGSs) hold the potential to identify patients who respond favorably to specific psychiatric treatments. However, their biological interpretation remains 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.
METHODS
Using sets of genes involved in pathways affected by lithium, we developed 9 PS and evaluated their associations with lithium response in the International Consortium on Lithium Genetics (ConLiGen) ( = 2367), with validation in combined PsyCourse (Pathomechanisms and Signatures in the Longitudinal Course of Psychosis) ( = 105) and BipoLife ( = 102) cohorts. The association between each PS and lithium response-defined both as a continuous ALDA score and a categorical outcome (good vs. poor responses)-was evaluated using regression models, with adjustment for confounders. The cutoff for a significant association was < .05 after multiple testing correction.
RESULTS
The PGSs for acetylcholine, GABA (gamma-aminobutyric acid), and mitochondria were associated with response to lithium in both categorical and continuous outcomes. However, the PGSs for calcium channel, circadian rhythm, and GSK (glycogen synthase kinase) were associated only with the continuous outcome. Each score explained 0.29% to 1.91% of the variance in the categorical and 0.30% to 1.54% of the variance in the continuous outcomes. A multivariate model combining PS that showed significant associations in the univariate analysis (combined PS) increased the percentage of variance explained ( ) to 3.71% and 3.18% for the categorical and continuous outcomes, respectively. Associations for PGSs for GABA and circadian rhythm were replicated. Patients with the highest genetic loading (10th decile) for acetylcholine variants were 3.03 times more likely (95% CI, 1.95 to 4.69) to show a good lithium response (categorical outcome) than patients with the lowest genetic loading (1st decile).
CONCLUSIONS
PS achieved predictive performance comparable to the conventional genome-wide PGSs, with the added advantage of biological interpretability using a smaller list of genetic variants.
背景
多基因评分（PGS）有潜力识别出对特定精神科治疗反应良好的患者。然而，其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评分（PS），并评估了它们与双相情感障碍患者临床锂反应的关联。
方法
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（ConLiGen）（n = 2367）中评估了它们与锂反应的关联，并在综合的PsyCourse（精神病纵向病程中的发病机制和特征）（n = 105）和BipoLife（n = 102）队列中进行验证。使用回归模型评估每个PS与锂反应之间的关联，锂反应定义为连续的ALDA评分和分类结果（良好反应与不良反应），并对混杂因素进行调整。多次检验校正后，显著关联的临界值为p < 0.05。
结果
乙酰胆碱、GABA（γ-氨基丁酸）和线粒体的PGS在分类和连续结果中均与锂反应相关。然而，钙通道、昼夜节律和GSK（糖原合酶激酶）的PGS仅与连续结果相关。每个评分在分类结果中解释了0.29%至1.91%的方差，在连续结果中解释了0.30%至1.54%的方差。一个结合了在单变量分析中显示出显著关联的PS的多变量模型（组合PS），在分类和连续结果中分别将解释的方差百分比（R²）提高到3.71%和3.18%。GABA和昼夜节律的PGS关联得到了重复验证。乙酰胆碱变体基因负荷最高（第10分位数）的患者比基因负荷最低（第1分位数）的患者表现出良好锂反应（分类结果）的可能性高3.03倍（95%CI，1.95至4.69）。
结论
PS实现了与传统全基因组PGS相当的预测性能，具有使用较少基因变异列表进行生物学解释的额外优势。
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