精神分裂症多基因评分及HLA抗原与炎症基因与双相情感障碍患者锂盐治疗反应的关联：一项全基因组关联研究
Association of Polygenic Score for Schizophrenia and HLA Antigen and Inflammation Genes With Response to Lithium in Bipolar Affective Disorder: A Genome-Wide Association Study.
作者信息
Amare Azmeraw T, Schubert Klaus Oliver, Hou Liping, Clark Scott R, Papiol Sergi, Heilbronner Urs, Degenhardt Franziska, Tekola-Ayele Fasil, Hsu Yi-Hsiang, Shekhtman Tatyana, Adli Mazda, Akula Nirmala, Akiyama Kazufumi, Ardau Raffaella, Arias Bárbara, Aubry Jean-Michel, Backlund Lena, Bhattacharjee Abesh Kumar, Bellivier Frank, Benabarre Antonio, Bengesser Susanne, Biernacka Joanna M, Birner Armin, Brichant-Petitjean Clara, Cervantes Pablo, Chen Hsi-Chung, Chillotti Caterina, Cichon Sven, Cruceanu Cristiana, Czerski Piotr M, Dalkner Nina, Dayer Alexandre, Del Zompo Maria, DePaulo J Raymond, Étain Bruno, Falkai Peter, Forstner Andreas J, Frisen Louise, Frye Mark A, Fullerton Janice M, Gard Sébastien, Garnham Julie S, Goes Fernando S, Grigoroiu-Serbanescu Maria, Grof Paul, Hashimoto Ryota, Hauser Joanna, Herms Stefan, Hoffmann Per, Hofmann Andrea, Jamain Stephane, Jiménez Esther, Kahn Jean-Pierre, Kassem Layla, Kuo Po-Hsiu, Kato Tadafumi, Kelsoe John, Kittel-Schneider Sarah, Kliwicki Sebastian, 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, Mitjans Marina, Mondimore Francis M, Monteleone Palmiero, Nievergelt Caroline M, Nöthen Markus M, Novák Tomas, O'Donovan Claire, Ozaki Norio, Ösby Urban, Pfennig Andrea, 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, Volkert Julia, Witt Stephanie, Wright Adam, Zandi Peter P, Mitchell Philip B, Bauer Michael, Alda Martin, Rietschel Marcella, McMahon Francis J, Schulze Thomas G, Baune Bernhard T
机构信息
Discipline of Psychiatry, School of Medicine, University of Adelaide, Adelaide, South Australia, Australia.
Northern Adelaide Local Health Network, Mental Health Services, Adelaide, South Australia, Australia.
出版信息
JAMA Psychiatry. 2018 Jan 1;75(1):65-74. doi: 10.1001/jamapsychiatry.2017.3433.
IMPORTANCE
Lithium is a first-line mood stabilizer for the treatment of bipolar affective disorder (BPAD). However, the efficacy of lithium varies widely, with a nonresponse rate of up to 30%. Biological response markers are lacking. Genetic factors are thought to mediate treatment response to lithium, and there is a previously reported genetic overlap between BPAD and schizophrenia (SCZ).
OBJECTIVES
To test whether a polygenic score for SCZ is associated with treatment response to lithium in BPAD and to explore the potential molecular underpinnings of this association.
DESIGN, SETTING, AND PARTICIPANTS: A total of 2586 patients with BPAD who had undergone lithium treatment were genotyped and assessed for long-term response to treatment between 2008 and 2013. Weighted SCZ polygenic scores were computed at different P value thresholds using summary statistics from an international multicenter genome-wide association study (GWAS) of 36 989 individuals with SCZ and genotype data from patients with BPAD from the Consortium on Lithium Genetics. For functional exploration, a cross-trait meta-GWAS and pathway analysis was performed, combining GWAS summary statistics on SCZ and response to treatment with lithium. Data analysis was performed from September 2016 to February 2017.
MAIN OUTCOMES AND MEASURES
Treatment response to lithium was defined on both the categorical and continuous scales using the Retrospective Criteria of Long-Term Treatment Response in Research Subjects with Bipolar Disorder score. The effect measures include odds ratios and the proportion of variance explained.
RESULTS
Of the 2586 patients in the study (mean [SD] age, 47.2 [13.9] years), 1478 were women and 1108 were men. The polygenic score for SCZ was inversely associated with lithium treatment response in the categorical outcome, at a threshold P < 5 × 10-2. Patients with BPAD who had a low polygenic load for SCZ responded better to lithium, with odds ratios for lithium response ranging from 3.46 (95% CI, 1.42-8.41) at the first decile to 2.03 (95% CI, 0.86-4.81) at the ninth decile, compared with the patients in the 10th decile of SCZ risk. In the cross-trait meta-GWAS, 15 genetic loci that may have overlapping effects on lithium treatment response and susceptibility to SCZ were identified. Functional pathway and network analysis of these loci point to the HLA antigen complex and inflammatory cytokines.
CONCLUSIONS AND RELEVANCE
This study provides evidence for a negative association between high genetic loading for SCZ and poor response to lithium in patients with BPAD. These results suggest the potential for translational research aimed at personalized prescribing of lithium.
重要性
锂盐是治疗双相情感障碍（BPAD）的一线心境稳定剂。然而，锂盐的疗效差异很大，无反应率高达30%。目前缺乏生物学反应标志物。遗传因素被认为介导了对锂盐的治疗反应，并且先前有报道称BPAD和精神分裂症（SCZ）之间存在遗传重叠。
目的
检验SCZ的多基因分数是否与BPAD患者对锂盐的治疗反应相关，并探讨这种关联的潜在分子基础。
设计、设置和参与者：对2008年至2013年间接受锂盐治疗的2586例BPAD患者进行基因分型，并评估其长期治疗反应。使用来自一项针对36989例SCZ患者的国际多中心全基因组关联研究（GWAS）的汇总统计数据以及来自锂盐遗传学联盟中BPAD患者的基因型数据，在不同的P值阈值下计算加权SCZ多基因分数。为了进行功能探索，进行了跨性状元GWAS和通路分析，将SCZ的GWAS汇总统计数据与对锂盐治疗的反应相结合。数据分析于2016年9月至2017年2月进行。
主要结局和指标
使用双相情感障碍研究对象长期治疗反应的回顾性标准评分，在分类和连续量表上定义对锂盐的治疗反应。效应量包括比值比和解释的方差比例。
结果
在该研究的2586例患者（平均[标准差]年龄，47.2[13.9]岁）中，1478例为女性，1108例为男性。在分类结局中，SCZ的多基因分数与锂盐治疗反应呈负相关，阈值P<5×10⁻²。与处于SCZ风险第十分位数的患者相比，SCZ多基因负荷低的BPAD患者对锂盐反应更好，锂盐反应的比值比在第一分位数为3.46（95%CI，1.42 - 8.41），在第九分位数为2.03（95%CI，0.86 - 4.81）。在跨性状元GWAS中，鉴定出15个可能对锂盐治疗反应和SCZ易感性有重叠影响的基因位点。对这些位点的功能通路和网络分析指向HLA抗原复合体和炎性细胞因子。
结论及相关性
本研究为SCZ的高遗传负荷与BPAD患者对锂盐反应不佳之间的负相关提供了证据。这些结果表明了旨在实现锂盐个性化处方的转化研究的潜力。
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