Reinbold Céline S, Forstner Andreas J, Hecker Julian, Fullerton Janice M, Hoffmann Per, Hou Liping, Heilbronner Urs, Degenhardt Franziska, Adli Mazda, Akiyama Kazufumi, Akula Nirmala, Ardau Raffaella, Arias Bárbara, Backlund Lena, Benabarre Antonio, Bengesser Susanne, Bhattacharjee Abesh K, Biernacka Joanna M, Birner Armin, Marie-Claire Cynthia, Cervantes Pablo, Chen Guo-Bo, Chen Hsi-Chung, Chillotti Caterina, Clark Scott R, Colom Francesc, Cousins David A, Cruceanu Cristiana, Czerski Piotr M, Dayer Alexandre, Étain Bruno, Falkai Peter, Frisén Louise, Gard Sébastien, Garnham Julie S, Goes Fernando S, Grof Paul, Gruber Oliver, Hashimoto Ryota, Hauser Joanna, Herms Stefan, Jamain Stéphane, Jiménez Esther, Kahn Jean-Pierre, Kassem Layla, Kittel-Schneider Sarah, Kliwicki Sebastian, König Barbara, Kusumi Ichiro, Lackner Nina, Laje Gonzalo, Landén Mikael, Lavebratt Catharina, Leboyer Marion, Leckband Susan G, López Jaramillo Carlos A, MacQueen Glenda, Manchia Mirko, Martinsson Lina, Mattheisen Manuel, McCarthy Michael J, McElroy Susan L, Mitjans Marina, Mondimore Francis M, Monteleone Palmiero, Nievergelt Caroline M, Ösby Urban, Ozaki Norio, Perlis Roy H, Pfennig Andrea, Reich-Erkelenz Daniela, Rouleau Guy A, Schofield Peter R, Schubert K Oliver, Schweizer Barbara W, Seemüller Florian, Severino Giovanni, Shekhtman Tatyana, Shilling Paul D, Shimoda Kazutaka, Simhandl Christian, Slaney Claire M, Smoller Jordan W, Squassina Alessio, Stamm Thomas J, Stopkova Pavla, Tighe Sarah K, Tortorella Alfonso, Turecki Gustavo, Volkert Julia, Witt Stephanie H, Wright Adam J, Young L Trevor, Zandi Peter P, Potash James B, DePaulo J Raymond, Bauer Michael, Reininghaus Eva, Novák Tomáš, Aubry Jean-Michel, Maj Mario, Baune Bernhard T, Mitchell Philip B, Vieta Eduard, Frye Mark A, Rybakowski Janusz K, Kuo Po-Hsiu, Kato Tadafumi, Grigoroiu-Serbanescu Maria, Reif Andreas, Del Zompo Maria, Bellivier Frank, Schalling Martin, Wray Naomi R, Kelsoe John R, Alda Martin, McMahon Francis J, Schulze Thomas G, Rietschel Marcella, Nöthen Markus M, Cichon Sven
Human Genomics Research Group, Department of Biomedicine, University of Basel, Basel, Switzerland.
Institute of Medical Genetics and Pathology, University Hospital Basel, Basel, Switzerland.
Front Psychiatry. 2018 May 31;9:207. doi: 10.3389/fpsyt.2018.00207. eCollection 2018.
Bipolar disorder (BD) is a common, highly heritable neuropsychiatric disease characterized by recurrent episodes of mania and depression. Lithium is the best-established long-term treatment for BD, even though individual response is highly variable. Evidence suggests that some of this variability has a genetic basis. This is supported by the largest genome-wide association study (GWAS) of lithium response to date conducted by the International Consortium on Lithium Genetics (ConLiGen). Recently, we performed the first genome-wide analysis of the involvement of miRNAs in BD and identified nine BD-associated miRNAs. However, it is unknown whether these miRNAs are also associated with lithium response in BD. In the present study, we therefore tested whether common variants at these nine candidate miRNAs contribute to the variance in lithium response in BD. Furthermore, we systematically analyzed whether any other miRNA in the genome is implicated in the response to lithium. For this purpose, we performed gene-based tests for all known miRNA coding genes in the ConLiGen GWAS dataset ( = 2,563 patients) using a set-based testing approach adapted from the versatile gene-based test for GWAS (VEGAS2). In the candidate approach, showed a nominally significant association with lithium response, providing some evidence for involvement in both development and treatment of BD. In the genome-wide miRNA analysis, 71 miRNAs showed nominally significant associations with the dichotomous phenotype and 106 with the continuous trait for treatment response. A total of 15 miRNAs revealed nominal significance in both phenotypes with showing the strongest association with the continuous trait ( = 9.80E-04) and with the dichotomous phenotype ( = 5.79E-04). No association between miRNAs and treatment response to lithium in BD in either of the tested conditions withstood multiple testing correction. Given the limited power of our study, the investigation of miRNAs in larger GWAS samples of BD and lithium response is warranted.
双相情感障碍（BD）是一种常见的、高度可遗传的神经精神疾病，其特征为躁狂和抑郁反复发作。锂盐是BD最成熟的长期治疗药物，尽管个体反应差异很大。有证据表明，这种变异性部分具有遗传基础。这得到了国际锂盐遗传学联盟（ConLiGen）迄今为止开展的最大规模的锂盐反应全基因组关联研究（GWAS）的支持。最近，我们首次对BD中miRNA的参与情况进行了全基因组分析，并鉴定出9种与BD相关的miRNA。然而，尚不清楚这些miRNA是否也与BD中的锂盐反应相关。因此，在本研究中，我们测试了这9个候选miRNA的常见变异是否会导致BD中锂盐反应的差异。此外，我们系统地分析了基因组中的任何其他miRNA是否与锂盐反应有关。为此，我们使用一种基于集合的测试方法，该方法改编自通用的GWAS基因测试（VEGAS2），对ConLiGen GWAS数据集（n = 2563例患者）中所有已知的miRNA编码基因进行了基于基因的测试。在候选方法中，[具体基因名称]与锂盐反应显示出名义上的显著关联，为其参与BD的发生发展和治疗提供了一些证据。在全基因组miRNA分析中，71种miRNA与二分法表型显示出名义上的显著关联，106种与治疗反应的连续性状显示出名义上的显著关联。共有15种miRNA在两种表型中均显示出名义上的显著性，其中[具体基因名称]与连续性状的关联最强（p = 9.80E - 04），[具体基因名称]与二分法表型的关联最强（p = 5.79E - 04）。在任何一种测试条件下，miRNA与BD中锂盐治疗反应之间的关联均未通过多重检验校正。鉴于我们研究的检验效能有限，有必要在更大的BD和锂盐反应GWAS样本中对miRNA进行研究。
