A gene co-expression module implicating the mitochondrial electron transport chain is associated with long-term response to lithium treatment in bipolar affective disorder.
A gene co-expression module implicating the mitochondrial electron transport chain is associated with long-term response to lithium treatment in bipolar affective disorder.
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DOI：
10.1038/s41398-018-0237-0
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发表时间：
2018-09-05
影响因子：
6.8
通讯作者：
Baune BT
中科院分区：
文献类型：
--
作者：
Stacey D;Schubert KO;Clark SR;Amare AT;Milanesi E;Maj C;Leckband SG;Shekhtman T;Kelsoe JR;Gurwitz D;Baune BT
锂是双相情感障碍(BPAD)的一线治疗方法，但三分之二的患者只有部分反应或根本没有反应。锂反应的高度变异性的原因还不是很清楚。转录组范围的图谱测试了基因和环境之间的接口，是探索锂反应可变性背后的分子机制的可行手段。因此，在目前的研究中，我们对n个 = 50名接受锂治疗的BPAD患者的全血rna-seq数据进行了共表达网络分析。锂的反应是使用经过充分验证的Alda量表进行评估的，我们使用该量表来定义连续和二分测量。我们发现由46个基因组成的共表达模块与表现为连续(即，范围0-10)的锂反应之间存在名义上的显著相关性(COR = −0.299，p = 0.035)。在这46个基因中，43个基因在锂离子响应较好的患者中有43个基因的mRNA表达水平低于较差的患者，并且该模块的中央调节因子都是线粒体编码的(MT-ND1，MT-ATP6，MT-CyB)。因此，浓缩分析表明，参与线粒体功能的基因在这个模块中过度表达，特别是电子传输链(ETC)和氧化磷酸化(OXPHOS)是受影响的过程。ETC和OXPHOS活性的紊乱此前已被认为与BPAD的病理生理有关。我们的数据补充了之前的证据，表明这些过程的正常化可能是锂的作用模式的核心，并可能奠定有利的治疗反应。
Lithium is the first-line treatment for bipolar affective disorder (BPAD) but two-thirds of patients respond only partially or not at all. The reasons for this high variability in lithium response are not well understood. Transcriptome-wide profiling, which tests the interface between genes and the environment, represents a viable means of exploring the molecular mechanisms underlying lithium response variability. Thus, in the present study we performed co-expression network analyses of whole-blood-derived RNA-seq data from n = 50 lithium-treated BPAD patients. Lithium response was assessed using the well-validated ALDA scale, which we used to define both a continuous and a dichotomous measure. We identified a nominally significant correlation between a co-expression module comprising 46 genes and lithium response represented as a continuous (i.e., scale ranging 0–10) phenotype (cor = −0.299, p = 0.035). Forty-three of these 46 genes had reduced mRNA expression levels in better lithium responders relative to poorer responders, and the central regulators of this module were all mitochondrially-encoded (MT-ND1, MT-ATP6, MT-CYB). Accordingly, enrichment analyses indicated that genes involved in mitochondrial functioning were heavily over-represented in this module, specifically highlighting the electron transport chain (ETC) and oxidative phosphorylation (OXPHOS) as affected processes. Disrupted ETC and OXPHOS activity have previously been implicated in the pathophysiology of BPAD. Our data adds to previous evidence suggesting that a normalisation of these processes could be central to lithium’s mode of action, and could underlie a favourable therapeutic response.
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WGCNA：用于加权相关网络分析的 R 包。
影响因子：
3
作者：
Langfelder P;Horvath S
通讯作者：
Horvath S
影响因子：
3.4
作者：
de Sousa, Rafael T.;Streck, Emilio L.;Machado-Vieira, Rodrigo
通讯作者：
Machado-Vieira, Rodrigo
DOI：
10.1186/2045-5380-2-15
发表时间：
2012-09-12
期刊：
Biology of mood & anxiety disorders
影响因子：
--
作者：
Lowthert L;Leffert J;Lin A;Umlauf S;Maloney K;Muralidharan A;Lorberg B;Mane S;Zhao H;Sinha R;Bhagwagar Z;Beech R
通讯作者：
Beech R
DOI：
10.1016/s0140-6736(16)00143-4
发表时间：
2016-03-12
期刊：
Lancet (London, England)
影响因子：
--
作者：
Hou L;Heilbronner U;Degenhardt F;Adli M;Akiyama K;Akula N;Ardau R;Arias B;Backlund L;Banzato CEM;Benabarre A;Bengesser S;Bhattacharjee AK;Biernacka JM;Birner A;Brichant-Petitjean C;Bui ET;Cervantes P;Chen GB;Chen HC;Chillotti C;Cichon S;Clark SR;Colom F;Cousins DA;Cruceanu C;Czerski PM;Dantas CR;Dayer A;Étain B;Falkai P;Forstner AJ;Frisén L;Fullerton JM;Gard S;Garnham JS;Goes FS;Grof P;Gruber O;Hashimoto R;Hauser J;Herms S;Hoffmann P;Hofmann A;Jamain S;Jiménez E;Kahn JP;Kassem L;Kittel-Schneider S;Kliwicki S;König B;Kusumi I;Lackner N;Laje G;Landén M;Lavebratt C;Leboyer M;Leckband SG;Jaramillo CAL;MacQueen G;Manchia M;Martinsson L;Mattheisen M;McCarthy MJ;McElroy SL;Mitjans M;Mondimore FM;Monteleone P;Nievergelt CM;Nöthen MM;Ösby U;Ozaki N;Perlis RH;Pfennig A;Reich-Erkelenz D;Rouleau GA;Schofield PR;Schubert KO;Schweizer BW;Seemüller F;Severino G;Shekhtman T;Shilling PD;Shimoda K;Simhandl C;Slaney CM;Smoller JW;Squassina A;Stamm T;Stopkova P;Tighe SK;Tortorella A;Turecki G;Volkert J;Witt S;Wright A;Young LT;Zandi PP;Potash JB;DePaulo JR;Bauer M;Reininghaus EZ;Novák T;Aubry JM;Maj M;Baune BT;Mitchell PB;Vieta E;Frye MA;Rybakowski JK;Kuo PH;Kato T;Grigoroiu-Serbanescu M;Reif A;Del Zompo M;Bellivier F;Schalling M;Wray NR;Kelsoe JR;Alda M;Rietschel M;McMahon FJ;Schulze TG
通讯作者：
Schulze TG
DOI：
10.1177/070674370705200606
发表时间：
2007-06-01
影响因子：
4
作者：
Duffy, Anne;Alda, Martin;Grof, Paul
通讯作者：
Grof, Paul