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Type: Journal article
Title: A gene co-expression module implicating the mitochondrial electron transport chain is associated with long-term response to lithium treatment in bipolar affective disorder
Author: Stacey, D.
Schubert, K.
Clark, S.
Amare, A.
Milanesi, E.
Maj, C.
Lechband, S.
Shekhtman, T.
Kelsoe, J.
Gurwitz, D.
Baune, B.
Citation: Translational Psychiatry, 2018; 8(1):183-1-183-11
Publisher: Nature Publishing Group
Issue Date: 2018
ISSN: 2158-3188
Statement of
David Stacey, K. Oliver Schubert, Scott R. Clark, Azmeraw T. Amare, Elena Milanesi, Carlo Maj, Susan G. Leckband, Tatyana Shekhtman, John R. Kelsoe, David Gurwitz and Bernhard T. Baune
Abstract: 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.
Keywords: Mitochondria; Humans; Lithium; Antimanic Agents; Treatment Outcome; Gene Expression Profiling; Bipolar Disorder; Gene Expression; Electron Transport; Phenotype; Adult; Aged; Aged, 80 and over; Middle Aged; Female; Male; Gene Regulatory Networks; Young Adult
Rights: © The Author(s) 2018. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit
RMID: 0030097314
DOI: 10.1038/s41398-018-0237-0
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