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Lithium-responsive genes and gene networks in bipolar disorder patient-derived lymphoblastoid cell lines

Lithium-responsive genes and gene networks in bipolar disorder patient-derived lymphoblastoid cell lines
Lithium-responsive genes and gene networks in bipolar disorder patient-derived lymphoblastoid cell lines

Lithium (Li) is the mainstay mood stabilizer for the treatment of bipolar disorder (BD), although its mode of action is not yet fully understood nor is it effective in every patient. We sought to elucidate the mechanism of action of Li and to identify surrogate outcome markers that can be used to better understand its therapeutic effects in BD patients classified as good (responders) and poor responders (nonresponders) to Li treatment. To accomplish these goals, RNA-sequencing gene expression profiles of lymphoblastoid cell lines (LCLs) were compared between BD Li responders and nonresponders with healthy controls before and after treatment. Several Li-responsive gene coexpression networks were discovered indicating widespread effects of Li on diverse cellular signaling systems including apoptosis and defense response pathways, protein processing and response to endoplasmic reticulum stress. Individual gene markers were also identified, differing in response to Li between BD responders and nonresponders, involved in processes of cell cycle and nucleotide excision repair that may explain part of the heterogeneity in clinical response to treatment. Results further indicated a Li gene expression signature similar to that observed with clonidine treatment, an α2-adrenoceptor agonist. These findings provide a detailed mechanism of Li in LCLs and highlight putative surrogate outcome markers that may permit for advanced treatment decisions to be made and for facilitating recovery in BD patients.

Journal Article
1470-269X
446-453
Breen, M.S.
2a4241cd-4f16-4f7f-9165-1459ed2c8890
White, C.H.
45233a78-f0c9-4696-8aaf-1b2673f83c91
Shekhtman, T.
e46425c6-e576-49af-8e9b-e3f684649934
Lin, K.
082c0aab-4a80-4f5a-9d29-643ec99b73be
Looney, D.
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Woelk, C.H.
4d3af0fd-658f-4626-b3b5-49a6192bcf7d
Kelsoe, J.R.
51e9b97a-20ce-4254-85a4-31aa028db323
Breen, M.S.
2a4241cd-4f16-4f7f-9165-1459ed2c8890
White, C.H.
45233a78-f0c9-4696-8aaf-1b2673f83c91
Shekhtman, T.
e46425c6-e576-49af-8e9b-e3f684649934
Lin, K.
082c0aab-4a80-4f5a-9d29-643ec99b73be
Looney, D.
40a6197e-dd09-46d7-b4ac-0c6608a4cc0d
Woelk, C.H.
4d3af0fd-658f-4626-b3b5-49a6192bcf7d
Kelsoe, J.R.
51e9b97a-20ce-4254-85a4-31aa028db323

Breen, M.S., White, C.H., Shekhtman, T., Lin, K., Looney, D., Woelk, C.H. and Kelsoe, J.R. (2016) Lithium-responsive genes and gene networks in bipolar disorder patient-derived lymphoblastoid cell lines. The Pharmacogenomics Journal, 16 (5), 446-453. (doi:10.1038/tpj.2016.50).

Record type: Article

Abstract

Lithium (Li) is the mainstay mood stabilizer for the treatment of bipolar disorder (BD), although its mode of action is not yet fully understood nor is it effective in every patient. We sought to elucidate the mechanism of action of Li and to identify surrogate outcome markers that can be used to better understand its therapeutic effects in BD patients classified as good (responders) and poor responders (nonresponders) to Li treatment. To accomplish these goals, RNA-sequencing gene expression profiles of lymphoblastoid cell lines (LCLs) were compared between BD Li responders and nonresponders with healthy controls before and after treatment. Several Li-responsive gene coexpression networks were discovered indicating widespread effects of Li on diverse cellular signaling systems including apoptosis and defense response pathways, protein processing and response to endoplasmic reticulum stress. Individual gene markers were also identified, differing in response to Li between BD responders and nonresponders, involved in processes of cell cycle and nucleotide excision repair that may explain part of the heterogeneity in clinical response to treatment. Results further indicated a Li gene expression signature similar to that observed with clonidine treatment, an α2-adrenoceptor agonist. These findings provide a detailed mechanism of Li in LCLs and highlight putative surrogate outcome markers that may permit for advanced treatment decisions to be made and for facilitating recovery in BD patients.

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More information

Accepted/In Press date: 18 May 2016
e-pub ahead of print date: 12 July 2016
Published date: October 2016
Keywords: Journal Article

Identifiers

Local EPrints ID: 413286
URI: https://eprints.soton.ac.uk/id/eprint/413286
ISSN: 1470-269X
PURE UUID: 1e9a862d-f13f-4b9a-9016-7eaf19c845ca

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Date deposited: 18 Aug 2017 16:32
Last modified: 19 Jul 2019 18:30

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