Network of co-expressed circadian genes, childhood maltreatment and sleep quality in bipolar disorders

ABSTRACT

Bipolar disorder (BD) is a chronic and burdensome psychiatric disease, characterized by variations in mood and energy. The literature has consistently demonstrated an association between BD and childhood maltreatment (CM), and genetic variants of circadian genes have been associated with an increased vulnerability to develop BD. In this context, environmental factors such as CM may also contribute to the susceptibility to BD through alterations in the functioning of the biological clock linked to modifications of expression of circadian genes. In this study, we explored the associations between childhood maltreatment, sleep quality, and the level of expression of a comprehensive set of circadian genes in lymphoblastoid cell lines from patients with BD. The sample consisted of 52 Caucasian euthymic patients with a diagnosis of BD type 1 or type 2. The exposure to CM was assessed with the Childhood Trauma Questionnaire (CTQ), and the sleep quality was assessed using the Pittsburgh Sleep Quality Index. We measured the expression of 18 circadian genes using quantitative RT-PCR: ARNTL2, BHLHE40, BHLHE41, CLOCK, CRY1, CRY2, CSNK1D, CSNK1E, DBP, GSK3B, NPAS2, NR1D1, PER1, PER2, PER3, PPARGC1A, RORA, and RORB. Gene expression networks were analyzed with the disjoint graphs method. Compared to the other investigated transcripts, PPARGC1A was the only one whose expression level was differentially affected in patients who have experienced CM and, more specifically, physical abuse. We observed no significant effects of the other CTQ subscores (emotional and sexual abuses, physical and emotional neglects), nor of the sleep quality on the network of circadian genes expression. Although requiring replication in larger cohorts, the result obtained here is consistent with the hypothesis of an influence of CM exposure on circadian systems and highlights the importance of PPARGC1A in these processes.

KEYWORDS:

• Bipolar disorder
• circadian gene
• childhood trauma
• childhood maltreatment
• sleep
• early life stress
• gene expression

Acknowledgements

We thank INSERM and Labex BioPsy for the PhD funding (Poste Accueil) to DGL. Dr. C. Marie-Claire is supported by the Centre National de la Recherche Scientifique. Lymphoblastoid cell lines were established at the Centre de Ressources Biologique, Hôpital Cochin AP-HP, Paris. We thank the clinicians and nursing staff of the French Academic Centers for Expertise in BD (FACE-BD) for the recruitment and clinical characterization of individuals with BD.

Disclosure statement

F. Bellivier has received honoraria and financial compensation as an independent symposium speaker from Sanofi-Aventis, Lundbeck, AstraZeneca, Eli Lilly, Bristol-Myers Squibb and Servier. B. Etain has received honoraria from Sanofi-Aventis. All other authors have no conflicts of interest relevant to the subject matter of this article.

Contributors

D. Grillault Laroche: Formal analysis, Writing - original draft

E. Curis: Formal analysis,

F. Bellivier: Writing -review & editing

C. Nepost: Methodology

G. Gross: Methodology

C. Marie-Claire: Conceptualization, Writing -review & editing

B. Etain: Conceptualization, Funding acquisition, Writing -review & editing

Supplementary material

Supplemental data for this article can be accessed on the publisher’s website.

Additional information

Funding

This work was supported by INSERM (Institut National de la Santé et de la Recherche Médicale), AP-HP (Assistance Publique des Hôpitaux de Paris).