Is the molecular clock ticking differently in bipolar disorder? Methylation analysis of the clock gene ARNTL

Abstract

Nearly all patients with bipolar disorder have severely disrupted circadian rhythms. Treatment with mood stabilizers can restore these daily rhythms, and this is correlated with patient recovery. However, it is still uncertain whether clock abnormalities are the cause of bipolar disorder or if these rhythm disruptions are secondary to alterations in other circuits. Furthermore, the mechanism by which the circadian clock might influence mood is still unclear. With cloning and characterization of the circadian genes and recent advances in molecular biology, we are starting to understand this strong association between circadian rhythms and bipolar disorder. Recent human genetic and mouse behavioral studies indicate that the Clock gene is particularly relevant in the mood disruptions associated with this disorder. Furthermore, it appears that Clock expression outside of the central pacemaker of the suprachiasmatic nucleus (SCN) is involved in mood regulation. In this chapter, the evidence linking circadian rhythms, the Clock gene, and bipolar disorder is discussed, along with the possible biology that underlies this connection.

Polygenic Risk Scores and Bipolar Disorder

“…Many association studies already prove a connection between individual SNPs (Single Nucleotide Polymorphisms) of ARNTL and BD, while others could not replicate this finding recently [30][31][32][33][34][35] . ARNTL showed also significantly higher methylation at cg05733463 in individuals with BD compared to controls in a sample from Graz, Austria [38] . The association between circadian rhythms and mood was also found in a recent large scale GWAS of circadian rhythmicity in 71,500 UK Biobank participants and polygenic association of circadian rest-activity rhythmicity with mood instability, MDD (Major Depressive Disorder) and neuroticism [39] .…”

“…One further important function of the molecular clock is the transcription activation of the MAOA gene, which encodes for the enzyme Monoamine oxidase A that is responsible for the breakdown of the neurotransmitter serotonin, noradrenaline and dopamine. The gene product of the clock gene ARNTL binds as heterodimer to E-boxes of MAOA and activates the transcription of the enzyme MAOA, which explains the strong interconnection between mood and the molecular clock [37,38] .…”

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“…In various other tumor cell lines, hypermethylation of the Bmal1 promoter was shown to silence this gene and to suppress circadian rhythmicity [11,25,[45][46][47]. Hypermethylation of a CpG island in the 5' region and hypomethylation in the first exon of Bmal1 were reported for cases of bipolar disorder [48]. Changes in CpG methylation of Bmal1 were also observed upon dietary changes [49].…”

Dissecting the Epigenetic Changes Induced by Non-Antipsychotic Mood Stabilizers on Schizophrenia and Affective Disorders: A Systematic Review

“…Twenty-one described studies of rodent samples (Tremolizzo et al, 2002;Dong et al, 2005;Tremolizzo et al, 2005;Kim et al, 2008;Dong et al, 2010;Hobara et al, 2010;Perisic et al, 2010;Matrisciano et al, 2011;Wang et al, 2012;Zimmermann et al, 2012;Calabrese et al, 2013;Leng et al, 2013;Ookubo et al, 2013;Liu et al, 2014;Mackowiak et al, 2014;Balasubramanian et al, 2015;Bator et al, 2015;Dwivedi and Zhang, 2015;Lee et al, 2015;Leng et al, 2016;Bahna and Niles, 2017). Seven articles studied human cell lines (Asai et al, 2013;Kao et al, 2013;Dyrvig et al, 2017;Zong et al, 2017;Billingsley et al, 2018;Dyrvig et al, 2019;Manca et al, 2019) and eight focused on blood samples of subjects diagnosed with either of the selected psychiatric disorders (Gavin et al, 2009;D'Addario et al, 2012;Dell'Osso et al, 2014;Huzayyin et al, 2014;Burghardt et al, 2015;Burghardt et al, 2016;Houtepen et al, 2016;Bengesser et al, 2018). One article studied rodents and human cell lines and subjects (Kaminsky et al, 2015) and one focused on patients and human cell lines (Kakiuchi et al, 2003).…”

“…Lithium was also associated with reduced methylation at one site in the 5′ regulatory region of ARNTL (cg05733463) when compared to individuals with BD not taking lithium, suggesting an activation of epigenetic marks with an associated increased gene expression (Bengesser et al, 2018). ARNTL, a core component of the circadian clock, is involved in the expression of the MAOA gene, therefore imbalances in the relation between circadian rhythms and neurotransmitter degradation may contribute towards an increased BD susceptibility (Geoffroy, 2018).…”