Modeling Strengthens Molecular Link between Circadian Polymorphisms and Major Mood Disorders

Abstract

Anxiety and other mood disorders, such as major depressive disorder (MDD) and seasonal affective disorder (SAD), affect nearly one-fifth of the global population and disproportionately affect young adults. Individuals affected by mood disorders are frequently plagued by sleep and circadian problems, and recent genetic studies provide ample support for the association of circadian and sleep syndromes with depression and anxiety. Mathematical modeling has been crucial in understanding some of the essential features of the mammalian circadian clock and is now a vital tool for dissecting how circadian genes regulate the molecular mechanisms that influence mood. Here, we model the effect of five clock gene polymorphisms, previously linked to mood disorders, on circadian gene expression and, ultimately, on the period length and amplitude of the clock, two parameters that dictate the phase, or alignment, of the clock relative to the environment. We then test whether these gene variants are associated with circadian phenotypes (Horne-Ostberg Morningness-Eveningness scores) and well-established measures of depression (Beck Depression Inventory) and anxiety (State-Trait Anxiety Inventory) in a population of undergraduates ( n = 546). In this population, we find significant allelic and/or genotypic associations between CRY2 and two PER3 variants and diurnal preference. The PER3 length polymorphism (rs57875989) was significantly associated with depression in this sample, and individuals homozygous for the PER3 single nucleotide polymorphism (SNP) (rs228697) reported significantly higher anxiety. Our simple model satisfies available experimental knockdown conditions as well as existing data on clock polymorphisms associated with mood. In addition, our model enables us to predict circadian phenotypes (e.g., altered period length, amplitude) associated with mood disorders in order to identify critical effects of clock gene mutations on CRY/BMAL binding and to predict that the intronic SNPs studied represent gain-of-function mutations, causing increased transcription rate. Given the user-friendly structure of our model, we anticipate that it will be useful for further study of the relationships among clock polymorphisms, circadian misalignment, and mood disorders.

Genome-Wide Association Study of Circadian Rhythmicity in 71,500 UK Biobank Participants and Polygenic Association with Mood Instability

“…This is perhaps surprising given the literature on circadian rhythmicity and mood disorders. Core circadian clock genes have been associated with both BD and depression, with altered circadian biology suggested to be a vulnerability marker for mood disorders [ [70] , [71] , [72] , [73] , [74] ]. It has been suggested that the treatment of disrupted circadian rhythmicity could be used in combination with current pharmaceutical therapies to develop more effective treatments for mood disorders [ 75 ].…”

Circadian Effects on Performance and Effort in Collegiate Swimmers

“…The two specific polymorphisms examined in this study alter coding regions containing phosphorylation sites. Reduced phosphorylation of PER3 may be associated with a lengthening of period and a delay in the circadian phase, both of which are typically associated with an evening phenotype [14462524]. This delay in circadian phase exacerbates the social jetlag (or misalignment of internal rhythms with daily sleep patterns) [423043], and likely enhances the offset in the physiological peak of evening-types.…”

Sleep Quality, Sleep Structure, and PER3 Genotype Mediate Chronotype Effects on Depressive Symptoms in Young Adults

“…One candidate mechanism is the PER3 gene, a highly rhythmic, circadian-related gene with expression in both the central nervous system and peripheral tissues (Archer et al, 2018). In humans, variants of the PER3 gene are associated with chronotype, sleep homeostasis, and mental disorders (Archer et al, 2003;Johansson et al, 2003;Akashi et al, 2010;McClung, 2013;Hida et al, 2014;Zhang et al, 2016;Liberman et al, 2017Liberman et al, , 2018Nguyen et al, 2019). A well-studied PER3 polymorphism in exon 18, rs57875989, encodes a variable number tandem repeat region (VNTR) containing a motif of 54 base pairs or 18 amino acids.…”