PER/CRY heterodimers, in turn, inhibit the activity of the BMAL1-CLOCK complex. The CLOCK protein forms a heterodimer with BMAL1, which activates additional core clock genes. The core feedback loop includes the transcription factor CLOCK, which regulates the transcription of genes in the Period ( per1, per2, and per3) and Cryptochrome ( cry1 and cry2) gene families. The molecular clock driving these rhythms is created by feedback loops in core clock genes and their associated transcription factors that control physiological cycles in the body via the regulation of over a third of all transcribed genes 9, 10. Clinical studies have also demonstrated that circadian rhythms and circadian clock genes can modulate mood and psychiatric disorders but few of these studies have explicitly focused on anxiety 8.Ĭircadian rhythms regulate a sleep–wake cycle that is reset every 24 h based on exposure to natural or artificial light–dark cycles. The search for genetic and environmental factors contributing to the epidemic of mental health has uncovered numerous links between circadian rhythm disruptions and mood disorders including major depressive disorder (MDD), schizophrenia, bipolar disorder (BD), and generalized anxiety disorder 2, 3, 4, 5, 6, 7. These disorders negatively impact productivity, social relationships, and overall quality of life in individuals.

Mood disorders, including depression and anxiety, are becoming more prevalent globally, affecting nearly one-fifth of the adult population 1. Unraveling the complex molecular mechanisms underlying the links between circadian physiology and mood is essential to identifying the core clock genes to target in future functional studies, thereby advancing the development of non-invasive treatments for anxiety-related disorders.

Our results support both direct and indirect influences of clock gene variants on mood: while sex-specific clock genotype combinations predictive of anxiety symptoms suggest direct effects on mood pathways, the mediation of PER3 effects on anxiety via diurnal preference measures and the association of circadian phase with anxiety symptoms provide evidence for indirect effects of the molecular clockwork on mood. Further analyses revealed that individuals with advanced phases and pronounced circadian misalignment were at higher risk for severe anxiety symptoms. We identified multiple novel circadian genotypes predictive of anxiety, with the PER3(rs17031614)-AG/ CRY1(rs2287161)-CG genotype being the strongest predictor of anxiety risk, particularly in males. Molecular chronotyping, using clock gene expression oscillations, revealed that advanced circadian phase and robust circadian amplitudes are associated with high levels of anxiety symptoms. Employing machine learning combined with statistical approaches, we explored clock genotype combinations that predict risk for anxiety symptoms in a deeply phenotyped population. Molecular mechanisms underlying these connections may be direct-via transcriptional activity of clock genes on downstream mood pathways in the brain, or indirect-via clock gene influences on the phase and amplitude of circadian rhythms which, in turn, modulate physiological processes influencing mood. Mood disorders, including generalized anxiety disorder, are associated with disruptions in circadian rhythms and are linked to polymorphisms in circadian clock genes.

Abi time clock