{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nPER3 is a core circadian clock gene that plays a crucial role in regulating sleep‐wake cycles by modulating both the timing and intensity of sleep. Genetic variants—most notably variable‐number tandem‐repeat polymorphisms (e.g., PER3(5/5) versus PER3(4/4))—lead to differences in sleep structure, such as altered slow‐wave activity and sleep efficiency, and confer differential vulnerability to sleep loss–induced cognitive decline. In healthy individuals, these polymorphisms influence diurnal preference and the phase of circadian rhythms, as demonstrated by studies in young adults, older subjects, and even elite athletes. In parallel, molecular analyses in peripheral tissues and the brain have revealed robust oscillations in PER3 expression that underpin its regulatory role in sleep homeostasis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "21"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its impact on sleep regulation, PER3 has emerged as an important modulator of mood and affective disorders. Variations in this gene have been linked to differences in the onset and severity of bipolar disorder, depression (including postpartum depression), and seasonal affective tendencies. Such genetic influences likely interact with sleep and circadian disturbances to shape mood phenotypes. Furthermore, differential responses to mood‐stabilizing treatments such as lithium have been observed in relation to PER3 genotype, suggesting that PER3 may serve as a biomarker for therapeutic efficacy and for defining endophenotypes in psychiatric illnesses."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "22", "end_ref": "32"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nA growing body of evidence also implicates PER3 in tumor biology. Several studies indicate that reduced PER3 expression—often mediated by promoter hypermethylation rather than coding mutations—is associated with tumor progression in multiple cancers, including breast cancer, hepatocellular carcinoma, colorectal cancer, prostate cancer, and non‐small cell lung cancer. Such findings suggest that PER3 may act as a tumor suppressor by helping to regulate the cell cycle and apoptosis, thereby linking disruptions in circadian rhythms with carcinogenesis and paving the way for chronotherapeutic interventions in oncology."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "33", "end_ref": "43"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Carolina Johansson, Matthäeus Willeit, Christina Smedh, et al. 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