Circadian rhythm sleep-wake disorders (CRSWDs) arise from alterations in the circadian timing system or from misalignments between endogenous circadian rhythms and environmental or behavioral demands, leading to sleep disturbances and impaired functioning. Diagnosis remains challenging and largely reliant on subjective assessments, highlighting the need for biologically informed markers. Although genetic and epigenetic factors have been implicated in circadian regulation, their contribution to clinically defined CRSWDs has not previously been systematically evaluated across disorders. This systematic review, registered in PROSPERO (ID: 1117673), examined genetic polymorphisms and epigenetic modifications associated with CRSWDs in studies published up to October 2024. Of 871 articles screened, 38 met the inclusion criteria. Delayed sleep-wake phase disorder was investigated in 18 studies (47 %), shift work disorder in 17 studies (45 %), and non-24-h sleep-wake rhythm disorder in eight studies (21 %). Of these, 27 examined genetic variants, predominantly using candidate-gene approaches targeting core clock genes and circadian-related pathways. Ten studies investigated epigenetic alterations, all limited to DNA methylation and conducted exclusively in the context of shift work disorder. Only one study assessed both genetic and epigenetic variations. The findings suggest that genetic variations, particularly in but not limited to core clock genes, are implicated in an increased susceptibility to CRSWDs. In addition, DNA methylation changes in clock genes and genes as MTNR1B, SIRT1, and SLC6A4 may play a role in modulating circadian adaptation, particularly in the context of shift work. However, substantial heterogeneity in phenotypic definitions, study design, and confounder control limits causal inference and cross-disorder comparison. Only five findings met the review-defined evidentiary standards: the functionally validated PER2 S662G and CSNK1D T44A mutations causing familial advanced sleep phase syndrome (FASPS), the independently replicated PER2 p.Val1205Met and RORC rs3828057 associations with delayed sleep-wake phase disorder (DSWPD), and the MTNR1B rs10830963 × night-shift-work interaction associated with prostate cancer risk. All other reported genetic and epigenetic associations remain exploratory. In conclusion, this review identifies a fragmented and uneven evidence base, with major gaps in epigenetic research and integrative genetic-epigenetic analyses across CRSWDs. Epigenetic studies have been conducted almost exclusively in shift work populations, leaving intrinsic CRSWDs largely unexplored. Future research should prioritize longitudinal, genome-wide, and systematically phenotyped studies involving diverse populations and genetic backgrounds. Expanding epigenetic investigation across CRSWD subtypes will be essential to improve the generalizability of findings and advance biomarker development and personalized approaches in circadian and sleep medicine.
