Circadian syndrome and incident Parkinson’s disease: a population-based cohort study

Circadian syndrome (CircS), a cluster of conditions stemming from circadian rhythm disruption, is a potential contributor to Parkinson’s disease (PD), but its longitudinal association with PD remains unclear. This study aimed to assess the longitudinal association between CircS and PD risk, examine interaction with genetic susceptibility, and evaluate whether CircS provides additional risk information beyond metabolic syndrome. We included 303,613 participants from the UK Biobank cohort who were free of PD at baseline. Associations were estimated using Cox proportional hazards regression, with results presented as hazard ratios (HRs) and 95% confidence intervals (CIs). Following adjustment for sociodemographic, lifestyle, and genetic factors, participants with CircS exhibited a 22% increased risk of PD (HR 1.22, 95% CI: 1.11–1.34) compared to those without, while metabolic syndrome showed no independent association. The dose-response relationship between CircS component burden and PD risk was significantly nonlinear ( P nonlinearity < 0.0001). The adjusted HRs were 1.51 (95% CI 1.21–1.88), 1.88 (95% CI 1.36–2.61), and 5.74 (95% CI 2.90–11.37) for CircS scores of 5, 6, and 7, respectively. A notable interaction was found between CircS and PD polygenic risk score, with CircS conferring the greatest increase in PD risk in individuals exhibiting low genetic risk. These findings suggest that the prespecified CircS phenotype may capture risk-related information beyond that reflected by MetS and highlight circadian health as a potentially modifiable domain that may inform future PD prevention strategies.