Circadian behaviors and genetic architecture: independent and interactive associations of time-restricted eating window, sleep duration, and CLOCK variants with metabolic risk

Circadian rhythms regulate sleep, metabolism, and hormone secretion, and their disruption has been linked to increased risk of metabolic disorders. CLOCK variants may relate to disease susceptibility through interactions with behaviors such as sleep duration. We conducted a cross-sectional analysis of 12,092 adults to examine associations between habitual sleep duration, time-restricted eating window (TREW) and common CLOCK single-nucleotide polymorphisms (SNPs) rs1801260 and rs3749474 with metabolic pathologies. Genetic, demographic, and lifestyle data were analyzed using logistic regressions adjusted for age, sex, physical activity and BMI. Sleep duration ('6 h vs. ≥6 h) and TREW (≤8 h/day) were self-reported. TREW of ≤8 h/day was significantly associated with lower odds of obesity (BMI≥30) (OR = 0.88, 95%CI0.75–0.90, p = 2 × 10⁻⁵), morbid obesity (BMI≥40) (OR = 0.81, 95%CI:0.67–0.97, p = 0.02), T2DM (OR = 0.81, 95%CI: 0.67–0.99, p = 0.03), and hypertension (HTN) (OR = 0.84, 95%CI:0.75–0.95, p = 0.004). Sleep duration showed a U-shaped association with obesity-related outcomes, with lower odds observed for 6–8 h but no lower odds observed for longer sleep durations. Significant gene-sleep interactions were observed; Among CLOCK rs1801260 GG carriers, sleeping '6 h was associated with higher prediabetes odds compared to ≥6 h (OR = 2.11, 95%CI:1.39–3.18, p = 0.0004). Among CLOCK rs3749474 TT carriers, sleeping '6 h was associated with higher odds for T2DM (OR = 1.70, 95%CI:1.22–2.37, p = 0.004) and for morbid obesity (OR = 1.81, 95%CI:1.34–2.44, p = 9 × 10⁻⁵) compared to ≥6 h. In summary, interaction between CLOCK variants and insufficient sleep duration was associated with metabolic outcomes. These findings suggest that sleep duration may be relevant to metabolic risk stratification across CLOCK genotype groups; however, prospective studies are needed to confirm these associations.