Associations Between Chronotype, Genetic Susceptibility and Risk of Colorectal Cancer in UK Biobank.

Abstract

Background: Sleep problems are common in the general population, with evidence suggesting a link between circadian rhythm disruptions and various health outcomes. However, the role of chronotype in influencing colorectal cancer (CRC) risk, particularly in conjunction with genetic predisposition, remains unclear and warrants further investigation.

Methods: We analyzed data from 295,729 UK Biobank participants, among whom 4305 developed colorectal cancer. Chronotype was self-reported as morning or evening type, and a polygenic risk score for chronotype was generated from 316 genome-wide significant SNPs using 23andMe effect sizes to reduce overlap bias. Colorectal cancer risk was estimated using Cox proportional hazards models adjusted for age, sex, smoking, alcohol consumption, and the Townsend index.

Results: Late chronotype and high polygenic risk were independently associated with an increased risk of CRC. Compared to participants with an early chronotype, those with a late chronotype exhibited a 6.5% increased risk of CRC [HR 1.065, P = 0.046]. Similarly, individuals in the high genetic risk group had a 11.0% increased risk compared with those in the low genetic risk group [HR, 1.110, P = 0.032]. Stratified analyses revealed that individuals with an intermediate genetic risk who had a late chronotype showed a 17.6% higher risk of CRC [OR, 1.176, P = 0.004], whereas those with a high genetic risk had a 25.3% increase [OR, 1.253, P = 0.001]. Through analyzing the combined effects of chronotype and PRS, we found that among individuals with an early chronotype, those with intermediate PRS had a 15.4% increased risk of CRC [HR, 1.154, P = 0.005], and those with high PRS had a 14.7% increased risk [HR, 1.147, P = 0.027].

Conclusions: Our findings highlight the importance of considering circadian rhythm patterns and genetic predispositions when assessing CRC risk, suggesting that chronotype may be associated with CRC risk, but further studies are needed to integrate objective circadian measurements.