Chronotype and Cardiovascular Disease Risk Factors among Middle-aged and Older Adults: An observational and Mendelian Randomization Study.

Introduction: Circadian misalignment is an emerging risk factor for poor cardiovascular health, and chronotype may reflect underlying circadian processes. While previous conventional observational studies have reported adverse associations between evening chronotype and individual cardiovascular risk factors, Mendelian randomization (MR) may provide further insights into the role of chronotype in overall cardiovascular health, as measured by the American Heart Association's Life's Essential 8 (LE8; a composite lifestyle and cardiovascular health score ranging from 0 to 100; higher scores indicate better health). Methods: We conducted both observational cross-sectional and one-sample MR analyses among 317,730 UK Biobank (UKB) participants of White ethnicity. Chronotype was self-reported and modeled on a five-level continuous scale from "definitely evening" to "definitely morning". A polygenic risk score including 341 morning chronotype-associated SNPs from a UKB GWAS served as the MR instrument. Two-stage least-squares regression estimated difference in LE8 per one-unit increment in chronotype towards more morningness, adjusting for age, sex, assessment center, genotyping batch, and 40 genetic principal components. To mitigate potential winner's curse bias in UKB due to inflated GWAS estimates, we replicated the analysis in 13,396 White women in the Nurses' Health Study II (NHSII). Results: In UKB, the multivariable-adjusted difference in LE8 score for each one-unit increment toward more morningness was 0.75-points higher (95% CI: 0.72, 0.78; P<0.001) in observational analysis and a 0.75-points higher (95% CI: 0.55, 0.96; P<0.001) in MR analysis. MR results were similar for men and women (P-heterogeneity = 0.70). In NHSII, while both estimates were positive, increased morningness was associated with higher overall LE8 scores in observational analysis (β = 1.57, 95% CI: 1.40, 1.75; P<0.001), but not in MR analysis (β = 0.89, 95% CI: -0.67, 2.44; P = 0.26), although the MR association became significant when the score was based only on behavioral components (β = 2.04; 95% CI: 0.43, 3.65; p = 0.0130). Further, morning chronotype was consistently associated with healthy diet across observational and MR analyses in both cohorts. Conclusions: Our findings suggest a modest causal relationship between morning chronotype and better cardiovascular health profiles, particularly diet quality, although replication in other populations remains necessary.