Abstract 4365055: Chronotype and Cardiovascular Disease Risk Factors among Middle-aged and Older Adults: A Mendelian Randomization Study

Introduction: Circadian misalignment is an emerging risk factor for poor cardiovascular health, and chronotype may reflect underlying circadian processes. While previous studies have primarily reported cross-sectional associations between 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). Hypothesis: We hypothesize that individuals with a morning chronotype have better overall cardiovascular health measured by LE8 scores. Methods: Cross-sectional and one-sample MR analyses included 272,571 UK Biobank (UKB) participants of White European ancestry. Chronotype was self-reported using a five-level ordinal scale modeled linearly from -2 (evening) to 2 (morning). An unweighted genetic score from 341 chronotype-associated SNPs from a UKB GWAS served as the MR instrument (R 2 = 2.2%). Two-stage least-squares regression estimated difference in LE8 per one-unit increment in chronotype, adjusting for age, sex, assessment center, genotyping batch, and 40 principal components (PCs). To mitigate winner’s curse bias (inflated GWAS estimates), we replicated the analysis in 11,217 White women from the Nurses’ Health Study II (NHSII), using a weighted genetic score (R 2 = 1.4%) and a reduced LE8 score based on six self-reported components (diet, physical activity, nicotine exposure, sleep, body weight, and blood pressure). Results: In UKB, each one-unit increment toward more morningness was associated with a 0.75-point higher LE8 score for self-reported chronotype (95% CI: 0.72, 0.78; P < 2.2×10 -16 ) and a 0.76-point higher LE8 score for genetically predicted chronotype (95% CI: 0.54, 0.98; P = 1.8×10 -11 ). Observational and MR results were slightly stronger in women. In NHSII, self-reported morning chronotype was associated with a higher LE8 score (β = 1.47, 95% CI: 1.28, 1.67; P = 3.32×10 -52 ). However, the MR estimate, while positive, did not reach statistical significance (β = 1.27, 95% CI: -0.44, 2.98; P = 0.14). When examining individual components, morning chronotype was consistently associated only with diet score across both observational and MR analyses and in both cohorts. Conclusions: Our findings suggest a causal relationship between morning chronotype and better cardiovascular health, particularly diet quality, although replication in other populations remains necessary.