0022 Associations of Circadian Shifts in Heart Rate Phase with Human Disease in the All of Us Research Program

Abstract Introduction An individual’s day or night preference, known as chronotype, has been linked to numerous health outcomes and is thought to influence these outcomes through changes in circadian timing. However, continuous circadian measures related to chronotype have not been examined in large human cohorts. Here, we quantified wearable-derived heart rate phase (HRP) as an indicator of chronotype-relevant circadian shifts and determined its associations with human diseases. Methods Heart rate was binned over 5-minute intervals in All of Us participants with wearable data and fit to a sine curve with 24-hour period to determine HRP. Phenome-wide association study (PheWAS) was performed by multiple logistic regression. One-sample Mendelian randomization (MR) was performed by 2-stage residual inclusion. Results Average HRP was 9.48±1.57 hours (N=15,960). PheWAS identified associations of later HRP with addiction, mood, sleep, and metabolic disorders, while certain conditions of pregnancy were associated with earlier HRP. In focused analyses of type 2 diabetes mellitus (T2DM), later HRP was associated with increased T2DM risk (OR 1.09 [1.06,1.13], P=1.58x10-7). The morningness genomic variant rs1144566(T) was associated with decreased HRP (P=1.38x10-7) and decreased risk of T2DM (OR 0.69 [0.55,0.88], P=0.0027). MR analysis suggested a causal effect of rs1144566 on T2DM risk through HRP. Conclusion We report the use of HRP as a quantitative longitudinal circadian metric. We combine HRP with phenomics, genomics, and EHR data to provide evidence for a relationship between circadian shifts and disease. HRP may hold clinical value as a circadian indicator. Support (if any)