Heart rate phase is an indicator of chronotype‐relevant circadian shifts associated with human disease: an <i>All of Us</i> Research Program analysis

Chronotype describes an individual's day or night preference and is thought to exert health effects through circadian timing, yet continuous circadian measures related to chronotype have never been examined in large human cohorts. We sought to quantify wearable-derived heart rate phase (HRP) as an indicator of chronotype-relevant circadian shifts and determine its associations with human disease. Heart rate was aggregated over 5 min intervals in All of Us participants with wearable data and fit to a sine curve with 24 h period to determine HRP. Associations between HRP and circadian genomic variants were determined by linear regression. A phenome-wide association study (PheWAS) was performed by multiple logistic regression. One-sample Mendelian randomization (MR) was performed by two-stage residual inclusion. Average HRP was 9.48 ± 1.57 h (n = 15,960). PheWAS identified phenome-wide 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 [odds ratio (OR) 1.09 [1.06,1.13], P = 1.58 × 10^-7). The morningness genomic variant rs1144566(T) was associated with earlier HRP (P = 1.38 × 10^-7) and decreased risk of T2DM (OR 0.69 [0.55,0.88], P = 2.67 × 10^-3). MR analysis suggested a causal effect of rs1144566 on T2DM risk through HRP (P = 2.70 × 10^-3). We introduce the use of a quantitative longitudinal circadian metric, HRP. We combine HRP with phenomics, genomics and electronic health records data to provide evidence for a relationship between circadian shifts and disease. HRP may hold value in the management and surveillance of human health. KEY POINTS: Chronotype is a genetically influenced innate preference for the timing of daily activity and is believed to affect health outcomes through shifts in circadian rhythms. Measurement of chronotype-relevant circadian changes may be possible through wearable technology. We show that the timing of daily heart rate rhythms, which we call heart rate phase (HRP), is associated with chronotype-relevant genetic and demographic factors. We report associations of HRP with addiction, mood, sleep and metabolism disorders as well as certain pregnancy conditions. We show that HRP is associated with type 2 diabetes mellitus (T2DM) risk and that a morning genetic chronotype variant may causally influence T2DM risk through HRP.