Integrating Genome-wide information and Wearable Device Data to Explore the Link of Anxiety and Antidepressants with Heart Rate Variability

Background Anxiety disorders are associated with decreased heart rate variability (HRV), but the underlying mechanisms remain elusive. Methods We selected individuals with whole-genome sequencing, Fitbit, and electronic health record data (N=920; 61,333 data points) from the All of Us Research Program. Anxiety PRS were derived with PRS-CS after meta-analyzing anxiety genome-wide association studies from three major cohorts-UK Biobank, FinnGen, and the Million Veterans Program (N Total =364,550). The standard deviation of average RR intervals (SDANN) was calculated using five-minute average RR intervals over full 24-hour heart rate measurements. Antidepressant exposure was defined as an active antidepressant prescription at the time of the HRV measurement in the EHR. The associations of daily SDANN measurements with the anxiety PRS, antidepressant classes, and antidepressant substances were tested. Participants with lifetime diagnoses of cardiovascular disorders, diabetes mellitus, and major depression were excluded in sensitivity analyses. One-sample Mendelian randomization (MR) was employed to assess potential causal effect of anxiety on SDANN. Results Anxiety PRS was independently associated with reduced SDANN (beta=-0.08; p=0.003). Of the eight antidepressant medications and four classes tested, venlafaxine (beta=-0.12, p=0.002) and bupropion (beta=-0.071, p=0.01), tricyclic antidepressants (beta=-0.177, p=0.0008), selective serotonin reuptake inhibitors (beta=-0.069; p=0.0008) and serotonin and norepinephrine reuptake inhibitors (beta=-0.16; p=2×10 −6 ) were associated with decreased SDANN. One-sample MR indicated an inverse effect of anxiety on SDANN (beta=-2.22, p=0.03). Conclusions Anxiety and antidepressants are independently associated with decreased HRV, and anxiety appears to exert a causal effect on HRV. Our observational findings provide novel insights into the impact of anxiety on HRV.