Fig. 1: Study flowchart showing the study design, in silico annotations, and functional analyses.

a Schematic overview of the study design for the discovery and replication of genetic loci associated with resting heart rate (RHR) using mixed linear models with a two-sided P-value of P < × 10⁻⁸ to define genome-wide significance. A genome-wide significant genetic variant was considered replicated if P < 0.01 in the UK Biobank and IC-RHR cohort with concordant effect sizes. The black-bordered boxes show the methodology, the red-bordered boxes show the most important results. b Analyses performed to evaluate RHR-associated genetic variants and to gain further insights into the underlying biology. c Schematic presentation of the two-sample Mendelian randomization analyses of genetically predicted RHR on mortality and cardiovascular diseases. Effect sizes were taken from the IC-RHR data to test the associations with mortality and cardiovascular diseases in the UK Biobank. Effect sizes were taken from the UK Biobank to test the association with coronary artery disease and myocardial infarction in the CARDIoGRAMplusC4D cohort, atrial fibrillation in the AFGen cohort, and any, ischemic, cardio-embolic, large artery and small vessel stroke within the MEGASTROKE consortium. BMI body mass index, GWAS genome-wide association study, HRC Haplotype Reference Panel, IC-RHR International Consortium for Resting Heart Rate, MB megabase, N sample size, Neff effective sample size, PC principal components, RHR resting heart rate, SNPs single nucleotide polymorphisms, QC quality control, 1000G = 1000 Genomes.