A population-based human enCYCLOPedia for circadian medicine

Abstract

The discovery that half of the mammalian protein-coding genome is clock-regulated has clear implications for medicine. Indeed, recent studies demonstrate time-of-day impact on therapeutic outcomes in human heart disease and cancer. Yet biological time is rarely given clinical consideration. A key barrier is the absence of information on the what and where of molecular rhythms in the human body. Here, we have applied CYCLOPS, an algorithm designed to reconstruct sample order in the absence of time-of-day information, to the GTEx collection of 632 human donors contributing 4,292 RNA-seq samples from 13 distinct human tissue types. We identify rhythms in expression across the body that persist at the population-level. This includes a set of ubiquitous cyclers comprised of well-established circadian clock factors but also many genes without prior circadian context. Among thousands of tissue-divergent rhythms, we discover a set of genes robustly oscillating in cardiovascular tissue, including key drug targets relevant to heart disease. These results also have implications for genetic studies where circadian variability may have masked genetic influence. It is our hope that the human enCYCLOPedia helps drive the translation of circadian biology into prospective clinical trials in cardiology and many other therapeutic areas.\n\nOne Sentence SummaryBioinformatic analyses on thousands of human tissue samples reveals an enCYCLOPedia of rhythmic gene expression across the body and identifies key translational opportunities for circadian medicine in cardiovascular disease.