These GEITP pages have discussed genome-wide association studies (GWAS) in which an ever-widening range of unusual phenotypes (traits) are studied in large cohorts — to find genetic loci correlated with that trait. Today that trait is circadian rhythms; these are known to affect a wide range of molecular and behavioral processes — such as hormone levels, core body temperature, and sleep–wake patterns. “Chronotype” is the trait often referred to as “circadian preference,” which describes an individual’s proclivity for earlier (or later) sleep timing; this is a physical and behavioral manifestation of coupling between internal circadian cycles and the need for sleep, driven by sleep homeostasis. Significant natural variation is known to exist among humans (with ‘chronotype’ typically measured on a continuous scale).
However, individuals are often separated into “morning people” (or “morning larks” — who prefer going to bed early and waking early), and “evening people” (or “night owls” — who prefer a later bedtime and later rising time). Of course, many individuals are intermediates who lie between the two extremes. Age and gender — as well as environmental light levels — can explain a substantial proportion of variation in chronotype, but genetic variation is also an important contributor.
Alterations in circadian timing are linked to disease development — particularly metabolic and psychiatric disorders. Studies in animal models have shown that mutations in, and altered expression of, key circadian-rhythm genes can cause obesity, high blood sugar, and defective (pancreas) beta-cell function leading to type-2 diabetes. In humans, there are many reported associations between disrupted circadian rhythms and disease, but the evidence for a causal role of chronotype on disease is limited [e.g. evening people exhibit an increased frequency of obesity, type-2 diabetes, and mental depression — independent of sleep disturbances; studies of shift workers show an increased risk of type-2 diabetes, mental depression, and other diseases. However, these associations could be explained by reverse causality (diseases that might affect sleep patterns or dictating job options) or confounders (common risk factors influencing both chronotype and disease)].
Genetic analyses identifying variants robustly associated with putative risk factors (i.e. ‘chronotype’) can improve causal understanding by
providing genetic instruments for use in Mendelian Randomization analyses — which minimize the effect of both reverse causality and bias caused by confounding [Mendelian Randomization is a method of ‘using measured variation in genes of known function’ to examine the causal effect of a modifiable exposure on disease in observational studies]. Identifying genetic variants associated with chronotype and sleep timing should also provide insight into biological processes underlying circadian rhythms and sleep homeostasis.
Authors [see attached article] performed a GWAS meta-analysis of a large set of 697,828 individuals — including 248,098 participants from 23andMe Inc. (a personal genetics company), and 449,734 participants from UK Biobank. In addition to confirming an enrichment of circadian rhythm- and brain-expressed genes at chronotype-associated loci and genetic correlation with mental health disorders, authors identified 327 additional chronotype-associated loci. Authors show that the chronotype-associated variants are associated with objective measures of sleep timing — but not sleep duration or quality — in 85,760 UK Biobank participants. By fine-mapping the genetic associations at all loci, authors identified 10 coding variants with a high likelihood of each being “a major causal variant,” providing prospective drug targets for chronobiological investigation. The loci are enriched for genes involved in circadian regulation, cAMP, glutamate- and insulin-signaling pathways — and genes expressed in the retina, hindbrain, hypothalamus, and pituitary. Using Mendelian Randomization, authors show that being a morning person is causally associated with better mental health, but this phenotype does not affect body mass index (BMI) or risk of type-2 diabetes. Now, I want to see EVERYONE get to sleep EARLY tonight. 🙂
DwN
Nat Commun Feb 2o19; 10: 343