Genetics of circadian rhythms and sleep in human health and disease

Abstract

Circadian rhythms and sleep are fundamental biological processes integral to human health. Their disruption is associated with detrimental physiological consequences, including cognitive, metabolic, cardiovascular and immunological dysfunctions. Yet many of the molecular underpinnings of sleep regulation in health and disease have remained elusive. Given the moderate heritability of circadian and sleep traits, genetics offers an opportunity that complements insights from model organism studies to advance our fundamental molecular understanding of human circadian and sleep physiology and linked chronic disease biology. Here, we review recent discoveries of the genetics of circadian and sleep physiology and disorders with a focus on those that reveal causal contributions to complex diseases.

Fig. 1 |. An overview of the circadian and sleep systems.

a | Left: the simplified circadian cell-autonomous transcriptional-translational feedback loop mechanism is depicted together with key anatomic and physiologic features. The master circadian pacemaker, located in the suprachiasmatic nucleus (SCN, orange circle) of the hypothalamus, is entrained primarily by external cues from light. This SCN coordinates 24-hour rhythms in physiology and behaviour through neuronal and hormonal output signals that influence the activity of organs and tissues either directly (for example, the SCN modulating sympathetic tone to the liver or pineal gland, orange arrow) or indirectly by synchronizing peripheral clocks, such that the molecular clock (blue-red circular arrows) in those peripheral organs or tissues then influences their function through the expression of clock-controlled genes. Peripheral oscillators, present in most organs and tissues, can also be synchronized by behaviours such as eating and physical activity. Right: neuroanatomy and sleep-wake circuitry. Many neurotransmitters switch our brains between sleep and wakefulness in a carefully regulated cycle. Key sleep and wake neurotransmitters and known sleep regulators in the brain are listed in the purple and red bubbles. In addition, sleep is regulated both by the circadian process (orange bubble) and the homeostatic process, the drive to sleep that accumulates based on time spent awake (blue bubble). b | The two-process model of sleep. The timing and structure of sleep are determined by the interaction of a homeostatic (S) and a circadian (C) process. Process S mediates the gradual rise of sleep pressure during wakefulness and its dissipation during sleep. Process C describes the circadian drive for wakefulness. Time courses for processes S and C are shown under aligned sleep-wake cycles, under sleep-deprived conditions and under misaligned sleep-wake cycles. The orange-shaded areas indicate being sleepy or alert at the wrong time. The grey-shaded areas represent sleep episodes except in the sleep-deprived condition, where it represents being awake at the habitual sleep time. ANS, autonomic nervous system; CBT, core body temperature.

Fig. 2 |. A timeline of circadian and sleep research discoveries with a focus on genetics.

Discoveries are based on publication dates from PubMed (REFS.^{,,–,,,,,,,,,,–}). GWAS, genome-wide association study; REM, rapid eye movement; RLS, restless leg syndrome; SCN, suprachiasmatic nucleus.

Fig. 3 |. Measurable approximates of circadian rhythm and sleep physiologic phenotypes.

Properties of circadian rhythms include phase, amplitude and period (top panel), whereas sleep phenotypes include sleep latency, duration and quality, sleep stage duration, intensity and depth, as well as temporal and spatial organization of complex sleep brain waves, and associated physiologic and behavioural changes (some aspects shown in bottom panel). Phenotypes affected by both systems are highlighted in the middle panel. Sleep progresses through the individual stages of sleep during the night in 4–6 cycles lasting 70–120 minutes each. Cycles consist of three stages of non-REM sleep (NREM, N1-N3) and the rapid eye movement (REM) sleep stage. N1 involves the transition from wakefulness to sleep with brain waves beginning to slow. N2 involves the further slowing of heart rate and breathing together with a drop in body temperature. N2 is marked by brief bursts of brain activity including spindles and K-complexes. N3 is deep sleep marked by the slowest brain waves. Awakening is difficult during N3. Top part of figure (circadian phenotypes) reprinted with permission from REF., OUP. Bottom part of figure (sleep phenotypes) adapted from REF., CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/).

Fig. 4 |. Sleep and circadian rhythms link to health using genetics.

a | Number of genetic loci identified for circadian and sleep phenotypes in the general population shows domain-specific overlap primarily for measures of sleep timing (summarized from published genome-wide association studies (GWAS) discussed in the main text^–,,,,,,,,). b | Evidence of genetic links between sleep/circadian traits/disease and neuropsychiatric and metabolic traits showing a heatmap of genetic correlations between insomnia symptoms GWAS and sleep, neuropsychiatric and metabolic trait GWAS. Positive genetic correlation is shown in red and negative genetic correlation is shown in blue. Significant correlations are shown with an asterisk. c | Utilizing GWAS results to probe the causal relationship between diurnal preference (chronotype) and major depression, using Mendelian randomization (MR) to demonstrate a protective association of earlier diurnal preference with lower odds of depressive symptoms. d | Sleep duration interacts with genetic risk of myocardial infarction (MI) to affect the risk of incident MI. Bars represent 95% confidence intervals (CIs). GxE, gene-by-environment interaction; OR, odds ratio; RLS, restless legs syndrome. Part b reprinted from REF., Springer Nature Limited. Part c adapted from REF., CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/). Part d adapted with permission from REF., Elsevier.

Fig. 5 |. Potential sources of sleep and circadian genetic relationships to environmental factors and other traits and disorders.

a | Gene by environment (GxE) interactions of sleep and circadian traits and disorders where sleep and circadian rhythms can act both as outcomes and environmental modifiers of disease. b | Similar to part a with shared causal factors (pleiotropy). Non-causal relationships between sleep/circadian traits or disorders and other traits or disorders can occur when genetic factors are independently associated with both outcomes. c | Graphical representation of a causal genetic relationship between sleep/circadian traits and disorders with downstream traits/disorders interrogated by Mendelian randomization analysis. For causality testing using Mendelian randomization, the three causal assumptions highlighted must be satisfied: (1) genetic factors (for example, associated SNPs) are strongly and clearly linked to sleep/circadian traits/disorders (‘the exposure’); (2) the genetic factors are not linked to any confounders; and (3) the genetic factors should be linked to the outcomes through the sleep/circadian traits/disorders only. Black arrows indicate causal links and red-dashed lines indicate potential violations of Mendelian randomization assumptions.