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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.

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Fig. 1: An overview of the circadian and sleep systems.
Fig. 2: A timeline of circadian and sleep research discoveries with a focus on genetics.
Fig. 3: Measurable approximates of circadian rhythm and sleep physiologic phenotypes.
Fig. 4: Sleep and circadian rhythms link to health using genetics.
Fig. 5: Potential sources of sleep and circadian genetic relationships to environmental factors and other traits and disorders.

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Acknowledgements

J.M.L. is supported by NIH grant number K01 HL136884. J.Q. is supported by NIH grant number K99HL148500. S.R. is supported by NIH grants on genetics of sleep apnea. E.M. is supported by NIH grants. F.A.J.L.S. is supported by NIH grants R01 DK105072, R01 HL140574, R01 HL153969 and R01 DK102696. R.S. is supported by NIH grants R01 DK105072, R01 DK102696, R01 DK107859, R01 HL146751 and R21 AG068890, DOD grant W81XWH2010776, a Dreem Jury prize (in-kind support) and a Phyllis and Jerome Lyle Rappaport MGH Research Scholar Award.

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J.M.L., F.A.J.L.S., J.Q. and R.S. wrote the article. All authors contributed to discussions of the content, and reviewed and/or edited the manuscript.

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Correspondence to Frank A. J. L. Scheer or Richa Saxena.

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S.R. reports receipt of NIH grants that include studies of the genetics of sleep apnea. F.A.J.L.S. served on the Board of Directors for the Sleep Research Society and has received consulting fees from the University of Alabama at Birmingham. The interests of F.A.J.L.S. were reviewed and managed by Brigham and Women’s Hospital and Partners HealthCare in accordance with their conflict-of-interest policies. The consultancies of F.A.J.L.S. are not related to the current work. R.S. is a founder and shareholder of Magnet Biomedicine, not related to the current work. R.S. has received in-kind support from Dreem. The other authors report no competing interests.

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Glossary

Suprachiasmatic nucleus

(SCN). Located in the hypothalamus, the SCN is the master circadian oscillator and coordinates circadian rhythms throughout the body.

Circadian rhythm

An approximately 24-hour rhythm in cellular, physiological or behavioural processes that are driven by the internal circadian timekeeping system; this rhythm is sustained in the absence of environmental and behavioural rhythms and can be entrained to solar day/night cycle by light.

Molecular clock

Molecular mechanism driving circadian rhythms, consisting of transcriptional–translational feedback loops of core clock genes.

Homeostatic

The sleep–wake homeostat balances the need for sleep and wakefulness and regulates sleep intensity. The longer you are awake the greater your body’s need for sleep (‘homeostatic sleep pressure’), which subsides during sleep (‘sleep dissipation’). The sleep–wake homeostat works in concert with the circadian rhythm.

REM sleep

REM sleep, which occurs primarily during the latter half of a sleep cycle (primarily owing to the influence of process C), is associated with the highest brain activity during sleep and with dreaming. During REM sleep, most of the body’s skeletal muscles are paralysed.

Clock genes

Core clock genes are directly involved in the primary transcriptional–translational feedback loops. By contrast, clock-controlled genes are those genes whose expression is driven by the transcriptional–translational feedback loops within cells and tissues, resulting in circadian oscillations in their function.

Circadian period

Duration of time for completion of a full cycle, that is, the time it takes to move from a reference point in a rhythmic process (a particular phase) to return to the same point (for example, time difference between two sequential dim light melatonin onsets). In humans, the endogenous circadian period is roughly 24.15 hours.

Phase

Reference time within the circadian cycle, for example, at which a particular event occurs such as the minimum or maximum of a circadian measure.

Electroencephalograph

(EEG). A measurement of electrical brain activity that uses sensors and can be used to identify stages of sleep.

Polysomnography

(PSG). A measurement of multiple parallel channels of data during sleep, typically including EEG and measures of muscle activity (electromyography), eye movements (electrooculography), and heart rate (electrocardiography). For clinical PSGs, the following measures are typically measured in addition: oxygen levels (pulse oximetry), breathing (respiratory belts, nasal pressure sensor, thermistor), and leg movements (leg electromyography). PSG is frequently used to diagnose a variety of sleep disorders, such as sleep apnea.

Wearable devices

Also known as wearables, these devices record real-time environmental, behavioural and/or physiological parameters such as accelerometry, skin temperature and heart rate.

Melatonin

A hormone produced by the pineal gland during the circadian night, and which can be suppressed by retinal light in mammals. Synthesis and secretion of melatonin into the circulation is controlled by the SCN, and therefore melatonin is used as a marker of the phase of internal circadian time.

Actigraphy

A non-invasive wrist-worn accelerometer-based objective measurement of average motor activity over a period of time.

Polygenic score

Also known as polygenic risk score. A score that summarizes genetic liability to a trait or disease and is typically calculated by aggregating the weighted effect of many trait-associated genetic variants

Excessive daytime sleepiness

Difficulty staying awake or alert during the day, which is often a symptom of sleep problems and/or disorders.

Entrainment

The synchronization of a (here, circadian) rhythm to an environmental, behavioural, or other circadian cycle, such as the light/dark cycle, eating/fasting or temperature cycles.

Sleep–wake cycle

The daily pattern of alternating wakefulness and sleep with a periodicity typically approximating the 24-hour day–night cycle.

Nearables

Devices worn not on but near to the body, with a variety of sensors that can measure and record signals, such as snoring sounds, body movement or heart rate, as physiological proxies to estimate (for example) sleep duration, timing and/or quality.

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Lane, J.M., Qian, J., Mignot, E. et al. Genetics of circadian rhythms and sleep in human health and disease. Nat Rev Genet (2022). https://doi.org/10.1038/s41576-022-00519-z

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