Category: Home

Circadian rhythm genetics

Circadian rhythm genetics

Physiological significance of a Circadian rhythm genetics tissue circadian clock. The mPer2 Cicadian encodes a functional component of the mammalian circadian clock. Other circadian mutant mice show more intact sleep patterns compared with the ones described thus far. Eastman CI, Tomaka VA, Crowley SJ.

Circadian rhythm genetics -

Most living things have circadian rhythms, including animals, plants, and microorganisms. In humans, nearly every tissue and organ has its own circadian rhythm, and collectively they are tuned to the daily cycle of day and night.

A master clock coordinates all the biological clocks in an organism. In vertebrate animals, including humans, the master clock exists in the brain. The human master clock is a large group of nerve cells that form a structure called the suprachiasmatic nucleus SCN.

Among other functions, the SCN controls production of the hormone melatonin based on the amount of light the eyes receive. The SCN also synchronizes the circadian rhythms in different organs and tissues across the body.

In , NIGMS-funded researchers Jeffrey C. Hall, Michael Rosbash, and Michael W. Young won the Nobel Prize for their circadian rhythms research. They identified a protein in fruit flies that has a role in controlling normal daily biological rhythms.

During the daytime, this protein called PER is produced by the cell but immediately broken down in the cytoplasm , keeping PER protein levels low. When night falls, a protein called TIM binds directly to PER, protecting it from breaking down.

The PER-TIM complexes enter the nucleus and stop the cell from making additional PER. Then, as day breaks, the PER-TIM complexes break down, the block on PER transcription is lifted, and the cycle repeats. In this way, PER regulates its own synthesis through a negative feedback loop.

Feedback loops are coordinated systems that link the output of the system to its input. In the case of PER, the protein directly controls the transcription of the gene that codes for it. Circadian rhythms can fall out of sync with the outside world due to factors in the human body or environment.

For example:. Drowsiness, poor coordination, and difficulty with learning and focus may occur when circadian rhythms fall out of sync short term. Long-term sleep loss and continually shifting circadian rhythms can increase the risks of obesity , diabetes , mood disorders , heart and blood pressure problems, and cancer , and can also worsen existing health issues.

Researchers are studying circadian rhythms to gain better insight into how they work and how they affect human health. Some of the most pressing questions that scientists seek to answer are:. Microorganisms, fruit flies, zebrafish, and mice are often the research organisms that scientists study because they have similar biological clock genes as humans.

For example, the cyanobacterium Synechococcus elongatus has a fully functional circadian rhythm. Using techniques including CRISPR genome editing, researchers remove clock genes from cells of this cyanobacterium species to shed light on the function of individual proteins.

The two-process model, first described by Borbely in , puts forth a description of sleep regulation that relies on both the circadian system termed process C and sleep homeostasis termed process S [ 18 ].

Process C is dependent on the ~h rhythmic variation of propensity to sleep, and this is balanced with process S, which increases as a function of time awake. Process S is estimated by EEG slow-wave activity and has an exponential decline during sleep.

The model posits that it is the interaction of process C and process S that determines when we wake and when we sleep. It explains that circadian factors help us stay awake throughout the day as sleep pressure, modeled by process S, builds up and also help us stay asleep in the latter part of the night once this sleep pressure has largely declined.

Sleep pressure also explains why more time awake can lead to more and deeper sleep. Given that light is the main zeitgeber for our circadian system, and most of the light we experience day to day is artificial light, the overall input to the circadian system is far weaker than it was for our ancestors exposed to even cloudy skies on a daily basis [ 19 ].

In addition, light suppresses melatonin release by the pineal gland which can further influence the timing of sleep [ 20 ]. Social and occupational obligations can also alter sleep patterns and contribute to desynchrony between the internal rhythm and the timing of sleep for an individual.

With reduced external input and increased evening obligations, the majority of people trend towards later bedtimes and later wake times. There is greater variation in the timing of both melatonin onset and sleep under artificial light conditions compared with natural light conditions, suggesting that the weaker zeitgebers in the artificial lighting environment allow individual circadian differences to emerge.

Increased time spent outside correlates with earlier chronotypes [ 12 ]. Work and school start times have not changed with increasing indoor lighting, causing shorter sleep duration for many people and increased difficulty arising in the morning. Here we discuss how the circadian system can vary across the population and lead to extreme phenotypes through genetic variation, sometimes resulting in disorders of sleep and wake.

We will also discuss how sleep homeostasis can vary across the population, resulting in short and long sleep need, an area with increasing evidence that merits far more study. Variations in τ, strength and angle of entrainment, and coupling of the clock to outputs result in a range of preferred sleep timing throughout the h day.

An individual with ASP may sleep 8 p. instead of a more conventional 11 p. An individual with DSP may sleep 4 a. to 12 p. The majority of people have a schedule intermediate between morning larks and night owls Fig. The exact timing of what denotes a morning lark or night owl varies by location, and an intermediate chronotype in Eastern Europe has a mid-sleep time of 4 a.

Typical sleep period timing compared with delayed sleep phase, advanced sleep phase, and natural short sleep. Chronotype is a life-long trait, though there is variation across the lifespan. Infants and small children are relative morning larks, and there is an abrupt shift later in adolescence, peaking around age 20, following which there is a slow drift back to earlier sleep—wake tendencies over the subsequent decades [ 24 ].

At each age the distribution across the population remains stable with the same number of relative morning and evening types. Across the lifespan, an individual also retains his or her relative position within the group of similar age and sex.

As individuals age past 65 there becomes greater variation across the population [ 24 ]. The prevalence of morning vs. evening types depends on the age of the population surveyed.

In contrast, among college students, there is greater evening preference than the general population with an even greater evening trend in freshman compared with seniors [ 27 ].

There are also differences by gender. Men are later chronotypes until around age 50 after which men and women have similar chronotypes.

Just as puberty tends to appear earlier for girls, eveningness peaks in woman at age There are also variations by race, though all ethnicities show an approximately normal distribution of chronotype.

In a report by Eastman et al. There are also differences by ethnicity in morningness, with African Americans 1. intermediate compared with Caucasian [ 26 ].

This may be related to differential response to light, as African Americans show a larger phase advance in response to bright morning light and smaller phase delay in response to bright evening light [ 30 ].

Short sleep is also twice as common in African Americans, which is likely multifactorial with a strong influence of social, cultural, and environmental factors. Individuals with ASP who report a family history in a first degree relative are considered to have familial ASP FASP. While genetic and environmental factors both contribute, those whose early chronotype started at a young age are very likely to have a strong family history of this trait [ 31 ].

Many with ASP and FASP do not find earlier sleep and awakening troublesome, and these individuals do not typically come to medical attention. Among a population presenting to a sleep clinic, the prevalence of ASP, defined as onset of sleepiness by p. and spontaneous awakening by a. with this tendency beginning prior to age 30, is estimated to be 0.

The estimated prevalence of FASP in this population is at least 0. The two major methods shedding light on the genetics of ASP are single-gene mutations determined from families with an autosomal dominant inheritance pattern and genome-wide association studies GWAS.

In the first paper identifying a Mendelian inheritance pattern of FASP was published [ 16 ]. The proband from the largest identified family was noted to have a τ of At that time, genetic mutations leading to alterations in the circadian period had been generated in forward genetic screens in Drosophila and rodents but no clock gene mutations were yet identified in humans [ 32 ].

Linkage analysis led to genetic mapping of the first FASP allele to chromosome 2q and positional cloning led to identification of PER2 , a homolog of the Drosophila period gene. This mutation was engineered into mice and led to a semidominant ASP trait, recapitulating the phenotype of the humans harboring the mutation [ 34 ].

Further study suggests this mutation, PER2SG, is a stronger transcriptional repressor than wild-type PER2 , supporting the role of PER2 in setting the speed of the molecular clock [ 35 ].

Many additional families have been identified with a similar pattern including an allelic series of PER2 mutations, but most FASP families do not have a recognized mutation in PER2. Study of these families has shown genetic heterogeneity and led to identification of multiple additional causative mutations.

These mutations are present in only a small minority of a large FASP family cohort, suggesting there are novel human circadian alleles and potentially novel genes yet to be identified. Several circadian genes have pleiotropic effects influencing other aspects of health and disease.

Mutations conferring an FASP phenotype have been show to cosegregate with migraine and depression. In two of the families with a Mendelian inheritance pattern of FASP, identification of the cosegregation of migraines with the extreme morning lark trait led to the identification that a mutation in CK1δ confers both migraine and FASP in the affected individuals [ 39 ].

The two identified families have distinct missense mutations, T44A and H46R, and mice engineered to carry one of these mutations were more sensitive to pain when a typical migraine trigger was provided.

They also demonstrated reduced thresholds for inducing cortical spreading depression, the physiology underlying migraine aura. FASP, depression, and seasonal mood traits have also been linked in two variants in the PER3 gene [ 37 ].

This causes seasonal affective disorder in humans and a depression-like phenotype in mice that worsens under shorter photoperiods. The work, compiling up to , individuals in a single study, primarily derives chronotype by asking about self-reported morning or evening preference.

In a more limited sample, activity-monitor derived sleep preference is also used [ 43 ]. Through this work, morningness has been associated with lower rates of depression and with better mental health [ 28 , 42 ]. Up to loci have shown association with chronotype in GWAS studies. These include PER2 , PER3 , and Cry1 , already known to cause FASP or familial DSP FDSP in familial studies.

CK1δ, Cry2 , and TIMELESS mutations, also identified as causative in individual FASP families, have not been identified through GWAS. Notably, many loci found to be associated with chronotype in GWAS have not been replicated in independent cohorts.

This suggests genetic complexity and may also be related to systematic biases depending on the tools used for defining chronotype. However, several genes arise in multiple studies. Four large GWAS published in the last 4 years found loci near the PER2 , FBXL13 , RGS16 , and AK5 genes [ 28 , 40 , 41 , 43 ].

As PER2 is already established to be involved in the circadian clock and causative of FASP, it seems likely that this association is a direct effect via PER2. RGS16 is involved in signaling in the SCN and FBXL13 is associated with lengthened circadian period in mice [ 44 ]. Interestingly, AK5 is a gene not previously known to be involved in the circadian system prior to this work [ 45 ].

At least three studies have shown involvement of hypocretin receptor type 2, known to be involved in alertness and also associated with sleep duration via GWAS study; [ 46 ] 5-hydroxytrptamine serotonin receptor 6, known to be involved in sleep regulation though not circadian regulation; and trinucleotide repeat containing 6b, previously shown to have involvement in the circadian system in Drosophila and mice.

A remaining and daunting challenge of this field is the elucidation of pathways relevant to chronotype in the region of an associated locus. It will not always be the case that the closest gene to an associated locus will be causative for the chronotype.

DSP, when more extreme, is also commonly a life-long tendency, worsening during adolescence and lessening with age. When DSP exists in a first degree relative it is termed FDSP. Prevalence estimates for DSP vary by definition, location, and age, but range up from as low as 0.

Despite this, fewer genes have been identified that lead to DSP than ASP. This suggests DSP is likely multigenic with several genes each playing a smaller role, though nongenetic factors such as artificial evening lighting and social pressures confound the picture making the detection of genetic variants more challenging.

A length polymorphism in the PER3 gene due to a variable-number tandem repeat 4 or 5 repeats has been linked to DSP in which the longer allele is associated with morningness and the shorter allele with eveningness [ 50 ]. A missense PER2 variant, Rs, is associated with longer circadian period and later chronotype [ 40 , 51 ].

A single mutation in the CRY1 gene, CRY1 c. This allele has a prevalence of 0. The frequency of FDSP is not known and thus, it is not clear what proportion of this trait is explained by this CRY1 variant.

The terms ASP and DSP are descriptions of preferred sleep timing and do not describe pathology. However, society has conventional hours of operation, and if an individual is not able to sync with this schedule, it can make the regular routine of life more challenging as propensity for sleep may fall in daylight and highest alertness in darkness.

When this causes complaint, distress or trouble with function, it is termed circadian misalignment. A subset of ASP individuals present to their doctor with a sleep—wake complaint such as evening sleepiness, bothersome early morning awakenings not from another cause such as depression, insomnia, or sleep apnea, or daytime sleepiness from insufficient sleep due to trying to stay up for social, family, or work obligations.

This subset with a complaint related to their early circadian timing meet criteria for advanced sleep—wake phase disorder ASWPD in the International Classification of Sleep Disorders ICSD-3 [ 53 ]. One in eight with ASP meet criteria for ASWPD, suggesting a prevalence of at least 0.

This prevalence estimate does not account for those who become advanced only in later years as part of the common phase advance associated with aging ASP of aging.

Only those individuals who complain of this trait will carry the diagnosis of ASWPD. Figure 3 details the relationship between FASP, ASWPD, and ASP of aging. The relative size of the circles in Fig.

ASP of aging, as the prevalence of ASP of aging is not known. Diagram of the relationship between familial advanced sleep phase FASP , advanced sleep—wake phase disorder ASWPD , and ASP of Aging. This figure is adapted from a figure that is reprinted with permission from the journal SLEEP [ 31 ].

Relatives sizes do not reflect relative prevalence as the prevalence of ASP of Aging is not known. For those who have a related complaint of insomnia or daytime sleepiness and feel better when allowed to sleep on their chosen delayed sleep schedule, the ICSD-3 classification is DSWPD [ 53 ].

It is likely that a larger proportion of those with DSP have a complaint compared with those with ASP due to several factors. The increase in evening artificial light helps ASP individuals delay, keeping them closer to a conventional schedule, while evening light only further exacerbates the misalignment for those with DSP.

Also, those with DSP experience greater sleep inertia, the phenomenon of a delay to feeling fully alert after awakening, compared with those with ASP [ 12 ].

While ASP individuals commonly feel alert within seconds or minutes of waking, those with DSP may take minutes to hours [ 31 ]. Some individuals are not able to entrain to a h day and instead of having a stably advanced or delayed schedule, their sleep timing is continually shifting, resulting in alternating insomnia and excessive daytime sleepiness.

This is termed non sleep—wake disorder N24SWD [ 53 ]. While the incidence of N24SWD is not known, over half of blind individuals do complain of sleep disturbance. Less commonly, some individuals are not able to entrain due to dementia, developmental abnormalities, or psychiatric disorders.

Those with developmental delay and neurodegenerative disease may also suffer from irregular sleep—wake rhythm disorder in which the affected individual sleeps throughout the h day and does not have a day vs.

night preference [ 53 ]. This problem has also been reported following traumatic brain injury [ 54 ]. Circadian misalignment has negative health impacts. Causes of misalignment include shift work and social jetlag. Epidemiologic data reveals higher incidence of ischemic heart disease, metabolic syndrome, obesity, and cancer among shift workers [ 55 , 56 , 57 , 58 ].

Misalignment may influence breast cancer progression and long-term rotating night shift workers have a higher risk of breast cancer [ 60 , 61 ]. Lack of entrainment, as demonstrated by melatonin rise during nonsleep hours, correlates with impaired learning and memory [ 62 ].

Destabilization of circadian rhythmicity may be a factor in tumor progression as the circadian rhythmicity of multiple circadian genes has been noted to be lower or absent in cancer cells [ 63 ].

Misalignment can occur between an individual and the environment, such as with ASWPD, DSWPD, or shift work, and within an individual, called internal misalignment. The SCN is responsible for synching internal physiologic processes including feeding and fasting, and peripheral clocks are subservient to the SCN.

The body anticipates nightly fasting and stimulates gluconeogenesis, putting lipids and glucose levels under tight circadian control [ 64 , 65 ].

This is demonstrated by mice with a liver specific deletion of the essential clock gene Bmal1 who developed hypoglycemia during fasting [ 66 ]. While light is the major input to the SCN, food is the most important input to peripheral oscillators.

When meals are not synchronized to the light driven SCN, peripheral clocks can become decoupled. For example, when rodents are put on a restricted feeding schedule in which the timing of food offering is not synched with expected timing by the light cycle, the SCN remains synched with light but multiple peripheral oscillators including the liver, kidney, heart, and pancreas become synched with the eating schedule [ 67 , 68 ].

This desynchrony with the liver has been shown to contribute to metabolic consequences such as obesity and type 2 diabetes [ 69 ]. Chronotype alone also appears to impact disease.

Recent work suggests decreased well-being, shorter lifespan, and increase mortality in evening types [ 25 , 70 ]. There are higher rates of a wide range of disorders including psychological disorders, diabetes, neurological, gastrointestinal, and respiratory in definite evening types compared with definite morning types [ 25 ].

Morning preference appears to have a protective effect against breast cancer using a Mendelian randomization study model to investigate the impact of chronotype on breast cancer diagnosis in the UK Biobank [ 71 ].

Within diseases, such as bipolar and chronic migraine, evening type may impact frequency of episodes [ 72 , 73 ]. Whether this negative impact of evening chronotype is mediated by increased misalignment is not known.

When patients in clinic complain of trouble falling asleep, staying asleep, early morning awakenings, or daytime sleepiness, chronotype is an important factor to consider in devising optimal treatment.

There are many tools used for this purpose currently, but all have limitations. The timing of sleep is one tool. To characterize chronotype, it is important to ask about timing of first falling asleep and final awakening on long weekends or vacations without obligations. It is important to focus on prolonged time off because weekday and weekend obligations often shape sleep timing and rebound sleep on the weekend can prolong sleep.

Two questionnaires, the Munich ChronoType Questionnaire, which generates a mean sleep on free days MSF time, and the morningness—eveningness questionnaire are used to screen for chronotype. Objective measures include DLMO, which is considered the most reliable measure of central circadian timing.

Melatonin levels are very low during the day and start to rise in the evening. The timing of this rise represents the action of the central circadian pacemaker, the SCN, which signals the pineal gland to release melatonin [ 74 ]. However, light suppresses melatonin release [ 20 , 75 ].

Therefore, this collection must be done at frequent intervals in the hours before habitual bedtime in dim light conditions. It is not widely available clinically and is cumbersome to collect and therefore is not routinely used in clinical practice.

Core body temperature minimum is also a strong indicator of the timing of the central pacemaker. However, this is difficult to obtain clinically and is not typically done outside of a research setting. In determining how to treat circadian disorders, it is also useful to understand the τ of an individual, but this is difficult to determine as optimal testing requires a challenging protocol called the forced desynchrony protocol, carried out only in research settings.

Promising future approaches to identify intrinsic rhythm rely on the fact that transcription and metabolism are under circadian regulation in mammals [ 76 , 77 ]. The transcriptome for mammals has been characterized [ 78 ] and work is underway to utilize this to better define circadian phase.

Nearly half of protein-coding genes express rhythmicity at some site in the body [ 79 ]. Thus, the transcriptome or metabolome of cells in blood promises to be useful as a marker for circadian phase.

Multiple efforts have been made on that front. Liang et al. Braun et al. have created a machine-learning algorithm that can be trained to use gene expression to predict circadian rhythms [ 81 ].

Wittenbrink and colleagues report a monocyte NanoString-based gene expression profile based on 12 genes that can predict circadian timing with a single daytime sample [ 82 ].

This approach has the potential to improve detection of chronotype in routine clinical practice, however no tool is currently clinically validated and available. Similar to chronotype, habitual sleep duration varies across the population and follows a normal distribution [ 83 ].

This has led to an important national conversation about the value of adequate sleep. The majority of information regarding adequate sleep duration comes from epidemiologic data and sleep deprivation experiments. Epidemiologic data shows an association between short and long sleep and increased mortality.

This relationship has been shown in numerous cultures across the world [ 86 ]. There is a similar relationship between short and long sleep duration and glucose tolerance, type 2 diabetes, elevated BMI, obesity, and metabolic syndrome [ 87 , 88 , 89 ].

It is important to note that these studies measure an association in a population of people. It is likely that the optimal amount of sleep for an individual varies dramatically across the population.

Epidemiologic data is based on self-reported sleep duration and does not incorporate a reason for short sleep hours. Thus, such studies do not differentiate between those who have short sleep accompanied by a sleep-related complaint, such as insomnia or excessive daytime sleepiness, and those who do not.

In fact, a u-shaped curve of sleep complaints has also been reported, indicating many of those reporting short sleep also complain about trouble with nocturnal sleep or have daytime sleep-related symptoms [ 90 ]. The other major factor driving recommendations on sleep duration is sleep deprivation experiments.

Numerous laboratory studies show that sleep deprivation has negative consequences for health. Metabolic consequences of acute sleep deprivation include insulin resistance, endocrine dysfunction, decreased leptin, increases ghrelin, and increased blood pressure [ 92 , 93 , 94 , 95 ].

Sleepiness and reduced sleep time have been linked to motor vehicle accidents [ 96 , 97 , 98 ]. Short sleep has been associated with increased incidence of depression [ 99 ].

Acute sleep deprivation causes sleepiness and deficits in alertness, attention, learning, and memory [ ]. Notably, however, cognitive function tests during sleep deprivation experiments reveal a range of responses following sleep loss, with some individuals having minimal negative consequences.

These interindividual differences in vulnerability to the cognitive effects of sleep loss appear trait-like, remaining stable over time [ ]. Variable response to sleep loss is, at least in part, genetic. EEG delta power recorded during non-REM sleep, which increases the longer an individual has been awake prior to sleeping and dissipates during non-REM sleep, is a marker of homeostatic sleep pressure, and interindividual variation around delta power likely reflects a central factor in sleep need variation.

Studies in multiple inbred strains of mice show that delta power varies by strain with delta power depending on both prior wake time and genotype [ , ]. In humans, we have known since the s through twin studies that sleep length is heritable [ , ].

Two larger studies compiling data from 47, and , individuals both show associations of multiple loci with sleep duration, however the genes and mechanisms remain to be elucidated [ 46 , ].

A polymorphism at rs in a melatonin receptor gene, MTNR1B , correlates with more time in bed on weekends, suggesting a potential role in sleep duration, and a separate variant, rs, has been shown to impact duration of melatonin secretion [ , ].

The sleep EEG is remarkably stable for an individual and follows a trait-like pattern with repeated assessment at baseline and following sleep deprivation showing reproducible characteristics [ , ]. Non-REM EEG delta power was among the most stable of the sleep parameters for an individual over multiple assessments with the greatest variability between individuals.

Much of this interindividual variability in the sleep EEG is thought to be driven by genetics [ , ]. There are multiple genes, including PER2 and DEC2 , identified as clock genes that have also been demonstrated to influence the sleep homeostat and vice versa [ 33 , , , ]. This implies a deep interdependence between the systems.

Given the systems coevolved, this interdependence is not surprising. However the dynamics of this interplay remain unknown and more study is needed to better understand this complex relationship. There has been limited investigation on the physiologic changes in sleep of habitual short and long sleepers.

Familial natural short sleep FNSS is a subgroup within those reporting habitual short sleep. Thus, this research does not describe FNSS specifically. Short sleepers have a shorter duration of melatonin release and earlier times of cortisol peak and temperature nadir compared with long sleepers [ ].

Increased time awake in the short sleepers leads to higher waking levels of theta and low-frequency activity. Short sleepers appear to have more spectral power in the 5. Aeschbach et al. This was primarily made up by differences in REM and stage N2 sleep; SWS did not significantly differ between groups on any night.

With sleep deprivation, sleep latency and REM density decreased more in long sleepers than in short sleepers. Short sleepers also appeared to awaken with a higher sleep pressure, suggesting that short sleepers tolerate a higher homeostatic sleep pressure [ ]. In the first human genetic variant leading to a short sleeping phenotype was described in the DEC2 gene, PR [ ].

Fu and colleagues termed this FNSS. FNSS is defined as a stable trait of sleeping 4—6. However, when these individuals are asked how they feel after sleeping 4—6. Engineering this mutation in Drosophila and transgenic mice produces a similar phenotype.

DEC2 is a transcriptional repressor and increases expression of hypocretin [ ]. Hypocretin, also known as orexin, is wake promoting and involved in sleep—wake transitions. Loss of hypocretin producing neurons in the lateral hypothalamus leads to narcolepsy with cataplexy.

A novel mutation in DEC2 has also been identified in a pair of dizygotic twins with the same BMI but in which one twin had reduced sleep duration, less recovery sleep following sleep deprivation, and fewer performance lapses following sleep deprivation [ ].

Another mutation causing FNSS has been identified in the beta 1 adrenergic receptor gene ADRB1 [ ]. ADRB1 is highly expressed in the dorsal pons and the neurons are active during REM and wake. Multiple additional families with an autosomal dominant pattern of decreased sleep need have been collected, and two additional genes have been identified with the short sleep phenotype recapitulated in mouse models [ ].

Individuals with FNSS report decreased sleep need throughout adult life, some dating to childhood. They report sleep durations ranging from 4 to 6. FNSS individuals are in part distinguished from facultative short sleepers by their lack of catch-up sleep on weekends and free days.

They report greater flexibility around sleep timing and less subjective deficit after sleep deprivation. They often deny experiencing jetlag unpublished data. However, it is not just sleep duration that characterizes this group of individuals.

There is a high behavioral drive among those with FNSS, and individuals report a need to always be mentally active resulting commonly in high profile, high pressure jobs or holding multiple jobs.

FNSS individuals also appear to have high pain thresholds and relative resilience to life stressors unpublished data. Thus, the phenotype does not only encompass a sleep pattern but also daytime behavior. Individuals with short sleep and increased behavioral drive have been described in the literature as early as when Hartmann et al.

It is possible that DEC2, ADRB1 and other causative mutations all lead to a higher behavioral drive, which allows those with FNSS to overcome increased homeostatic sleep pressure though much work needs to be done to test this hypothesis.

Similar to short sleep, there is likely a group of individuals who need a greater amount of sleep. However there are not yet any identified genetic variants causing FNLS.

Comorbidities such as depression and lifestyle factors complicate the picture making this group harder to detect. Additional understanding about how to define and measure sleep need is in order. Across the population, there is a normal distribution of chronotype and habitual sleep duration.

Genetics accounts for a lot of this variation in the population, most clearly at the extremes for circadian rhythm and short sleep duration. Single-gene mutations have been found that lead to extreme chronotypes in FASP and FDSP.

Single-gene mutations also cause extremes of sleep duration in FNSS families and likely FNLS though this is not yet described in the literature.

There are many FASP and FNSS families with an autosomal dominant pattern of inheritance without an identified gene, suggesting extension beyond known clock genes. Forward genetic screens in flies and mice have focused on mutations with large effects on period or rhythmicity.

We postulate that some of the FASP genes will affect entrainment or coupling of clock to physiologic outputs. FNSS genes likely impact behavioral drive, delta power, and sleep efficiency. There are many unanswered questions regarding variations in sleep need and FNSS.

These include whether those with FNSS are resistant to any of the reported metabolic and cognitive consequences of sleep deprivation and whether they are susceptible to the epidemiologically described long-term health consequences.

We hypothesize they are resistant to many of these given the observation that they are often high achieving without any clear medical comorbidities. Better individual and epidemiologic studies of this population are merited. Further, understanding the possible tolerance to higher sleep pressure and behavioral drive may have implications for a wide range of occupations requiring long durations of wakefulness including pilots, military personnel, and physicians and for treatment of disorders of sleep and arousal.

We need a conceptual framework for genetic and biologic contributions to sleep in individuals vs. The current model of circadian factors and sleep homeostasis does not explain this third dimension of behavioral drive observed in FNSS.

The circadian clock, sleep homeostat, behavioral drive, and environmental factors such as light exposure and daily obligations together impact the ultimate timing and duration of sleep Fig.

Future work should focus on circadian factors affecting entrainment and clock-output coupling and sleep homeostatic factors affecting biologic sleep need, tolerance of homeostatic sleep pressure, and sleep efficiency.

Finally, genes and proteins impacting behavioral drive merit direct investigation. A conceptual framework for the relationship among different aspects of biology leading to innate traits of sleep timing and duration. These genetic factors interact with environmental factors such as electric lights, chemicals ethanol, caffeine, medications , and familial and societal responsibilities which together may manifest as sleep duration and timing different from that programed by genetics.

The relative contribution of each component is likely variable and remains under investigation. Coupled with data demonstrating that many of these pathways are clock-regulated, Zhang et al. postulated that the clock is interconnected with many aspects of cellular function. A systems biology approach may relate circadian rhythms to cellular phenomena that were not originally considered regulators of circadian oscillation.

For example, a workshop [37] at NHLBI assessed newer circadian genomic findings and discussed the interface between the body clock and many different cellular processes.

While a precise hour circadian clock is found in many organisms, it is not universal. Organisms living in the high arctic or high antarctic do not experience solar time in all seasons, though most are believed to maintain a circadian rhythm close to 24 hours, such as bears during torpor.

Some spiders exhibit unusually long or short circadian clocks. Some trashline orbweavers , for example, have This adaptation may help the spiders avoid predators by allowing them to be most active before sunrise.

Contents move to sidebar hide. Article Talk. Read Edit View history. Tools Tools. What links here Related changes Upload file Special pages Permanent link Page information Cite this page Get shortened URL Download QR code Wikidata item.

Download as PDF Printable version. In other projects. Wikimedia Commons. Biological mechanism that controls circadian rhythm.

Harvard Gazette. Retrieved February Nature Genetics. doi : PMID S2CID Trends in Endocrinology and Metabolism. PMC Annual Review of Cell and Developmental Biology. Annual Review of Genomics and Human Genetics. May Bibcode : Natur.

Proceedings of the National Academy of Sciences of the United States of America. Bibcode : PNAS.. PLOS ONE. Bibcode : PLoSO Gumz ML ed. Circadian Clocks: Role in Health and Disease 1 ed.

Springer, New York, NY. ISBN PLOS Computational Biology. Bibcode : PLSCB Bibcode : PNAS Bibcode : Sci April Archived from the original PDF on January New Scientist.

Current Biology. Annual Review of Biochemistry. PLOS Biology. Annual Review of Cancer Biology. ISSN October

Thank you for visiting nature. You rrhythm using a browser version Oats and nutrient absorption limited support for CSS. To obtain Circadian rhythm genetics rhuthm experience, Circaadian recommend Recharge your body use a more up to date browser or turn off compatibility mode in Internet Explorer. In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript. Timing and duration of sleep are controlled by the circadian system, which keeps an ~h internal rhythm that entrains to environmental stimuli, and the sleep homeostat, which rises as a function of time awake. Nearly all living organisms, from cyanobacteria to humans, have an internal circadian oscillation Cirxadian a periodicity Oats and nutrient absorption approximately 24 Nitric oxide and blood pressure. In mammals, circadian Circadian rhythm genetics rhyythm diverse physiological processes including the body temperature, rhytgm metabolism, immunity, Injury prevention programs secretion, and daily sleep-wake cycle. Sleep is tightly regulated by circadian rhythms, whereas a misalignment between the circadian rhythms and external environment may lead to circadian rhythm sleep disorders CRSD. CRSD includes four main kinds of disorders: the advanced sleep-wake phase disorder ASPDthe delayed sleep-wake phase disorder DSPDthe irregular sleep-wake rhythm disorder and the nonh sleep-wake rhythm disorder. Recent studies have begun to shed light on the genetic basis of CRSD.

ICrcadian rhythms ryhthm Injury prevention programs physical, geneetics, and behavioral Circadlan an organism experiences Crcadian a hour genstics.

Light and dark have rhuthm biggest influence on circadian rhythms, but food intake, stress, physical activity, social gsnetics, and temperature also affect rhyhhm.

Most living things have Circaidan Circadian rhythm genetics, Circadiqn animals, plants, and microorganisms. In humans, nearly every tissue and organ rgythm its Natural remedy for indigestion circadian rhythm, rhyhtm collectively they are ryythm to the daily cycle of day and night.

A master clock coordinates all the biological fhythm in an rgythm. In vertebrate animals, including Pycnogenol and cholesterol, the rhytnm clock exists in Oats and nutrient absorption brain.

The human master clock is a large group of nerve cells Cirvadian form a structure called the grnetics nucleus SCN. Rhhthm other functions, genetice SCN controls production of the hormone Circaadian based on the amount of light the eyes Circacian.

The SCN also synchronizes the circadian rhythms in different rhytym and genetisc across the body. Circadian rhythm geneticsNIGMS-funded researchers Jeffrey C. Hall, Michael Rhyth, and Michael W.

Young won the Nobel Prize for genrtics circadian rhythms research. Injury prevention programs identified a protein in genetkcs flies that has a role in controlling normal Circadlan biological rhythms.

During the genetifs, this Herbal anti-cancer supplements called PER is produced geneticw the Injury prevention programs but immediately venetics down Injury rehab and nutrition the cytoplasmkeeping PER protein levels low.

When night falls, rhytmh protein rhytgm TIM binds Cirvadian to PER, protecting it from benetics down. Sports nutrition for vegetarians PER-TIM complexes enter Circadiam nucleus and stop the cell from rhtyhm additional PER, Circadian rhythm genetics.

Then, as day breaks, the PER-TIM Cirxadian break down, rythm block genetucs PER transcription is lifted, rhyrhm the cycle repeats. In this way, PER regulates its own synthesis through a rgythm feedback loop. Feedback loops are coordinated rhythmm that link the output of the system to its input.

In Circxdian case of Rhytum, the protein ehythm controls the transcription of the gene genehics codes for it.

Circadian rhythms Circadain fall out of Fueling for Performance with Circadixn outside world due to factors in the human body or rhyythm. For example:. Circasian, poor coordination, Circdian difficulty Citcadian learning fenetics focus may occur Cicadian circadian rhythms fall out Artisan coffee beans sync short genetisc.

Long-term sleep loss and continually shifting circadian rhythms can increase the risks of obesitydiabetesmood disordersheart and blood pressure Ryythm, and cancer thythm, and can also rhtyhm existing health issues. Researchers are studying circadian geneticz to gain better insight into how they work and Crcadian they affect human health.

Some of Astaxanthin and memory support most pressing questions that scientists seek to answer are:. Microorganisms, fruit flies, zebrafish, and mice are often the research organisms that scientists study because they have similar biological clock genes as humans.

For example, the cyanobacterium Synechococcus elongatus has a fully functional circadian rhythm. Using techniques including CRISPR genome editing, researchers remove clock genes from cells of this cyanobacterium species to shed light on the function of individual proteins.

Similar experiments in fruit flies advance the study of the molecular mechanisms underlying circadian rhythms and their effects on behavior.

They then look for changes in gene activity, molecular signals, or behavior caused by the changes in light and dark. NIGMS is a part of the National Institutes of Health that supports basic research to increase our understanding of biological processes and lay the foundation for advances in disease diagnosis, treatment, and prevention.

Connect With Us: Facebook Instagram Linkedin X Subscriptions YouTube. Skip to main content National Institute of General Medical Sciences. It looks like your browser does not have JavaScript enabled. Please turn on JavaScript and try again. Facebook Instagram Linkedin Subscriptions X YouTube.

Research Areas Areas of Research Biophysics, Biomedical Technology, and Computational Biosciences Genetics and Molecular, Cellular, and Developmental Biology Pharmacology, Physiology, and Biological Chemistry Research Capacity Building Training, Workforce Development, and Diversity.

Related Information Contacts by Research Area Funding Opportunities and Notices Post Award Information Submitting an Application.

Resources NIH RePORTER. Programs Dashboard of TWD Funded Programs High School and Undergraduate Postbaccalaureate and Graduate Students Postdoctoral, Early Career, and Faculty Workforce Development.

Related Information Contact Information Division Structure and Programs. Resources Enhancing Diversity in Training Programs Evaluation Resources Laboratory Safety and Guidelines Training Resources. Division for Research Capacity Building Institutional Development Award IDeA Native American Research Centers for Health NARCH Science Education Partnership Awards SEPA Support for Research Excellence SuRE.

Related Information DRCB News DRCB Staff Contacts. Funding Opportunities Current NIGMS Funding Opportunities Parent Announcements for Investigator-Initiated Applications.

Grant Application and Post-Award Information How to Apply Grant Application and Review Process NIGMS Funding Policies Post-Award Information Talking to NIH Staff About Your Application and Grant Considerations for Multiple Principal Investigator MPI Applications. STEM Education STEM Teaching Resources Pathways Coloring Pages Educator's Corner.

Other Resources Biomedical Beat Blog Featured Topics Glossary Past Campaigns. News News from NIGMS NIGMS in the News COVID News Biomedical Beat Blog NIGMS Feedback Loop Blog. Meetings and Events NIGMS-Supported Meetings Webinars for the NIGMS Training Community Face to Face with Program Directors Grant Writing Webinar Series for Institutions Building Research and Research Training Capacity.

Media Resources Image and Video Gallery. Who We Are Overview Director's Corner Organization and Staff History Staff Directory. What We Do Budget, Financial Management, and Congressional Material Strategic Plans Data Integration, Modeling, and Analytics Advisory Council Communications and Public Liaison Branch.

Work With Us Job Vacancies. Where We Are Visitor Information. Circadian Rhythms. Fold1 Content. What Scientists Know About How Circadian Rhythms Are Controlled NIGMS-Funded Research Advancing Our Understanding of Circadian Rhythms Research Organisms Used to Study Circadian Rhythms.

What Are Circadian Rhythms? Health Effects of Disrupted Circadian Rhythms Circadian rhythms can fall out of sync with the outside world due to factors in the human body or environment.

For example: Variants of certain genes can affect the proteins that control biological clocks. Travel between time zones jet lag and shift work alters the normal sleep-wake cycle.

Light from electronic devices at night can confuse biological clocks. Circadian rhythm cycle of a typical teenager. Credit: NIGMS. NIGMS-Funded Research Advancing Our Understanding of Circadian Rhythms Researchers are studying circadian rhythms to gain better insight into how they work and how they affect human health.

Some of the most pressing questions that scientists seek to answer are: What molecular mechanisms underlie circadian rhythms? Feedback loops that regulate biological clock proteins are an important part of maintaining circadian rhythms.

Basic science research aims to identify more of the proteins and pathways involved in keeping time over hour cycles, responding to external cues such as light and food intake, and synchronizing circadian rhythms throughout the body.

Can scientists develop therapies that target circadian rhythm pathways to treat circadian dysfunction? Scientists are looking for therapies that may affect circadian rhythm pathways and help relieve the symptoms of circadian dysfunction.

What genetic variants lead to circadian rhythm dysfunction? Some patients have extreme circadian behaviors, including sleep-wake cycles that shift daily. These screens may also identify genes previously unknown to be associated with the biological clock.

Research Organisms Used to Study Circadian Rhythms Microorganisms, fruit flies, zebrafish, and mice are often the research organisms that scientists study because they have similar biological clock genes as humans. Traveling across time zones disrupts circadian rhythms.

Credit: iStock. Picture selected ×. Home Contact Us Your Privacy Accessibility Disclaimers FOIA HHS Vulnerability Disclosure. Department of Health and Human Services National Institutes of Health: NIH Turning Discovery Into Health® USA.

gov National Institute of General Medical Sciences 45 Center Drive MSC Bethesda, MD

: Circadian rhythm genetics

Mobile Main Navigation

This study utilizes the Mass General Brigham Biobank to assess the relationship between sleep timing, sleep disorders, and delirium.

Validating Circadian Rhythm Sleep Wake Disorders Using Machine Learning. We are using machine learning approaches to identify potential cases of Circadian Rhythms Sleep Wake Disorders.

Genetics of chronotype and impact on metabolic disease. The project aims to define the genetic basis of subjectively and objectively assessed chronotype, characterize the functional molecular, cellular, and physiologic consequences of causal genes, and variants, and dissect shared genetic relationships between chronotype and metabolic disease outcomes.

How timing of dinner and genetics affect blood sugar level control. Health Europa. January 26, A Genetic Basis for Insomnia Emerges from the Twilight. Scientific American. March 12, Morning or night person? It depends on many more genes than we thought.

The Conversation. This trait proved to be heritable. Mice bred to be heterozygous showed longer periods of Mice homozygous for the mutation showed CLOCK protein has been found to play a central role as a transcription factor in the circadian pacemaker.

Once in the nuclei, CLK is localized in nuclear foci and is later redistributed homogeneously. CYCLE CYC also known as dBMAL for the BMAL1 ortholog in mammals dimerizes with CLK via their respective PAS domains.

This dimer then recruits co-activator CREB-binding protein CBP and is further phosphorylated. A large molar excess of period PER and timeless TIM proteins causes formation of the PER-TIM heterodimer which prevents the CLK-CYC heterodimer from binding to the E-boxes of per and tim , essentially blocking per and tim transcription.

A similar model is found in mice, in which BMAL1 dimerizes with CLOCK to activate per and cryptochrome cry transcription. PER and CRY proteins form a heterodimer which acts on the CLOCK-BMAL heterodimer to repress the transcription of per and cry. PER and CRY proteins accumulate and dimerize during subjective night, and translocate into the nucleus to interact with the CLOCK:BMAL1 complex, directly inhibiting their own expression.

This research has been conducted and validated through crystallographic analysis. CLOCK exhibits histone acetyl transferase HAT activity, which is enhanced by dimerization with BMAL1.

Paolo Sassone-Corsi and colleagues demonstrated in vitro that CLOCK mediated HAT activity is necessary to rescue circadian rhythms in Clock mutants. The CLOCK-BMAL dimer is involved in regulation of other genes and feedback loops.

An enzyme SIRT1 also binds to the CLOCK-BMAL complex and acts to suppress its activity, perhaps by deacetylation of Bmal1 and surrounding histones. The CLOCK-BMAL dimer acts as a positive limb of a feedback loop.

The binding of CLOCK-BMAL to an E-box promoter element activates transcription of clock genes such as per 1, 2, and 3 and tim in mice. It has been shown in mice that CLOCK-BMAL also activates the Nicotinamide phosphoribosyltransferase gene also called Nampt , part of a separate feedback loop. This feedback loop creates a metabolic oscillator.

The CLOCK-BMAL dimer activates transcription of the Nampt gene, which codes for the NAMPT protein. NAMPT is part of a series of enzymatic reactions that covert niacin also called nicotinamide to NAD. SIRT1, which requires NAD for its enzymatic activity, then uses increased NAD levels to suppress BMAL1 through deacetylation.

This suppression results in less transcription of the NAMPT, less NAMPT protein, less NAD made, and therefore less SIRT1 and less suppression of the CLOCK-BMAL dimer. This dimer can again positively activate the Nampt gene transcription and the cycle continues, creating another oscillatory loop involving CLOCK-BMAL as positive elements.

The key role that Clock plays in metabolic and circadian loops highlights the close relationship between metabolism and circadian clocks. The first circadian rhythms were most likely generated by light-driven cell division cycles in ancestral prokaryotic species.

Cryptochromes , light-sensitive proteins regulated by Cry genes , are most likely descendents of kaiC resulting from a genome duplication predating the Cambrian explosion and are responsible for negative regulation of circadian clocks. Other distinct clock gene lineages arose early in vertebrate evolution, with gene BMAL1 paralogous to CLOCK.

Their common ancestor, however, most likely predated the insect-vertebrate split roughly mya. Allelic variations within the Clock1a gene in particular are hypothesized to have effects on seasonal timing according to a study conducted in a population of cyprinid fishes. On average, longer allele lengths were correlated with recently derived species and earlier-spawning species, most likely due to seasonal changes in water temperature.

All other amino acids remained identical across native species, indicating that functional constraint may be another factor influencing CLOCK gene evolution in addition to gene duplication and diversification.

One study investigating the role of CLOCK expression in neurons determined its function in regulating transcriptional networks that could provide insight into human brain evolution. When CLOCK activity was disrupted, increased neuronal migration of tissue in the neocortex was observed, suggesting a molecular mechanism for cortical expansion unique to human brain development.

Clock mutant organisms can either possess a null mutation or an antimorphic allele at the Clock locus that codes for an antagonist to the wild-type protein. The presence of an antimorphic protein downregulates the transcriptional products normally upregulated by Clock.

In Drosophila , a mutant form of Clock Jrk was identified by Allada, Hall , and Rosbash in The team used forward genetics to identify non-circadian rhythms in mutant flies.

Jrk results from a premature stop codon that eliminates the activation domain of the CLOCK protein. This mutation causes dominant effects: half of the heterozygous flies with this mutant gene have a lengthened period of Homozygous flies lose their circadian rhythm.

Furthermore, the same researchers demonstrated that these mutant flies express low levels of PER and TIM proteins, indicating that Clock functions as a positive element in the circadian loop. While the mutation affects the circadian clock of the fly, it does not cause any physiological or behavioral defects.

A recessive allele of Clock leads to behavioral arrhythmicity while maintaining detectable molecular and transcriptional oscillations. This suggests that Clk contributes to the amplitude of circadian rhythms. The mouse homolog to the Jrk mutant is the ClockΔ19 mutant that possesses a deletion in exon 19 of the Clock gene.

This dominant-negative mutation results in a defective CLOCK-BMAL dimer, which causes mice to have a decreased ability to activate per transcription.

The discovery of a null Clock mutant with a wild-type phenotype directly challenged the widely accepted premise that Clock is necessary for normal circadian function. Furthermore, it suggested that the CLOCK-BMAL1 dimer need not exist to modulate other elements of the circadian pathway.

Mice with one NPAS2 allele showed shorter periods at first, but eventual arrhythmic behavior. In humans, a polymorphism in Clock , rs, may be related to the personality trait agreeableness.

PER levels are highest during early evening and lowest early in the day. In fruit flies, the clk and cyc gene products work together to activate the per and tim genes so they produce proteins. Those proteins, PER and TIM, then combine and slowly accumulate in the cell nucleus, where they slow down the clk and cyc genes, which in turn deactivates per and tim and stops further production of the PER and TIM proteins.

As PER and TIM diminish, clk and cyc kick into action again, starting a new daily cycle. The cycle is a bit more complicated in mammals, in which clk works with a gene named Bmal1 instead of with cyc. Also, mammals have three versions of the Per gene.

Other clock genes also play a role. In the fruit fly, the dbt gene codes for a protein that helps break down the PER protein to keep it at just the right levels for the particular time of day.

A gene named pdf , for pigment-dispersing protein, codes for a protein that appears to tell the rest of the fly's body what time it is according to the master clock in its brain.

In , scientists at the University of Utah discovered the first human clock gene. They found it while studying a rare inherited disorder that makes people fall asleep early and wake spontaneously hours before dawn.

Clock genes normally keep us awake during the day and asleep at night. But this clock gene is altered in a way that disrupts the normal sleep cycle.

This inherited sleep pattern, known as "familial advanced sleep phase syndrome" FASPS , has been linked to a variation in the hPer2 gene. People with FASPs are "morning larks" who usually get sleepy by 7 pm and wake up around 2 am.

Another sleep condition, called "delayed sleep-phase syndrome," has the opposite effect, turning people who have it into extreme night owls. They fall asleep very late and have trouble waking up in the morning. Delayed sleep-phase syndrome has been linked to a variation in the hPer3 gene.

Any student who has studied during an "all-nighter" knows the circadian clock isn't the only sleep influencer. Our need for sleep also plays a role. When rats are awake and vigilant, their brain's master clock is more active. When rats are deprived of sleep, their master-clock doesn't respond normally.

Sunlight resets the internal biological clock every day, keeping it synchronized with a hour day. If you lived in an underground bunker under constant artificial light, you would continue to follow an approximately hour sleep-wake pattern, but because it is not exactly 24 hours long, your cycle would slowly get out of phase with actual daytime and nighttime.

Air travel to a distant time zone can also disrupt normal cycles. The resulting jet lag is both a disconnect between local time and your body's time, and a disconnect between your brain's master clock and local clocks in tissues throughout your body.

Once you arrive at your destination, the change in daylight hours will "entrain" or reset your internal clock, but it will take a few days to get rid of the jet lag. Understanding exactly how clock genes work may help scientists develop new medicines that adjust or reset the human biological clock to treat the ill effects of jet lag, night shift work, or wintertime depression.

Clock genes may also offer clues to sleep disorders such as narcolepsy, which makes people feel sleepy during the day. Our internal clock controls hormone levels, which can affect the way our bodies respond to certain medications.

Better knowledge of circadian rhythms may improve the effectiveness of medications by revealing the best times to take them. Light is used to treat people with seasonal affective disorder, the form of depression that surfaces during the shorter days of winter.

Some research indicates light therapy is more effective if it is synchronized with a patient's internal clock, which is why some patients are treated with exposure to bright light early in the morning.

Bright light also has been used to help people adjust to jet lag and to changes in work shifts. Clock genes may some day help scientists treat cancer. At least eight clock genes are known to coordinate normal functions such as cell proliferation which is uncontrolled in cancer and cell suicide which fails to occur in tumor cells.

One study found that without the mPer2 gene, mouse cells with damaged DNA become cancerous instead of committing cell suicide.

If clock genes actually play a role in cancer, they could be a target for new drugs that might disrupt the "clock" to halt the cancer.

Circadian clock genes and the transcriptional architecture of the clock mechanism

Genome-wide association study of circadian rhythmicity in 71, UK biobank participants and polygenic association with mood instability.

eBioMedicine 35 , — Chang, A. Chronotype genetic variant in PER2 is associated with intrinsic circadian period in humans. Lee, D. Evolutionarily conserved regulation of sleep by epidermal growth factor receptor signaling.

Gaspar, L. The genomic landscape of human cellular circadian variation points to a novel role for the signalosome. eLife 6 , e He, Y.

The transcriptional repressor DEC2 regulates sleep length in mammals. Science , — This paper described the first gene for natural short sleep discovered using a human genetic family-based approach. Hirano, A. DEC2 modulates orexin expression and regulates sleep.

USA , — Pellegrino, R. A novel BHLHE41 variant is associated with short sleep and resistance to sleep deprivation in humans. Sleep 37 , — Shi, G. Mutations in metabotropic glutamate receptor 1 contribute to natural short sleep trait.

e4 Xing, L. Mutant neuropeptide S receptor reduces sleep duration with preserved memory consolidation. Toda, H. Genetic mechanisms underlying sleep. Summa, K. The genetics of sleep: insight from rodent models. Cirelli, C.

The genetic and molecular regulation of sleep: from fruit flies to humans. Gottlieb, D. Novel loci associated with usual sleep duration: the CHARGE consortium genome-wide association study.

Nishiyama, T. Genome-wide association meta-analysis and Mendelian randomization analysis confirm the influence of ALDH2 on sleep duration in the Japanese population.

Wang, H. Genome-wide association analysis of self-reported daytime sleepiness identifies 42 loci that suggest biological subtypes. Genetic determinants of daytime napping and effects on cardiometabolic health.

Udler, M. Type 2 diabetes genetic loci informed by multi-trait associations point to disease mechanisms and subtypes: a soft clustering analysis. PLoS Med. Visscher, P. Discovery and implications of polygenicity of common diseases.

Diessler, S. A systems genetics resource and analysis of sleep regulation in the mouse. PLoS Biol. Harbison, S. Genome-wide association study of sleep in Drosophila melanogaster. BMC Genom.

Kumar, S. Identification of genes contributing to a long circadian period in Drosophila melanogaster. Rhythms 36 , — Aging and circadian rhythms. Ohayon, M.

Meta-analysis of quantitative sleep parameters from childhood to old age in healthy individuals: developing normative sleep values across the human lifespan.

Sleep 27 , — Marinelli, M. Heritability and genome-wide association analyses of sleep duration in children: the EAGLE consortium. Sleep 39 , — Merikanto, I. Circadian preference and sleep timing from childhood to adolescence in relation to genetic variants from a genome-wide association study.

Sleep Med. Sateia, M. International classification of sleep disorders-third edition: highlights and modifications. Chest , — American Psychiatric Association Diagnostic and Statistical Manual of Mental Disorders DSM-5 5th edn American Psychiatric Pub, Curtis, B. Extreme morning chronotypes are often familial and not exceedingly rare: the estimated prevalence of advanced sleep phase, familial advanced sleep phase, and advanced sleep—wake phase disorder in a sleep clinic population.

Sivertsen, B. Delayed sleep—wake phase disorder in young adults: prevalence and correlates from a national survey of Norwegian university students. Paine, S. Identifying advanced and delayed sleep phase disorders in the general population: a national survey of New Zealand adults.

Murray, J. Prevalence of circadian misalignment and its association with depressive symptoms in delayed sleep phase disorder. Sleep 40 , zsw Satoh, K. Two pedigrees of familial advanced sleep phase syndrome in Japan. Pereira, D. Association of the length polymorphism in the human Per3 gene with the delayed sleep—phase syndrome: does latitude have an influence upon it?

Sleep 28 , 29—32 Xu, Y. Functional consequences of a CKIδ mutation causing familial advanced sleep phase syndrome. Nature , — Jones, C. Familial advanced sleep—phase syndrome: a short-period circadian rhythm variant in humans.

Toh, K. An hPer2 phosphorylation site mutation in familial advanced sleep phase syndrome. This paper described the first gene for advanced sleep phase syndrome discovered using a human genetic family-based approach. Kurien, P. TIMELESS mutation alters phase responsiveness and causes advanced sleep phase.

MacArthur, D. Guidelines for investigating causality of sequence variants in human disease. Zhang, L. A PERIOD3 variant causes a circadian phenotype and is associated with a seasonal mood trait.

CAS Google Scholar. Kornum, B. Ollila, H. Narcolepsy type 1: what have we learned from genetics? Mignot, E. Genetic and familial aspects of narcolepsy. Neurology 50 , S16—S22 Langdon, N. Genetic markers in narcolepsy.

Lancet 2 , — Lin, L. The sleep disorder canine narcolepsy is caused by a mutation in the hypocretin orexin receptor 2 gene. Cell 98 , — Luo, G. Autoimmunity to hypocretin and molecular mimicry to flu in type 1 narcolepsy. Hor, H. Genome-wide association study identifies new HLA class II haplotypes strongly protective against narcolepsy.

Faraco, J. ImmunoChip study implicates antigen presentation to T cells in narcolepsy. Han, F. Genome wide analysis of narcolepsy in China implicates novel immune loci and reveals changes in association prior to versus after the H1N1 influenza pandemic.

Degn, M. Rare missense mutations in P2RY11 in narcolepsy with cataplexy. Brain , — HLA-DQ association and allele competition in Chinese narcolepsy. Tissue Antigens 80 , — Sleep 20 , — Capittini, C. A systematic meta-analysis. Miyagawa, T. Genetics of narcolepsy.

Genome Var. Trenkwalder, C. Comorbidities, treatment, and pathophysiology in restless legs syndrome. Lancet Neurol. Earley, C. Altered brain iron homeostasis and dopaminergic function in restless legs syndrome Willis—Ekbom disease. Jiménez-Jiménez, F. Neurochemical features of idiopathic restless legs syndrome.

Schormair, B. Identification of novel risk loci for restless legs syndrome in genome-wide association studies in individuals of European ancestry: a meta-analysis. Akçimen, F. Transcriptome-wide association study for restless legs syndrome identifies new susceptibility genes.

Genetics of restless legs syndrome: an update. Spieler, D. Restless legs syndrome-associated intronic common variant in Meis1 alters enhancer function in the developing telencephalon. Genome Res. Drgonova, J.

Mouse model for protein tyrosine phosphatase D PTPRD associations with restless leg syndrome or Willis—Ekbom disease and addiction: reduced expression alters locomotion, sleep behaviors and cocaine-conditioned place preference.

Stefansson, H. A genetic risk factor for periodic limb movements in sleep. Sarayloo, F. SKOR1 has a transcriptional regulatory role on genes involved in pathways related to restless legs syndrome.

Liang, J. Comparison of heritability estimation and linkage analysis for multiple traits using principal component analyses. Campos, A. Insights into the aetiology of snoring from observational and genetic investigations in the UK Biobank.

Strausz, S. Genetic analysis of obstructive sleep apnoea discovers a strong association with cardiometabolic health. Variants in angiopoietin-2 ANGPT2 contribute to variation in nocturnal oxyhaemoglobin saturation level.

Sequencing analysis at 8p23 identifies multiple rare variants in DLC1 associated with sleep-related oxyhemoglobin saturation level.

Cade, B. Care Med. Associations of variants In the hexokinase 1 and interleukin 18 receptor regions with oxyhemoglobin saturation during sleep. Chen, H. Multiethnic meta-analysis identifies RAI1 as a possible obstructive sleep apnea—related quantitative trait locus in men.

Cell Mol. Mukherjee, S. The genetics of obstructive sleep apnoea. Respirology 23 , 18—27 Morin, C. Insomnia disorder. Lind, M. A longitudinal twin study of insomnia symptoms in adults.

Sleep 38 , — Amin, N. Genetic variants in RBFOX3 are associated with sleep latency. Ban, H. Genetic and metabolic characterization of insomnia.

PLoS ONE 6 , e Spada, J. Genome-wide association analysis of actigraphic sleep phenotypes in the LIFE adult study. Replication of genome-wide association studies GWAS loci for sleep in the British G cohort.

B B , — Genome-wide association analyses of sleep disturbance traits identify new loci and highlight shared genetics with neuropsychiatric and metabolic traits. Biological and clinical insights from genetics of insomnia symptoms. Jansen, P. Genome-wide analysis of insomnia in 1,, individuals identifies new risk loci and functional pathways.

This largest-to-date GWAS for insomnia identified genetic loci associated with insomnia symptoms and causal links to cardiometabolic traits. Hammerschlag, A. Genome-wide association analysis of insomnia complaints identifies risk genes and genetic overlap with psychiatric and metabolic traits.

Khlghatyan, J. Fxr1 regulates sleep and synaptic homeostasis. EMBO J. Genetic pathways to insomnia. Brain Sci. Mainieri, G. The genetics of sleep disorders in children: a narrative review.

El Gewely, M. Reassessing GWAS findings for the shared genetic basis of insomnia and restless legs syndrome. Watanabe, K. Genome-wide meta-analysis of insomnia in over 2. Krystal, A. Sleep pharmacogenetics: the promise of precision medicine.

Barateau, L. Recent advances in treatment for narcolepsy. Equihua-Benítez, A. Orexin cell transplant reduces behavioral arrest severity in narcoleptic mice. Brain Res.

Pingault, J. Using genetic data to strengthen causal inference in observational research. Bulik-Sullivan, B. An atlas of genetic correlations across human diseases and traits. Byrne, E. The relationship between insomnia and complex diseases-insights from genetic data. Emdin, C.

Mendelian randomization. JAMA , — Smith, G. Voight, B. Plasma HDL cholesterol and risk of myocardial infarction: a Mendelian randomisation study. Lancet , — Vetter, C. Haraden, D. The relationship between depression and chronotype: a longitudinal assessment during childhood and adolescence.

Anxiety 34 , — Using Mendelian randomisation methods to understand whether diurnal preference is causally related to mental health. Daghlas, I. Genetically proxied diurnal preference, sleep timing, and risk of major depressive disorder.

JAMA Psychiat. Facer-Childs, E. Javaheri, S. Insomnia and risk of cardiovascular disease. Zheng, B. Insomnia symptoms and risk of cardiovascular diseases among 0.

Baranova, A. Shared genetic liability and causal effects between major depressive disorder and insomnia. Högl, B. Idiopathic REM sleep behaviour disorder and neurodegeneration — an update. Gan-Or, Z. Sleep disorders and Parkinson disease; lessons from genetics.

Gros, P. Overview of sleep and circadian rhythm disorders in parkinson disease. Leng, Y. Lucey, B. Medori, R. Fatal familial insomnia, a prion disease with a mutation at codon of the prion protein gene.

Watson, N. Sleep duration and body mass index in twins: a gene—environment interaction. Sleep 35 , — Multi-ancestry genome-wide gene-sleep interactions identify novel loci for blood pressure.

Psychiatry 26 , — Noordam, R. Multi-ancestry sleep-by-SNP interaction analysis in , individuals reveals lipid loci stratified by sleep duration.

Rask-Andersen, M. Gene—environment interaction study for BMI reveals interactions between genetic factors and physical activity, alcohol consumption and socioeconomic status. Celis-Morales, C. Sleep characteristics modify the association of genetic predisposition with obesity and anthropometric measurements in , UK Biobank participants.

This paper demonstrates genetic effects via sleep and chronotype behaviour interactions on obesity-related phenotypes. March 12, Morning or night person? It depends on many more genes than we thought. The Conversation.

January 29, Interplay of Dinner Timing and MTNR1B Type 2 Diabetes Risk Variant on Glucose Tolerance and Insulin Secretion: A Randomized Crossover Trial. Publication Date: March 1, Journal: Diabetes Care. Genetically Proxied Diurnal Preference, Sleep Timing, and Risk of Major Depressive Disorder.

Publication Date: August 1, Journal: JAMA Psychiatry. Morning diurnal preference and food intake: a Mendelian randomization study. Publication Date: November 11, Journal: The American Journal of Clinical Nutrition.

Steeves, M. Vitaterna, J. Kornhauser, P. Lowrey, F. Turek and J. Positional cloning of the mouse circadian Clock gene.

Cell Buhr, E. Yoo and J. Temperature as a universal resetting cue for mammalian circadian oscillators. Science Huang, N. Chelliah, Y. Shan, C. Taylor, S. Yoo, C. Partch, C. Green, H. Zhang and J. Crystal structure of the heterodimeric CLOCK:BMAL1 transcriptional activator complex.

Koike, N. Yoo, H. Huang, V. Kumar, C. Lee, T. Kim and J. Transcriptional architecture and chromatin landscape of the core circadian clock in mammals. Yoo, S. Mohawk, S.

Siepka, Y. Shan, S. Huh, H. Hong, I. Kornblum, V. Kumar, N. Koike, M. Xu, J. Nussbaum, X.

Genomics of circadian rhythms in health and disease Article PubMed Google Scholar Circzdian L, Circafian Injury prevention programs PA, Teshiba TM, Service SK, Fears SC, Araya Genefics, et al. Loss of Bmal1 results in an acceleration of aging and a shortened life span in mice [ 84 ]. Huang, V. Genes Brain Behav. Article PubMed PubMed Central Google Scholar. How does light reset the biological clock?

Video

Easy Memorization - Tim and Per in Drosophila Circadian Rhythms

Author: Shar

5 thoughts on “Circadian rhythm genetics

  1. Nach meiner Meinung sind Sie nicht recht. Geben Sie wir werden besprechen. Schreiben Sie mir in PM, wir werden umgehen.

Leave a comment

Yours email will be published. Important fields a marked *

Design by ThemesDNA.com