Familial sleep traits

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Familial sleep traits are heritable variations in sleep patterns, resulting in abnormal sleep-wake times and/or abnormal sleep length.

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Circadian rhythms are coordinated physiological and biological changes that oscillate on an approximately 24-hour cycle. Disruptions to these rhythms in humans may affect the duration, onset, and/or quality of sleep during this cycle, resulting in familial sleep traits. These traits are not necessarily syndromes because they do not always cause distress among individuals. Instead of being disorders, familial sleep traits are variations in an individual's biological tendencies of sleep-wake times, and are only considered syndromes if affected individuals complain about life interference, in which case they may fall under the category of Circadian Rhythm Sleep Disorders (CRSD) that affect sleep timing and circadian rhythms. Some of these circadian disorders include Advanced Sleep Phase Disorder (ASPD) and Delayed Sleep Phase Disorder (DSPD). Familial sleep traits are more specific than CRSD because they are heritable and involve a wide range of Mendelian genes. Evidence has shown that genes significantly influence sleep schedules in mammals, including humans, and account for one-third of the variation in sleep quality and duration. [1] Studies in human monozygotic twins have provided evidence that genetic factors affect "normal" sleep patterns as well, meaning ones where no individual has been diagnosed with an altered phenotypic sleep trait. [1]

Sleep timing is controlled by the circadian clock, which can entrain to environmental stimuli (usually a light-dark cycle) and is regulated by a transcription-translation feedback loop (TTFL). In humans, there are multiple genes involved in this molecular biological clock, which when mutated may result in sleep disorders such as Familial Advanced Sleep Phase (FASP), Familial Delayed Sleep Phase (FDSP), and Familial Natural Short Sleep (FNSS). Some mutations in Mendelian genes that are involved in the TTFL have been identified as the causes of these sleep traits, including PER2, PER3, CRY2, CRY1. [2] [3] Other Mendelian genes that are not known to play a core role in the TTFL but are involved in FNSS include DEC2 and ADRB1. [4] [5]

With some familial sleep traits, there may be a shift in an individual's chronotype, which describes the time of sleep-wake behaviors that result from circadian rhythms. Chronotype may shift depending on multiple factors including gender and age. Individuals with FASP have earlier chronotypes and individuals with FDSP have later chronotypes compared to a conventional sleep period which runs from approximately 10pm to 7am. [6] Individuals may meet the criteria for FASP or FDSP if they have Advanced Sleep Phase or Delayed Sleep Phase and at least one first degree relative with the trait. Researchers have examined the human prevalence of FASP to be 0.33-0.5% by including individuals who have a sleep onset at approximately 8:30pm and offset at 5:30am. FDSP, which includes individuals who have a delayed sleep onset and offset, has an unknown human prevalence and may vary based on location, definition, and age. [6]

History of discoveries

Familial sleep traits have been difficult to study due to the various environmental influences (such as entraining daily alarms, artificial light at night, and caffeine or stimulant intake) that can contribute to different behavioral phenotypes in humans. Despite these potential difficulties, Louis Ptáček and colleagues discovered evidence of a human familial circadian rhythm variant in the 1990s. This variant resulted in a shorter period and an advance of melatonin and temperature rhythms and was initially termed Advanced Sleep Phase Syndrome (ASPS) in a 1999 publication. [7] Individuals with ASPS have earlier sleep and wake onsets, meaning they both go to bed and wake up earlier compared to control groups. The first participant with this phenotype told researchers she recognized similar sleep patterns in her family. From structured interviews and family pedigree analysis, some of these individuals were identified to have ASPS as well, providing evidence that this phenotype could be genetic, resulting in Familial Advanced Sleep Phase (FASP). In this 1999 publication, researchers were also able to conclude that this trait has an autosomal dominant mode of inheritance with high penetrance. [7] This means that the genes involved in FASP are passed through non-sex chromosomes, and an individual only needs one copy of the gene across homologs for the gene to be expressed. Since this initial 1999 FASP publication, other circadian biologists including Phyllis Zee and Joseph Takahashi have conducted further genetic analysis. They published a paper in 2001 that presented data showing a phenotypically characterized case of Advanced Sleep Phase Syndrome to provide further evidence that this trait can be hereditary. [8] Since these studies, Csnk1d, PER2, PER3, and CRY2 have all been identified as important in hereditary FASP. [2] [9]

Another sleep trait, Delayed Sleep Phase Syndrome (DSPS) was first identified by Elliot Weitzman and colleagues in 1981. Individuals with DSPS typically cannot fall asleep until later and wake up later compared to control groups. They often cannot fall asleep until between 2:00-6:00am, but then have a normal sleep duration. However, DSPS was not hypothesized to have a genetic component until researchers at University of California, San Diego discovered a familial pedigree with DSPS in 2001, adding this Familial Delayed Sleep Phase (FDSP) to the list of heritable sleep traits. [10] [11] Almost two decades later in 2017, Michael Young and colleagues in New York published findings that further supported delayed sleep to have a genetic component, resulting in FDSP. These scientists reported that a mutation in CRY1, a component of the TTFL that represses Clock and Bmal1, results in a gain-of-function variation that lengthens circadian period. [3]

In addition to these findings, Familial Natural Short Sleep (FNSS) is another heritable sleep trait that has been studied over the past few years. In 2009, Ying-Hui Fu and Ptáček discovered the first short-sleep gene by identifying a mutation in the DEC2 gene that resulted in an average of 6.25 hours of sleep a night instead of 8.06 hours, an identifying feature of FNSS. [12] This was the first genetic discovery for this sleep trait, broadening the scope of familial sleep trait research. In 2019, Ptáček and Fu published further research about the genetic aspect of FNSS, identifying a mutation in the gene ADRB1 that increases the activity of ADRB1+ neurons in the dorsal pons. [4] [13]

Most of the research conducted thus far has been surrounding FASP, FDSP, and FNSS, with recent studies beginning to examine the roles of heritable sleep variability on autism-spectrum disorder (ASD) and Alzheimer's disease (AD). [2] ASD, a neurodevelopmental disorder, has evidence of genetic components and affected individuals have reported a high prevalence of insomnia. Fu, Ptáček, and colleagues have hypothesized that it may be interesting to examine if sleep traits and disruptions can exacerbate the atypical neurodevelopment in ASD. [2] Additionally, recent research about AD, a neurodegenerative disease, has suggested that sleep disruption might contribute to the disease. A characteristic factor of AD is the accumulation of plaques. These plaques are usually at a lower level in the brain interstitial space when an individual first wakes up and then during waking hours these levels increase. Sleep disruption can eliminate the reduction in levels, which is important during disease progression. [2] Both ASD and AD demonstrate how the heritability of sleep traits may also be involved in disorders and diseases that are not traditionally thought of as circadian, but more research must be done in this field. [2]

Heritable sleep traits

The functions of heritability for many sleep traits are not well known, underscoring the importance of continued research into the human genome.

Familial Advanced Sleep Phase

Familial Advanced Sleep Phase (FASP) results in an individual having a circadian clock that is entrained to their surroundings, but gives the impression that the individual is not. [8] This trait typically develops during middle age, and is more common in older adults. Affected individuals typically have a free-running period of about 22 hours, shorter than the average person who has a free-running period closer to 24 hours. This also means that certain physiological markers, such as body temperature and melatonin will be present at higher levels earlier in the day as compared to an average person. [8]

Symptoms

FASP is typically characterized by excessively early sleep and wake times. Additionally, individuals may experience excessive daytime sleepiness if they are forced to adhere to a schedule offset from their personal biological clock. [8] Individuals with FASP are typically phase advanced by 4 to 6 hours as compared to the average person. [6]

Treatments

FASP is traditionally treated with light therapy in the evenings, or behaviorally with chronotherapy. Individuals with FASP typically need to have a two-hour delay per day to remain entrained, due to their 22-hour period. Pharmacological interventions are typically avoided due to risks associated with daytime drug-induced sleepiness. [14]

Molecular Basis

FASP has been mapped to chromosome 2q. Genes that are known to influence the presentation of FASP are CRY2, PER2, PER3 and CK1∂. [8] TIMELESS (hTIM) has also been shown to cause FASP. [15] These mutations are critical in the trait's phenotype and heritability. [9] This trait is inherited in an autosomal dominant fashion. [7]

Familial Delayed Sleep Phase

Familial Delayed Sleep Phase (FDSP) results in an individual having a circadian clock that is entrained to their surroundings, but gives the impression that the individual is not. The trait typically develops in adolescence. [16] Affected individuals have a free-running period that is longer than the average 24 hours, meaning that certain physiological markers, such as body temperature and melatonin, are present in higher levels later in the day as compared to the average person.

Symptoms

FDSP is typically characterized by excessively late sleep times and wake times, and may include daytime sleepiness if the individual is forced to adhere to a schedule offset from their personal biological clock. Individuals with FDSP may have comorbidities with depression, Attention Deficit Hyperactivity Disorder (ADHD), obesity, and Obsessive-Compulsive Disorder (OCD). [17]

Treatments

Treatment is usually non-pharmacological, with light therapy being a common intervention. Phase delay chronotherapy is also occasionally used. Melatonin taken at night will not change the individual's circadian rhythm, but may act as a temporary solution. [18]

Molecular Basis

FDSP is heritable and linked to mutations in the PER3 and CRY1 genes, which result in the delayed sleep phenotype. [3]

Fatal Familial Insomnia

Fatal Familial Insomnia (FFI) is a disorder that results in trouble sleeping, speech and coordination problems, and eventually dementia. Most of those affected die within a few years, and the disorder has no cure. The disorder can manifest any time from age 18 to 60, but the average age of affected individuals is 50 years old. [19]

Symptoms

The disorder has a 4-stage progression, starting with individuals experiencing insomnia, progressing to seeing hallucinations, then inability to sleep and dramatic weight loss, and finally dementia, which is followed by death. Individuals have a 6-36 month prognosis after they begin experiencing symptoms. [19]

Treatments

Due to the prognosis of the disorder, treatment is often minimal and palliative in nature. Sleeping pills and other traditional treatments are not found to be beneficial in treating FFI. [20]

Molecular Basis

The disorder is caused by a mutation of the PRNP gene resulting in the creation of a prion. [21] These prions result in neurodegeneration, leading to FFI. This mutation can either occur spontaneously or be passed down in an autosomal dominant manner. [21]

Familial Natural Short Sleep

Familial natural short sleep (FNSS) is a distinct category of habitual short sleep. Individuals with this trait usually get 4–6.5 hours of sleep per day but do not have daytime sleepiness and do not need catch-up sleep on the weekends. After sleep deprivation, these individuals have less of a sleep deficit than individuals without FNSS. Additionally, affected individuals have a higher behavioral drive, resulting in many holding high pressure jobs, and they may have a better ability to deal with stress. People with FNSS are commonly mistaken for having insomnia. [6] The prevalence of FNSS is currently unknown, however mutations in the genes DEC2 and ADRB1, NPSR1, and GRM1 have been linked to FNSS. [6] [22] [23]

Symptoms

FNSS is unique because individuals with this sleep trait show no symptoms of shorter sleep. They are able to be active and function normally. [6]

Treatments

FNSS may be seen as advantageous rather than detrimental to some individuals. Therefore, because FNSS does not negatively impact most affected individuals, treatment options for it have not been well researched or documented. [6]

Health effects

Such mutations appear to reduce Alzheimer's pathology in mice. [24]

Molecular Basis

In 2009, Ying-Hui Fu and colleagues described how a genetic variant in DEC2 produced the short sleep phenotype. [6] In this variant, an arginine residue is substituted for a proline residue typically present at position 384. [25] Within the family studied, people having the DEC2 mutation had shorter sleep durations. The researchers found the same phenotype when mutating this gene in Drosophila and mice. [6] Interestingly, they found that the mutant mice did not display changes in their free-running activity period. [25] DEC2 functions as a transcriptional repressor and increases expression of hypocretin, which promotes a waked state. [6] DEC2 inhibits CLOCK/BMAL1 activation of PER, through protein-protein interaction or competition for the E-box transcriptional elements. [25] A separate study using dizygotic twins with a novel DEC2 mutation showed that one twin had shorter sleep duration. These results demonstrate that DEC2 is able to affect sleep length through weakened transcriptional repression. [6]

Another important gene involved in FNSS is ADRB1. ADRB1 neurons in mice are active they are awake and are found in the dorsal pons. Through additional family studies, mutations in ADRB1 have shown the reduced sleep phenotype. [6]

In a more recent study done by Lijuan Xing and colleagues, NPSR1 was linked to FNSS. In this study, researchers identified a family with a mutation in the NPSR1 gene, which caused a short sleep phenotype. NPSR1 is a G-protein coupled receptor that plays a role in arousal and sleep behaviors. This NPSR1 mutation was recreated in mice, and the researchers found the same short sleep phenotype present. [22]

In another study done by Guangsen Shi and colleagues, GRM1 was linked to FNSS. Here, researchers identified two GRM1 mutations in two different FNSS families. They recreated these same mutations in mouse models and found that they caused the mice to sleep less. [23]

Understanding how these individuals are able to tolerate higher sleep pressure and behavioral drive will prove useful for numerous people that hold jobs which require long durations of wakefulness. [6]

Familial Natural Long Sleep

Familial natural long sleep (FNLS) likely exists, however there have not been any genetic variants found that cause FNLS. People with FNLS likely need more than 8 hours of sleep per day to feel well rested. This group of individuals may be harder to detect due to comorbidities, such as depression. Additional research is necessary to learn more about this sleep trait. [6]

See also

Related Research Articles

<span class="mw-page-title-main">Circadian rhythm</span> Natural internal process that regulates the sleep-wake cycle

A circadian rhythm, or circadian cycle, is a natural oscillation that repeats roughly every 24 hours. Circadian rhythms can refer to any process that originates within an organism and responds to the environment. Circadian rhythms are regulated by a circadian clock whose primary function is to rhythmically co-ordinate biological processes so they occur at the correct time to maximise the fitness of an individual. Circadian rhythms have been widely observed in animals, plants, fungi and cyanobacteria and there is evidence that they evolved independently in each of these kingdoms of life.

<span class="mw-page-title-main">Delayed sleep phase disorder</span> Chronic mismatch between a persons normal daily rhythm, compared to other people and societal norms

Delayed sleep phase disorder (DSPD), more often known as delayed sleep phase syndrome and also as delayed sleep–wake phase disorder, is the delaying of a person's circadian rhythm compared to those of societal norms. The disorder affects the timing of biological rhythms including sleep, peak period of alertness, core body temperature, and hormonal cycles.

Advanced Sleep Phase Disorder (ASPD), also known as the advanced sleep-phase type (ASPT) of circadian rhythm sleep disorder, is a condition that is characterized by a recurrent pattern of early evening sleepiness and very early morning awakening. This sleep phase advancement can interfere with daily social and work schedules, and results in shortened sleep duration and excessive daytime sleepiness. The timing of sleep and melatonin levels are regulated by the body's central circadian clock, which is located in the suprachiasmatic nucleus in the hypothalamus.

In chronotherapy, an attempt is made to move bedtime and rising time later and later each day, around the clock, until a person is sleeping on a normal schedule. This treatment can be used by people with delayed sleep phase disorder (DSPD), who generally cannot reset their circadian rhythm by moving their bedtime and rising time earlier. DSPD is a circadian rhythm sleep disorder, characterised by a mismatch between a person's internal biological clock and societal norms. Chronotherapy uses the human phase response to light or melatonin. The American Academy of Sleep Medicine has recommended chronotherapy for the treatment of circadian rhythm and sleep disorders.

Non-24-hour sleep–wake disorder is one of several chronic circadian rhythm sleep disorders (CRSDs). It is defined as a "chronic steady pattern comprising [...] daily delays in sleep onset and wake times in an individual living in a society". Symptoms result when the non-entrained (free-running) endogenous circadian rhythm drifts out of alignment with the light–dark cycle in nature. Although this sleep disorder is more common in blind people, affecting up to 70% of the totally blind, it can also affect sighted people. Non-24 may also be comorbid with bipolar disorder, depression, and traumatic brain injury. The American Academy of Sleep Medicine (AASM) has provided CRSD guidelines since 2007 with the latest update released in 2015.

Smith–Magenis syndrome (SMS), also known as 17p- syndrome, is a microdeletion syndrome characterized by an abnormality in the short (p) arm of chromosome 17. It has features including intellectual disability, facial abnormalities, difficulty sleeping, and numerous behavioral problems such as self-harm. Smith–Magenis syndrome affects an estimated between 1 in 15,000 to 1 in 25,000 individuals.

Circadian rhythm sleep disorders (CRSD), also known as circadian rhythm sleep-wake disorders (CRSWD), are a family of sleep disorders which affect the timing of sleep. CRSDs arise from a persistent pattern of sleep/wake disturbances that can be caused either by dysfunction in one's biological clock system, or by misalignment between one's endogenous oscillator and externally imposed cues. As a result of this mismatch, those affected by circadian rhythm sleep disorders have a tendency to fall asleep at unconventional time points in the day. These occurrences often lead to recurring instances of disturbed rest, where individuals affected by the disorder are unable to go to sleep and awaken at "normal" times for work, school, and other social obligations. Delayed sleep phase disorder, advanced sleep phase disorder, non-24-hour sleep–wake disorder and irregular sleep–wake rhythm disorder represents the four main types of CRSD.

The Casein kinase 1 family of protein kinases are serine/threonine-selective enzymes that function as regulators of signal transduction pathways in most eukaryotic cell types. CK1 isoforms are involved in Wnt signaling, circadian rhythms, nucleo-cytoplasmic shuttling of transcription factors, DNA repair, and DNA transcription.

<span class="mw-page-title-main">CLOCK</span> Human protein and coding gene

CLOCK is a gene encoding a basic helix-loop-helix-PAS transcription factor that is known to affect both the persistence and period of circadian rhythms.

Period (per) is a gene located on the X chromosome of Drosophila melanogaster. Oscillations in levels of both per transcript and its corresponding protein PER have a period of approximately 24 hours and together play a central role in the molecular mechanism of the Drosophila biological clock driving circadian rhythms in eclosion and locomotor activity. Mutations in the per gene can shorten (perS), lengthen (perL), and even abolish (per0) the period of the circadian rhythm.

<span class="mw-page-title-main">PER3</span> Protein and coding gene in humans

The PER3 gene encodes the period circadian protein homolog 3 protein in humans. PER3 is a paralog to the PER1 and PER2 genes. It is a circadian gene associated with delayed sleep phase syndrome in humans.

<span class="mw-page-title-main">PER2</span> Protein-coding gene in the species Homo sapiens

PER2 is a protein in mammals encoded by the PER2 gene. PER2 is noted for its major role in circadian rhythms.

Irregular sleep–wake rhythm disorder (ISWRD) is a rare form of circadian rhythm sleep disorder. It is characterized by numerous naps throughout the 24-hour period, no main nighttime sleep episode, and irregularity from day to day. Affected individuals have no pattern of when they are awake or asleep, may have poor quality sleep, and often may be very sleepy while they are awake. The total time asleep per 24 hours is normal for the person's age. The disorder is serious—an invisible disability. It can create social, familial, and work problems, making it hard for a person to maintain relationships and responsibilities, and may make a person home-bound and isolated.

<span class="mw-page-title-main">Michael W. Young</span> American biologist and geneticist (born 1949)

Michael Warren Young is an American biologist and geneticist. He has dedicated over three decades to research studying genetically controlled patterns of sleep and wakefulness within Drosophila melanogaster.

Ying-Hui Fu is a Taiwanese-American biologist and human geneticist who has made important contributions to understanding the genetics of many neurological disorders. Her chief discoveries include describing Mendelian sleep phenotypes, identifying causative genes and mutations for circadian rhythm disorders, and characterizing genetic forms of demyelinating degenerative disorders. Fu is currently a professor of neurology at the University of California, San Francisco. She was elected to the US National Academy of Sciences in 2018.

Louis Ptáček is an American neurologist and professor who contributed greatly to the field of genetics and neuroscience. He was also an HHMI investigator from 1997 to 2018. His chief areas of research include the understanding of inherited Mendelian disorders and circadian rhythm genes. Currently, Ptáček is a neurology professor and a director of the Division of Neurogenetics in University of California, San Francisco, School of Medicine. His current investigations primarily focus on extensive clinical studies in families with hereditary disorders, which include identifying and characterizing the genes responsible for neurological variations.

Achim Kramer is a German chronobiologist and biochemist. He is the current head of Chronobiology at Charité – Universitätsmedizin Berlin in Berlin, Germany.

Carrie L. Partch is an American protein biochemist and circadian biologist. Partch is currently a Professor in the Department of Chemistry and Biochemistry at the University of California, Santa Cruz. She is noted for her work using biochemical and biophysical techniques to study the mechanisms of circadian rhythmicity across multiple organisms. Partch applies principles of chemistry and physics to further her research in the field of biological clocks.

<span class="mw-page-title-main">Familial natural short sleep</span> Medical condition

Familial natural short sleep is a rare, genetic, typically inherited trait where an individual sleeps for fewer hours than average without suffering from daytime sleepiness or other consequences of sleep deprivation. This process is entirely natural in this kind of individual, and it is caused by certain genetic mutations. A person with this trait is known as a "natural short sleeper".

In chronobiology, photoentrainment refers to the process by which an organism's biological clock, or circadian rhythm, synchronizes to daily cycles of light and dark in the environment. The mechanisms of photoentrainment differ from organism to organism. Photoentrainment plays a major role in maintaining proper timing of physiological processes and coordinating behavior within the natural environment. Studying organisms’ different photoentrainment mechanisms sheds light on how organisms may adapt to anthropogenic changes to the environment.

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