Familial sleep traits
Familial sleep traits are heritable variations in sleep patterns, resulting in abnormal sleep-wake times and/or abnormal sleep length.
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 that affect sleep timing and circadian rhythms. Some of these circadian disorders include Advanced Sleep Phase Disorder and Delayed Sleep Phase Disorder. 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. 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.
Sleep timing is controlled by the circadian clock, which can entrain to environmental stimuli and is regulated by a transcription-translation feedback loop. 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, Familial Delayed Sleep Phase, and Familial Natural Short Sleep. 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. Other Mendelian genes that are not known to play a core role in the TTFL but are involved in FNSS include DEC2 and ADRB1.
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. 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.
History of discoveries
Familial sleep traits have been difficult to study due to the various environmental influences 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 in a 1999 publication. 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. In this 1999 publication, researchers were also able to conclude that this trait has an autosomal dominant mode of inheritance with high penetrance. 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. Since these studies, Csnk1d, PER2, PER3, and CRY2 have all been identified as important in hereditary FASP.Another sleep trait, Delayed Sleep Phase Syndrome was first identified by 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 to the list of heritable sleep traits. 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.
In addition to these findings, Familial Natural Short Sleep 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. 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.
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 and Alzheimer's disease. 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. 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. 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.