- Biological and clinical insights from genetics of insomnia symptoms
- Genetic polymorphisms associated with sleep-related phenotypes; relationships with individual nocturnal symptoms of insomnia in the HUNT study
- Genetic and Metabolic Characterization of Insomnia
- Genetics of Sleep and Insomnia – 21 Genes & SNPs to Check
- The Genetic Circuit That Controls Circadian Rhythm
- 1) CLOCK and BMAL
- 2) PGC-1alpha
- 3) AhR
- 4) DEC2
- 5) Per3
- 6) ABCC9
- Genetics of Insomnia
- 1) 5-HT2A Serotonin Receptor
- Important SNPs
- 2) Adenosine Receptors
- 3) Uridine (P2Y2) Receptors
- 4) BDNF
- 5) Calcium Signaling Genes
- 6) SLC2A13
- Learn More
Biological and clinical insights from genetics of insomnia symptoms
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Genetic and Metabolic Characterization of Insomnia
Insomnia is reported to chronically affect 10∼15% of the adult population. However, very little is known about the genetics and metabolism of insomnia. Here we surveyed 10,038 Korean subjects whose genotypes have been previously profiled on a genome-wide scale. About 16.
5% reported insomnia and displayed distinct metabolic changes reflecting an increase in insulin secretion, a higher risk of diabetes, and disrupted calcium signaling. Insomnia-associated genotypic differences were highly concentrated within genes involved in neural function.
The most significant SNPs resided in ROR1 and PLCB1, genes known to be involved in bipolar disorder and schizophrenia, respectively. Putative enhancers, as indicated by the histone mark H3K4me1, were discovered within both genes near the significant SNPs.
In neuronal cells, the enhancers were bound by PAX6, a neural transcription factor that is essential for central nervous system development. Open chromatin signatures were found on the enhancers in human pancreas, a tissue where PAX6 is known to play a role in insulin secretion.
In PLCB1, CTCF was found to bind downstream of the enhancer and interact with PAX6, suggesting that it can probably inhibit gene activation by PAX6. PLCB4, a circadian gene that is closely located downstream of PLCB1, was identified as a candidate target gene.
Hence, dysregulation of ROR1, PLCB1, or PLCB4 by PAX6 and CTCF may be one mechanism that links neural and pancreatic dysfunction not only in insomnia but also in the relevant psychiatric disorders that are accompanied with circadian rhythm disruption and metabolic syndrome.
Citation: Ban H-J, Kim SC, Seo J, Kang H-B, Choi JK (2011) Genetic and Metabolic Characterization of Insomnia. PLoS ONE 6(4): e18455. https://doi.org/10.1371/journal.pone.0018455
Editor: Carlo Gaetano, Istituto Dermopatico dell'Immacolata, Italy
Received: November 5, 2010; Accepted: March 8, 2011; Published: April 6, 2011
Copyright: © 2011 Ban et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: This research was supported by grants from Korea Centers for Disease Control and Prevention, Republic of Korea (4845-301, 4851-302, 4851-307).
JKC is a recipient of the TJ Park Science Fellowship and is supported by a grant from the National Research Foundation of Korea (2009-0086964). CHUNG Moon Soul Center for BioInformation and BioElectronics provided computing facilities. JS is an employee of Omicsis, Inc.
The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: JS is an employee of Omicsis, Inc. However, this does not alter adherence to all the journal's policies on sharing data and materials.
Sleep is a complex physiological process. Genetic determinants underlying sleep phenotypes have only recently begun to be revealed. Reduced sleep has been associated with a mutation in the transcription factor DEC2 in a family-based genetic study .
Several quantitative traits related to sleep, such as sleepiness, usual bedtime, and sleep duration, have been examined in a genome-wide association study for 749 subjects .
A common sleep disorder, restless legs syndrome, has been characterized by genome-wide association analyses for larger populations , .
However, little is known about the genetic background of insomnia, one of the most common sleep disorders, which affects 10∼15% of the adult population. In a classic twin study , >1,000 monozygotic twins and >800 dizygotic twins were examined in terms of insomnia and sleepiness.
Heritability was estimated at 57% for insomnia and 38% for sleepiness. Interestingly, obesity was also under strong genetic influence and shared genetic effects were found between insomnia and obesity .
However, the particular genetic contributions common to the two phenotypes remain to be identified.
To study genetic and metabolic aspects of insomnia, we employed the population dataset from the Korea Association Resource (KARE) project. The Ansung and Ansan cohorts, consisting of 5,018 and 5,020 participants ranging in age from 40 to 69 years, were investigated.
A genome-wide association analysis has been carried out the genotypes of the subjects . In addition, demographic information, medical history and health conditions, family disease history, dietary intake, and lifestyle, were examined as part of the Korean Genome Epidemiology Study (KoGES) .
We focused on body composition, and biochemical and anthropometric traits.
The blood cells of the 10,038 subjects were genotyped using the Affymetrix Genome-Wide Human SNP array 5.0. We discarded SNPs with a minor allele frequency
Genetics of Sleep and Insomnia – 21 Genes & SNPs to Check
Sleep problems may be caused by lifestyle factors, health conditions, and genetics. If you struggle with insomnia, it is important to understand which genes may play a role. A genetic makeup may influence lifestyle factors and point to specific aspects that need to be addressed. Read on to learn the genetics of your circadian rhythm and sleep requirements.
The Genetic Circuit That Controls Circadian Rhythm
Every cell in the human body has a molecular clock. This molecular clock controls our circadian rhythm through the ebb and flow of cellular production in 24-hour cycles.
This ebb and flow are controlled by transcription factors (proteins that control cellular production) in a genetic circuit that includes the genes CLOCK, BMAL1, Period (Per1, Per2, Per3, often shorthanded collectively as Per), and Cryptochrome .
In addition to the circadian rhythm genes, DEC2 and Per3 are associated with changes in sleep requirements .
1) CLOCK and BMAL
Deactivating CLOCK and BMAL1 genes decrease total sleep time in animal models [2, 3].
Therefore, individuals with low functions of these genes may need less sleep.
The SNP rs1801260 (C) inside of CLOCK is linked to eveningness, being more sleepy during the day, and reduced morningness. People with the T allele are more ly to be morning people and have less total sleep duration [4, 5, 4].
The SNP rs2228099 inside of BMAL1 may be associated with insomnia and early awakening among middle-aged women .
PGC-1alpha has important roles in metabolism and mitochondrial health. It also activates clock genes, which control the circadian rhythm [7, 8].
Mice without PGC-1alpha have an abnormal circadian rhythm, body temperature, and metabolic rate .
In some individuals, the CC genotype of rs8192678 inside PGC-1alpha is associated with worse insomnia in combination with ApoE4 .
AhR (Aryl Hydrocarbon Receptor) has important roles in detoxification of certain toxins. In addition, AhR suppresses Per1 production, so it can disrupt CLOCK-BMAL activity and disturb the circadian rhythm . Therefore, it is better to have AhR deactivated most of the time.
The SNPs rs2066853 (AhR, A) and rs2292596 (AhRR, G or GC) are associated with insomnia and early awakening, especially in middle-aged women .
DEC2 (encoded by the BHLHE41 gene) represses CLOCK/BMAL1 activity. A mutation in DEC2 is associated with shorter sleep in humans and increased wakefulness in mice .
Morningness and eveningness are partly heritable. That means you are ly to have a similar type as one of your parents .
Per3 has a variant that lengthens its protein by 18 amino acids. People with the longer form are more ly to be a morning person, whereas those with the shorter form are more ly to be a night owl or have delayed sleep phase syndrome .
People with the longer form also tend to suffer worse from cognitive dysfunction due to sleep deprivation than those with the shorter form .
The longer form seems to increase slow-wave sleep, REM sleep, as well as theta (meditative) and alpha (relaxing) brainwave activities during wakefulness .
The SNP rs10462021 inside of Per3 is associated with delayed sleep phase syndrome .
The ABCC9 gene is used for making potassium channels mostly in the hearts and skeletal muscles. The A allele of the SNP rs11046205 correlates with reduced sleep duration, but how exactly this gene influences sleep is unclear .
Reducing the function of this gene in fruit flies prevent the flies from sleeping for the first three hours of the night .
Genetics of Insomnia
It’s important to note that just because certain genotypes are associated with a condition or irregular lab marker, it doesn’t necessarily mean that everyone with that genotype will actually develop the condition. Many different factors, including other genetic and environmental factors, can influence the risk of insomnia and other sleep disorders.
Insomnia is partly contributed by genetics; approximately 35% of people with insomnia have some insomniac family members, with the mother being the most commonly affected .
In addition to the circadian rhythm genes, BMAL, PER3 and CLOCK, there are other genes that may play a role in insomnia [18, 19, 20].
1) 5-HT2A Serotonin Receptor
Blocking the 5-HT2A receptor promotes sleep in rats. Drugs that block 5-HT2A receptors are under development and clinical trials for the treatment of insomnia in humans [21, 22].
The activation of the 5-HT2A receptor also exhibits a circadian rhythm .
Activation of this receptor decreases glutathione and BDNF, two substances that are important for quality sleep [24, 25].
Because stress activates this receptor, people who genetically have higher 5-HT2A activation might be more susceptible to insomnia from stress. Read this post to learn more about 5-HT2A, which might be problematic in people with insomnia.
- rs6311 -1438 G/A: The “T” allele results in more receptors/increased gene expression and more active receptors [26, 27].
- rs6313 102 T/C: The “A” allele is associated with lower general health and social function.
The A allele of rs6313 is almost always found together with the T allele of rs6311.
- rs6314 1354 C/T The A allele had reduced ability to activate the receptor or cause downstream signals.
This means it causes a blunted signal after activation .
2) Adenosine Receptors
Adenosine is one of the sleep-promoting substances that are present at low levels in the morning and build up throughout the day. At nighttime, high levels of adenosine and strong activation of adenosine receptors are important for quality sleep .
Because caffeine makes you feel awake by blocking adenosine receptors, mutations that reduce adenosine receptor function may correlate with insomnia from caffeine consumption.
There are four types of adenosine receptors (A1R, A2aR, A2bR, and A3R). Among these, A1R controls the sleep-wake cycle while A2aR helps induce sleep .
RS5751876 inside A2aR is linked to caffeine-related insomnia .
3) Uridine (P2Y2) Receptors
adenosine, uridine is another sleep-inducing substance. High levels of uridine in the brain and uridine receptor activation at night is important for sleep. Uridine binds to the P2Y receptors in areas of the brain which regulate natural sleep .
The SNP rs1791933 (T allele) in the P2Y2 gene is linked to caffeine-related sleep disturbance .
BDNF production during the day correlates with the amount of slow-wave (deep) sleep during the subsequent night, suggesting that BDNF is a measure of sleep pressure (the body’s desire to sleep) .
BDNF appears to have a circadian rhythm, being high during the day and lower at night .
People the T allele of the BDNF SNP rs6265, which lower BDNF levels, may not sleep as deeply as people with the C allele or the CC genotype. In addition, the T allele correlates with worse cognitive decline due to sleep deprivation .
5) Calcium Signaling Genes
Several genes that control calcium signaling in the brain, including ROR1, ROR2, PLCB1, CACNA1A, NOS3, and ADCY8, are linked to insomnia .
ROR1 controls the development of neurons together with ROR2. ROR1, ROR2, and PLCB1 are important in learning and memory. The significant SNP (rs11208305) inside of ROR1 gene is associated with insomnia among some female patients .
PCLB1 SNPs were strongly associated in male patients .
Other genes containing insomnia-associated SNPs are :
- CACNA1A (calcium voltage-gated channel subunit alpha 1A), a protein involved in moving calcium between neurons. It appears that rs2302729 affects sleep quality, while rs7304986 affects time laying in bed before falling asleep .
- GNAS (GNAS complex locus) stimulates adenylate cyclase, which converts ATP to cAMP
- NOS3 (nitric oxide synthase 3), which produces nitric oxide in the blood vessel
- ADCY8 (adenylate cyclase 8) also breaks down ATP to cAMP 
Increasing calcium and cAMP in the cells may help with this pathway.
SLC2A13 rs11174478 may also be associated with insomnia in some individuals .
How Brain and Neurotransmitters Affect Sleep