Your sleep problems may be caused both by lifestyle (e.g. eating habits, circadian rhythm entrainment, light exposure, and weight gain) and genetics. If you struggle with significant sleep issues, it is important to understand how your genetics may play a role so that you can use this information to your advantage.

Sometimes what appear like insomnia, low quality sleep, or other forms of sleep problems might just be because you live incompatibly with your genetic makeup. As a result, you might never wake up feeling rested, your stress response may be constantly overactivated, or you might really struggle to lose weight for no apparent reasons. Your genetic makeup plays a large role in determining the best chronobiology and lifestyle for you. Read this post to learn more about this.

Part 2 of a 2-Part Series

Part 1: How Brain and Neurotransmitters Affect Sleep

Part 2: Genetics of Insomnia – 21 Genes and SNPs to Pay Attention to If You Have Insomnia

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 is 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.

This 3.44-minute video explains the ebb and flow of these proteins.

Genes that Control Sleep Length and Requirements

In mammals, sleep phenotypes (characteristics) have been reported for activators of CLOCK and BMAL1, and also for repressors PER (period) and CRY (cryptochrome) (R1, R2, R3). In addition to the circadian rhythm genes, DEC2 and Per3 are associated with changes in sleep need.

1) CLOCK and BMAL Mutations Lead to Shorter Sleep

Deactivating CLOCK and BMAL1 genes decrease total sleep time in animal models (R, R2).

Therefore, if you have low functions of these genes, either due to genetics or the environment, you may need less sleep than people with higher functions of these genes.

The SNP rs1801260 (C) inside of CLOCK is linked to eveningness, being more sleepy during the day, and reduced morningness (R, R2). People with the T allele are more likely to be morning people and have less total sleep duration (R).

The SNP rs2228099 inside of BMAL1 is associated with the risk for insomnia and early awakening among middle-aged women (R).

2) Low PGC-1alpha May Contribute to Insomnia

PGC-1alpha has important roles in metabolism and mitochondrial health. It also activates clock genes, which control circadian rhythm. Therefore, low PGC-1alpha often contributes to insomnia (R, R2).

Mice without PGC-1alpha have abnormal circadian rhythm, body temperature, and metabolic rate (R).

The CC allele of rs8192678 inside PGC-1alpha is associated with worse insomnia in combination with ApoE4 (R).

3) AhR Disrupts Circadian Rhythm

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 (R). Therefore, it is better to have AhR deactivated most of the time.

AhR repressor (AhRR) inhibits AhR function. It is better to have this gene activated most of the time.

The SNPs rs2066853 (AhR, A) and rs2292596 (AhRR, G or GC, not in 23andme) are associated with insomnia risk and early awakening, especially in middle-aged women (R).

4) DEC2 is Associated with Shorter Sleep and Increased Wakefulness

DEC2 (encoded by the BHLHE41 gene) represses CLOCK/BMAL1 activity. A mutation in DEC2 (not tested by 23andme) is associated with shorter sleep in humans and increased wakefulness in mice (R).

5) Shorter Per3 Gene is Associated with Less Sleep Need and Being Night Owls

Screen Shot 2560-03-11 at 1.13.18 PM
The short (4R) and long (5R) forms Per3, source: https://www.ncbi.nlm.nih.gov/pubmed/12841365

Morningness and eveningness are heritable (R). That means you are likely to have the similar type as one of your parents, or that being a morning or night person tend to run in the family.

Per3 has a variant that lengthens its protein by 18 amino acids (not tested by 23andme). People with the longer form are more likely to be a morning person, whereas those with the shorter form are more likely to be a night owl or have delayed sleep phase syndrome (R). People with the longer form also tend to suffer worse from cognitive dysfunction due to sleep deprivation than those with the shorter form (R).

The longer form seems to increase slow wave sleep, REM sleep, as well as theta (meditative) and alpha (relaxing) brainwave activities during wakefulness (R).

The SNP rs10462021 inside of Per3 is also associated with delayed sleep phase syndrome (R).

6) The ABCC9 rs11046205 SNP May Be Linked to Reduced Sleep Need or Insomnia

The ABCC9 gene is used for making potassium channels mostly in the hearts and skeletal muscles. While we have strong human genetic data that the A allele of the SNP rs11046205 reduces sleep duration (R), 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 (R), so it’s possible that reduced function of this gene may cause insomnia in humans.

Genetics of Insomnia

Insomnia is partly contributed by genetics because approximately 35% of people with insomnia have some insomniac family members, with the mother being the most commonly affected (R).

In addition to the circadian rhythm genes, like BMAL , PER3 and CLOCK , there are other genes that may contribute to insomnia (R, R2, R3).

1) 5-HT2A Serotonin Receptor Activation May Cause Insomnia

Blocking the 5-HT2A receptor promotes sleep in rats (R), so 5-HT2A receptor activation may cause insomnia or worse sleep quality. In addition, drugs that block 5-HT2A receptors are under development and clinical trials for the treatment of insomnia in humans (R).

The activation of the 5-HT2A receptor also exhibits a circadian rhythm (R).

Activation of this receptor decreases glutathione (R) and BDNF (R), two substances that are important for quality sleep.

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 (very likely a problem if you have insomnia) and natural ways to decrease its function.

Important SNPs inside of 5-HT2A

  • rs6311 -1438 G/A: The “T” allele results in more receptors/increased gene expression and more active receptors (RR2).
  • rs6313 102 T/C: The “A” allele is associated with lower general health and social function. The A allele of rs6313 is 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 (R). 

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 (R). 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 can make you more susceptible to insomnia from caffeine consumption.

There are four types of adenosine receptors (A1R, A2aR, A2bR and A3R). Among these, A1R controls sleep-wake cycle while A2aR helps induce sleep (R).

RS5751876 inside A2aR is linked to caffeine-related insomnia (R).

3) Uridine Receptors

Like adenosine, uridine is another sleep-inducing substance. High levels of uridine in the brain and uridine receptor activation at night are 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 (R).

If your uridine receptors do not function well, increasing uridine levels might be particularly helpful with sleep.

4) BDNF is Important for Sleep

BDNF production during the day correlates with the amount of slow-wave (deep) sleep during the subsequent night (R), 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 (R).

If you have the T allele of the BDNF SNP called rs6265, which lower BDNF levels, you may not sleep as deeply as people with the C allele or the CC genotype. In addition, people with T allele (TT or CT genotype) have worse cognitive decline due to deprivation than people with the CC genotype (R).

6) Calcium Signaling Genes in the Brain Are Linked to Insomnia

Several genes that control calcium signaling in the brain, including ROR1, ROR2, PLCB1, CACNA1A, NOS3, and ADCY8, are linked to insomnia (R).

These genes are also important for the development of neurons, learning, and memory, and have been implicated in some neurological disorders. While they are statistically significantly linked to insomnia, we still don’t completely understand their roles in sleep.

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 female insomniacs (R). PCLB1 SNPs were strongly associated with male insomniacs(R).

Other genes containing insomnia associated SNPs are (R):

  • 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 (R).
  • 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) (R) also breaks down ATP to cAMP

Increasing calcium and cAMP in the cells may help with this pathway.

7) Other Genes that May Contribute to Insomnia

SLC2A13 rs11174478 is strongly associated with insomnia (R).

SelfDecode has all of these genes and SNPs that are covered by 23andme. In addition, it also suggests ways to increase or decrease these genes. Sign up for SelfDecode and upload your DNA data to find out if you have these SNPs.

2-Part Series

Part 1: How Brain and Neurotransmitters Affect Sleep

Part 2: Genetics of Insomnia – 20 Genes and SNPs to Pay Attention to If You Have Insomnia

SelfDecode has all of these genes and SNPs that are covered by 23andme. In addition, it also suggests ways to increase or decrease these genes. Sign up for SelfDecode and upload your DNA data to find out if you have these SNPs.

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2 COMMENTS

  • Nz

    Ok…and some solutions?

    1. Nattha Wannissorn, PhD

      You want to live according not against your genes. For example, if you are genetically a morning person, then sleep early and wake early.

      Drink less caffeine if you have mutations in adenosine or uridine receptors.

      Check out this post for insomnia tips: https://selfhacked.com/2014/10/29/top-23-methods-to-fall-asleep/

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