Using your genetic data to solve sleep problems

A good night’s sleep is invaluable, literally priceless — but so many people know the frustration of not being able to regularly sleep well.

And not getting enough sleep can lead to many chronic diseases such as diabetes, obesity, dementia, and heart disease. Sleep really is that important!

There are many factors involved in sleeping well, and genetics plays a role in some sleep disorders.

Looking at the genetic basis of sleep disorders may give you ideas on which path to take to fix the problem.

What is sleep and why do we need it?

So this turns out to be a more difficult question to answer than you would think.

We are asleep for about a third of our lives. All animals, both big and small, sleep. So you would think that scientists would know exactly why and how sleep works…  Instead, we have almost as many questions about sleep as we have answers.

Let’s look at the definition of sleep from a prominent sleep medicine textbook: “Sleep is a recurring, reversible neuro-behavioral state of relative perceptual disengagement from and unresponsiveness to the environment. Sleep is typically accompanied (in humans) by postural recumbence, behavioral quiescence, and closed eyes.”[ref]

Yep – big words for laying down, closing your eyes, and going to sleep.  The important thing here, though, is what goes on in the brain while you sleep.  While your body is inactive (hopefully), your brain is doing some pretty cool and weird stuff while you sleep. And there are different metabolic processes going on in your body while you are asleep.

Why is sleep so important? 

While you sleep, your brain consolidates memories — it makes the things that you learned during the day stick in your brain. This has been known for a long time and is something that researchers frequently experiment with.[ref]  Recently, researchers experimented with just decreasing certain stages of sleep and showed that the neuroplastic changes to the brain in learning happen specifically during deep sleep.[ref]

Studies of sleep deprivation show that there can be devastating consequences.

  • In general, sleep deprivation causes a decrease in speed and accuracy in tests for attention, working memory, processing speed, short-term memory, and reasoning. [ref]
  • One-third of accidents in a survey of commercial truck drivers were caused by drowsy driving due to sleep deprivation. [ref]
  • According to the NTSB, going more than 20 hours without sleep is equivalent to driving legally drunk. And your risk of being in a car crash goes up 3-fold! [ref]
  • This pretty much sums of the rest of the effects of sleep deprivation: ‘studies have shown that short sleep duration is associated with increased incidence of cardiovascular diseases, such as coronary artery disease, hypertension, arrhythmias, diabetes and obesity, after adjustment for socioeconomic and demographic risk factors and comorbidities.’ [ref]

Stages of sleep:

When you sleep, your brain goes through different periods of activity. These are categorized into slow-wave sleep and REM (rapid eye movement) sleep.  Slow wave sleep can further be broken down into deeps sleep and lighter sleep.  About 50% of sleep in adults is the light, non-REM sleep.

Most of your deep sleep comes during the early part of the night, while the latter half of the night has much more REM sleep. [ref]

What causes you to feel sleepy:

We feel the need to sleep each night due to two causes: our natural circadian rhythm and increased homeostatic sleep drive.

The homeostatic sleep drive is what researchers call the build up over the course of the day for the need to sleep. This is mainly driven by a build-up of adenosine in the brain, which is then cleared out during sleep.  Adenosine is part of the ATP (adenosine triphosphate) molecule which is used for cellular energy. As you use energy over the course of the day, you build up adenosine in the brain. (Caffeine makes you feel more awake by blocking the adenosine receptors) [ref]


Genes and Sleep Disturbance:

A recent genome-wide analysis of sleep duration, timing, and disturbances found that there was an overlap between sleep quality and the genetic variants that are associated with sleep disorders. The study was done using data from 5000+ people wearing sleep trackers, and then it was replicated [ref]

Morning Grogginess and the ADA gene:

Not clearing out adenosine quickly enough overnight can cause a person to still feel groggy when they wake up in the morning.  A variant of the ADA (adenosine deaminase) gene is associated with reduced activity which causes adenosine to be cleared away less quickly.

Check your genetic data for rs73598374 (23andMe v4, v5; AncestryDNA)::

  • C/C: normal clearance of adenosine
  • C/T: reduced clearance of adenosine, more deep sleep but may feel sleepy when waking up[ref]
  • T/T: reduce clearance of adenosine, more deep sleep but may feel sleepy when waking up

Restless Leg Syndrome and Periodic Limb Movement Disorder

Restless Leg Syndrome (RLS) is a fairly common disorder affecting about 10% of the US population. Periodic Limb Movement Disorder -PLMD (also called Periodic Limb Movements In Sleep – PLMS) is often lumped together with RLS in studies. The two often go together with about 80%-90% of RLS suffers also having PLMD.[ref]

About 40% – 60% of people with RLS have a family history of it, suggesting a strong genetic component. People with a family history of RLS tend to get it at a younger age.[ref]  In general, RLS is more likely to be found in women, in older people, and in those with iron storage issues. [ref]

People with restless leg syndrome are at an increased risk of psychiatric disorders. One study showed that 37% of people with RLS met the criteria for a psychiatric disorder – compared to only 15% of people without RLS. [ref]

MEIS1 gene:
The MEIS1 gene has been studied for restless leg syndrome.  MEIS1 encodes a homeobox protein. (Homeobox genes are involved in forming organs and limbs in embryonic development.) There are several MEIS1 SNPs that have been linked to an increased risk of RLS and PLMD.

Check your genetic data for rs2300478 (23andMe v4, v5; AncestryDNA):

  • G/G: greater than 1.7x risk of RLS, increased sympathovagal balance during N3 sleep stage[ref][ref]
  • G/T: 1.7x risk of RLS
  • T/T: normal risk of RLS

BTBD9 gene:

Check your genetic data for rs3923809:  (23andMe v4, v5; AncestryDNA):

  • A/A: approx. 50% with this genotype will have RLS, 1.9x risk of PLMD without RLS, serum ferritin levels decreased  26%  [ref]
  • A/G: higher risk of RLS and PLMD, serum ferritin levels decreased 13%
  • G/G: normal risk of RLS

Check your genetic data for rs9357271 (23andMe v4, v5; AncestryDNA):

  • C/C: lower risk (<0.63) of RLS  [ref]
  • C/T: slightly lower risk of RLS
  • T/T: normal risk of RLS

PTPRD gene:

Check your genetic data for rs1975197 (23andMe v4, v5; AncestryDNA):

  • A/A: increased (1.8x) risk of RLS  [ref]
  • A/G: increased risk of RLS
  • G/G: normal risk of RLS

GABA Receptors:

A study of patients with restless leg found that GABA receptor variants may affect restless leg syndrome. GABA is the main inhibitory neurotransmitter — it keeps the neurons from being overexcited.[ref]

Check your genetic data for rs2229940 (23andMe v4, v5; AncestryDNA):

  • G/G: normal
  • G/T: earlier age of onset for RLS
  • T/T: earlier age of onset for RLS[ref]  (also, faster motor reaction times [ref])

Narcolepsy Genes:

Narcolepsy, or excessive daytime sleepiness, is found in about 1 in every 2,000 people in the US.  It is now thought to be an autoimmune disease and is associated with HLA-DRB1*1501 and HLA-DQB1*0602. HLA-DRB1*1501 is highly correlated with rs3135388 and found to influence the risk of several autoimmune diseases including MS, lupus, and narcolepsy. HLA-DQB1*0602 is found in 90% of people who have narcolepsy, but it can’t be determined by a single SNP that I have found.

Check your genetic data for rs3135388  (23andMe v4, v5; AncestryDNA):

  • A/A: (HLA-DRB1*1501) increased risk of narcolepsy, MS  [ref]
  • A/G: (one copy of HLA-DRB1*1501) increased risk of narcolepsy
  • G/G: normal risk

Check your genetic data for  rs1154155 (23andMe v4, v5; AncestryDNA):

  • G/G: increased risk of narcolepsy (2.5x increased risk) [ref]
  • G/T: increased risk of narcolepsy
  • T/T: normal

Circadian Rhythm Genes:

Our natural circadian clock is run by several core genes that rise and fall over a 24 hour period, setting the rhythm for all of our body’s functions. Sunlight hitting the retina in the morning resets the circadian clock.

Circadian rhythm disruptions have been tied to obesity, difficulty in losing weight, diabetes, Parkinson’s, Alzheimer’s, heart disease, and ADHD symptoms.

CLOCK gene:
The aptly named CLOCK gene is part of the core molecular circadian clock.

Check your genetic data for rs1801260 (23andMe v4, v5; AncestryDNA):

  • G/G: higher activity levels in the evening, delayed sleep onset. [ref][ref]
  • A/G: somewhat delayed sleep
  • A/A: normal

 

PER2 gene:
The PER2 (period 2) gene is part of your core molecular circadian clock.

Check your genetic data for rs35333999 (23andMe v4 only):

  • C/C: normal
  • C/T: likely to stay up later, evening chronotype, longer circadian period
  • T/T: likely to stay up later, evening chronotype, longer circadian period [ref]

AANAT gene:
AANAT (arylalkylamine N-acetyltransferase) controls the production of melatonin in the pineal gland. AANAT enzyme activity is high at night and tied to a person’s circadian rhythm. Polymorphisms in AANAT are more common in those with Delayed Sleep Phase Disorder (Japanese Study).

Check your genetic data for rs28936679 (23andMe v4 only):

  • A/G: higher risk of Delayed Sleep Phase Disorder [ref]
  • G/G: normal

Insomnia Genes:

The GSK3B gene is involved in both circadian rhythm and glucose metabolism. This is one gene that is influenced by lithium.

Check your genetic data for rs334558 (23andMe v4, v5; AncestryDNA):

  • G/G: increased risk for severe insomnia in depression [ref]
  • A/G: increased risk for severe insomnia in depression
  • A/A: normal

One of the core circadian clock genes, PER2, is associated with insomnia.

Check your genetic data for rs7602358 (23andMe v4 only):

  • G/G: increased risk for insomnia, especially with stress [ref]
  • G/T: increased risk for insomnia
  • T/T: normal risk for insomnia

Waking up really early and not being able to fall back to sleep is a form of insomnia known as sleep maintenance insomnia.  A variant in the TPH2 gene, which converts tryptophan into serotonin and then melatonin, has been associated with an increased risk of sleep maintenance insomnia. (

Check your genetic data for rs4290270 (23andMe v4 only):

  • T/T: increased risk of waking early, increased risk of depression [ref][ref]
  • A/T: probably a slightly increased risk of waking early, depression (this is the most common genotype)
  • A/A: normal

 


Lifehacks

Overall sleep:

One small thing that will make a HUGE difference in sleep and circadian rhythm function is to block blue light at night. Our modern environment is full of light at night and especially in the blue wavelengths from LED bulbs, TV’s, and phones. The blue wavelength (~480nm) is the exact wavelength that resets our circadian genes each morning.

Other than changing all your light bulbs to red lights or going back to candlelight, your best bet for blocking the blue wavelengths at night is blue-blocking glasses. There are inexpensive options like the UVEX safety glasses or more stylish options like these Swannies.

Temperature is also important in sleep. Your body expects the temperature to drop when the sun goes down. Keep your bedroom as cool as you comfortably can at night. [ref]

Restless leg:

There are several new studies out that point to a role of adenosine in causing restless leg. [ref][ref]

Hops extract and valerian root combined can block the effects of caffeine on the adenosine receptors. Both are known for their sleep-promoting effects, and both can be found in OTC herbal remedies for sleep and restless leg.[ref[ref]

Near-infrared light therapy was shown in a small study to help with restless leg syndrome. [ref]

A medical device that puts pressure on the abductor hallucis and flexor hallucis brevis muscles was shown in a clinical trial to reduce sleep disturbances due to RLS. [ref]

A study showed that acupuncture plus gabapentin (prescription med for RLS) was more effective than gabapentin alone. [ref]

Transcutaneous spinal direct current stimulation has been shown to decrease RLS. [ref]

Morning Grogginess:

The ADA gene variant that causes morning grogginess (along with increased deep sleep) may indicate that you simply need to make sure that you get enough sleep. Most adults need between 7 and 8.5 hours of sleep per night. Try adding in an extra half hour of sleep time and see if it cures your morning grogginess. You may just need a little extra time each night to adequately clear adenosine.   (And yes, caffeine is an adenosine receptor antagonist and will probably make you feel much better on mornings when you haven’t gotten adequate sleep.)

 

More to read:

Circadian Rhythms: Genes at the Core of Our Internal Clocks

Circadian Rhythms: Of Owls, Larks, and Alarm Clocks

Narcolepsy, the Sleep Disorder, Linked to Immune System Problem

*article originally published July 2015, updated April 2019*

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