Do you wake up at 4am?

Do you wake up at 3:30 or 4:00 in the morning? Unable to fall back to sleep –or even worse, to fall back to sleep an hour before you need to get up?

This article is about genetic variants that are linked to early waking — and how you can apply that knowledge to get to the root of the problem.

Early Waking and Tryptophan Conversion

A recent study investigated patients with depression, part of them with early waking, as well as a control group without depression. The study found that a genetic variant in the TPH2 gene was found significantly more often in patients with early waking.[ref]

TPH2, tryptophan conversion to serotonin:

The TPH2 (tryptophan hydroxylase 2) gene codes for the rate-limiting enzyme in the production of neuronal serotonin.[ref]  Basically, this enzyme is the key to the amount of serotonin in your brain. The TPH2 enzyme causes a reaction to take place in the brain, converting tryptophan into serotonin.

Serotonin is categorized as a monoamine, which is a way of describing the structure of serotonin, norepinephrine, and dopamine. Serotonin is active both in the brain and in other parts of the body, such as the digestive system. In fact, most of the body’s serotonin (90%) is produced outside of the brain using a related enzyme called TPH1.

Serotonin that is produced in the brain acts as a neurotransmitter, relaying chemical messages between neurons. It is thought to be involved in arousal, mood, appetite, sleep, and memory.

Serotonin doesn’t readily cross the blood-brain barrier, so just taking serotonin orally, or eating foods high in serotonin, doesn’t change brain levels of serotonin.

Conversion of tryptophan:

To produce serotonin, your body uses the essential amino acid tryptophan, which is then converted in the brain using the enzyme TPH2 into 5-hydroxy-L-tryptophan (5-HTP). The 5-HTP then is converted to serotonin (5-HT).

If you follow the pathway further… serotonin is actually a precursor for melatonin, which is highly involved in your body’s circadian rhythm. (Brain levels of serotonin, though, may not affect melatonin levels since melatonin can cross the blood-brain barrier.)

Here is a quick diagram of the process:


Circadian rhythm in depression and early waking:
While depression is a multi-faceted disorder, at the root of it for a lot of people is circadian rhythm disruption. (Read: Circadian Rhythm Genes: Mood Disorders and Bipolar Disorder, Depression, and Circadian Clock Genes)

One obvious part of circadian rhythm disruption would be problems with sleep. The TPH2 gene variant seems to link together extremely early waking with depression and serotonin.

Digging into the study:

The  study on early waking and TPH2 was done in a Chinese population using a study group of 249 people. The researchers investigated a number of variants in the TPH2 gene, which has been associated with an increased risk of depression in various different studies.

The researchers found that one TPH2 SNP (rs4290270) was not only found more often in the depressed patients, but it was also twice as likely to be found in the depressed patients who woke early. The study also found that fMRI images of the brains showed differences in the carriers of the different alleles of this genetic variant.

Check your Genetic Data:

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

  • 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


Blue-blocking glasses at night help tremendously. Blocking the blue wavelengths at night increases melatonin production and resets the circadian clock to be in sync with the day/night light cycle. There are now lots of options for blue-blocking glasses on Amazon and elsewhere — just make sure they block 100% of blue light. You don’t want the video gamer glasses that block only 30-40% of blue light for blocking light at night.

Get more bright light during the day. Serotonin production is tied to bright light during the day. It isn’t only people with seasonal affective disorder who need light, we all do.[ref] Not only does bright light during the day increase serotonin, but it also increases melatonin at night. If you aren’t able to get outside for enough sunshine, light therapy devices are available and relatively inexpensive.

For most people, tryptophan is plentiful in the diet. It is found in nuts, meat, eggs, soy, and dairy. But if you are on a protein-restricted diet or a vegan diet, you may want to make sure you are getting enough tryptophan. Here is a list of foods containing tryptophan.


Related Genes and Topics:

Tryptophan: Building Serotonin and Melatonin
Tryptophan is an amino acid that the body uses to make serotonin and melatonin. Genetic variants can impact the amount of tryptophan that is used for serotonin. This can influence mood, sleep, neurotransmitters, and immune response.

Author Information:   Debbie Moon
Debbie Moon is the founder of Genetic Lifehacks. She holds a Master of Science in Biological Sciences from Clemson University. Debbie is a science communicator who is passionate about explaining evidence-based health information. Her goal with Genetic Lifehacks is to bridge the gap between scientific research and the lay person's ability to utilize that information. To contact Debbie, visit the contact page.