Do you wake up at 4 am?

I used to wake up often between 3:30 and 4:00 in the morning. It was so irritating not to be able to fall back to sleep –or even worse, to fall back to sleep just a half hour before I needed to wake up.  I knew it was an internal clock problem because I would always wake up within a minute or two of the same time: 3:42 am.

This article isn’t about me or my former sleep problems. It is about genetic variants that are linked to early waking — and how you can use that knowledge to get to the root of the problem.

What I find most interesting in genetics is how researchers can take a problem (in this case – early waking in depressed patients) and through finding the genetic variants in common among the patient can point the way to the real cause of the problem.

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. Depression and circadian rhythm disruption go hand-in-hand (more on that later).

Serotonin as a neurotransmitter: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. Serotonin is a monoamine that does a bunch of stuff in the body. (Most of the body’s serotonin (90%) is produced outside of the brain using the TPH1 enzyme.)

Serotonin that is produced in the brain (in the Raphe nuclei) 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.

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, probably don’t 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 recent 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 23andMe data for rs4290270 (v4 only):TT: increased risk of waking early, increased risk of depression [ref][ref]AT: probably slightly increased risk of waking early, depression (this is the most common genotype)AA: normal


Blue-blocking glasses at night help tremendously. For over a year now I’ve been wearing blue-blocking glasses regularly for an hour or two before bed. I now sleep like a log, all night. ¬†Blocking the blue wavelengths at night increases melatonin production and resets the circadian clock to be in sync with the day/night light cycle. Seriously, the best thing that I’ve done for my sleep. ¬†You can get some (slightly ugly) cheap blue blockers for around $8 on Amazon or you can get somewhat more expensive options that look a little better and are more comfortable. There are now a bunch of options — just make sure they block 100% of blue light. You don’t want the gamer glasses that block only 30-40% of blue light at night (wear those during the day when you work on the computer!).

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.

More to read:

Bipolar disorder, depression, and circadian clock genes

Note – this article is cross-posted with *

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