Circadian Rhythms: Genes at the Core of Our Internal Clocks

Circadian rhythms are the natural biological rhythms that shape our biology. Most people know about the master clock in our brain that keeps us on a wake-sleep cycle over 24 hours. This is driven by our master ‘clock’ genes.

It turns out that we also have circadian cycles (peripheral clocks) in most organs, such as the liver, pancreas, and fat cells. These peripheral rhythms drive the cyclical production of proteins in our organs. One example of the importance of these peripheral clocks includes research on the timing of chemotherapy drugs based on the circadian rhythm of enzymes produced in the liver.[ref]

Not to be left out, our gut microbiome also has a circadian rhythm, and disruption of our circadian rhythm can disrupt the microbial rhythm.[ref]

Table of Contents

Getting a little Geeky…

You want to be familiar with some pretty cool terminology involved in chronobiology (a nifty term for the study of biological rhythms) before digging into the research papers on the topic. The part of the hypothalamus controlling the central clock is the “suprachiasmatic nucleus” (SCN), which sounds a little sci-fi to me. And the external environmental inputs, like the time the sun rises or lights at night, are known as zeitgebers. Some things are named more predictably, like one gene controlling circadian rhythms is called the CLOCK gene ( an acronym for Circadian Locomotor Output Cycles Kaput).

It is probably not a big surprise that our core circadian rhythm is set by sunlight since night/day rhythms can be seen in all animals. In a nutshell, light from the sun in the short, blue wavelengths hits receptors in the eye (intrinsic photosensitive retinal ganglion cells), which signals to the suprachiasmatic nucleus synchronizing the circadian 24-hour cycle.

There are two factors that can mess up our circadian rhythms: light at night (specifically, blue wavelengths ~450-480nm) and lack of sunlight in the morning. Add to that the individual genetic variants that affect our clock gene functions, and you can begin to see the importance of this topic.

So what happens when our circadian rhythms go askew? The effects can be far-ranging and include increased risk for the following: diabetes, cardiovascular disease, certain cancers, mood disorders, and obesity. The amount of scientific research coming out on the topic in the past few years is astounding. While not talked about much in the mainstream press, the strong evidence led the IARC (the cancer research arm of the World Health Organization) in 2007 to list chronic exposure to light at night as a possible carcinogen.

Quick Recap:

Circadian rhythm is at the base of good health.
Blue wavelengths set the circadian rhythm.
Sunlight in the morning is good; blue light in the evening alters the circadian system.

Genotype Report: Clock Genes

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The CLOCK and BMAL1 (ARNTL) genes are the core clock genes that target and turn on other genes. They are regulated and turned off by rising levels of the cryptochromes, CRY1 and CRY2 and the period genes PER1, PER2, and PER3.[ref] This forms the daily feedback loop of rising CLOCK and BMAL1 that are then inhibited by rising levels of CRY and PER, giving a 24-hour rhythm.

CLOCK gene variants:

One well-studied variant of CLOCK with quite a variety of effects is rs1801260 (G is the minor allele for 23andMe orientation, also known as 3111T/C )

Carriers of the G allele have higher activity in the evening, delayed sleep onset, and less overall sleep time on average.[ref][ref]
A 2016 study looked at body temperature changes, activity, and position in a group of women based on carriers of the G allele. They found that those with the minor allele had higher evening activity and different body temperature variations over a day, leading to a conclusion of ‘less robust circadian rhythm’.[ref]
Carriers of the G allele had higher BMI and less weight loss on a calorie-restricted diet in a study of obese patients.[ref] They also lose less weight after bariatric surgery.[ref]
Those with the G allele had slower gastric motility.[ref]
G allele carriers had a higher resistance to weight loss, a lower intake of total carbohydrates and monounsaturated fat, and a high saturated fat intake. Ghrelin (hunger hormone) concentrations were also higher.[ref][ref][ref]
Related article: Ghrelin Genes

Blood pressure circadian rhythms are lower in those carrying the G allele.[ref]
In those with bipolar disorder, the G allele has links to increased manic episodes.[ref]

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

G/G: higher activity in the evening, possible delayed sleep onset, the risk for obesity
A/G: somewhere in between
A/A: typical

Members: Your genotype for rs1801260 is —.

Another CLOCK gene variant, rs11932595 (G is the minor allele), has been shown to affect circadian function:

Check your genetic data for rs11932595 (23andMe v4, v5, AncestryDNA):

G/G: somewhat increased risk of miscarriage, risk of male infertility, shorter sleep
A/G: somewhat increased risk of miscarriage, risk of male infertility, shorter sleep
A/A: typical, longer sleep duration

Members: Your genotype for rs11932595 is —.

Studies show:

Sleep duration for those with the A/A genotype is likely to be longer.[ref]
Those with the minor allele were less likely to have non-alcoholic fatty liver disease[ref]; sleep disturbance in depression[ref]
An increased risk of miscarriage for those with A/G, G/G.[ref]
An increased risk (1.9x) for male infertility for those with the G allele.[ref]

Check your genetic data for rs4864548 (23andMe v4, AncestryDNA):

G/G: increased risk of obesity[ref][ref]
A/G: increased risk of obesity
A/A: typical

Members: Your genotype for rs4864548 is —.

BMAL1 (ARNTL gene):

BMAL1 binds with CLOCK to increase the production of the PER and CRY circadian genes. One of the BMAL1 variants, rs3816358 (A is the minor allele), has been studied in reference to breast cancer risk, cardiovascular disease risk, and diabetes risk.

Check your genetic data for rs3816358 (23andMe v4, AncestryDNA):

A/A: less of a risk of breast cancer than other shift workers[ref]
A/C: less of a risk of breast cancer than other shift workers
C/C: typical risk of breast cancer compared with other shift workers

Members: Your genotype for rs3816358 is —.

Check your genetic data for rs7950226 (23andMe v4, AncestryDNA): (A is the minor allele)

increased risk of diabetes and gestational diabetes[ref][ref]

PER1 gene:

PER1 codes for the ‘period circadian protein homolog 1’ protein which, along with CRY (below), is the other half of the core genes involved in our circadian rhythm.

A study in 2012 found that a variant, rs7221412, altered the natural timing of activity. Those with the A/A genotype may naturally wake up about an hour earlier than those with G/G, while A/G falls in the middle.

Check your genetic data for rs7221412 (23andMe v4):

A/A: one hour earlier peak in circadian rhythm, more like to wake earlier[ref]
A/G: peak was midway between A/A and G/G
G/G: one hour later peak in circadian rhythm, more likely to wake later

Members: Your genotype for rs7221412 is —.

PER2 gene:

A recent study looked at the expression of clock genes after weight loss and found that PER2 expression increased after weight loss.[ref]

Check your genetic data for rs2304672 (23andMe v4):

C/C: associated with abdominal obesity, snacking, stress with dieting[ref]; higher lipids[ref]
C/G: associated with abdominal obesity, snacking, stress with dieting, higher lipid levels
G/G: typical (23andme orientation)

Members: Your genotype for rs2304672 is —.

CRY2 gene:

A study of obese and lean women tracked their clock gene expressions in fat tissue over a 24-hour period. The study found CRY2 and REV-ERB ALPHA up-regulate in obesity over a 24-hour period.[ref]

Check your genetic data for rs7123390 (23andme v4, AncerstyDNA):

postmenopausal women with A/A had half the risk of estrogen and progesterone receptor-negative breast cancer.[ref]

NR1D1 (REV-ERB Alpha)

Check your genetic data for rs2314339 (23andMe v4, v5, AncestryDNA): (T is the minor allele)

REV-ERB alpha has associations with both a circadian mechanism and the biological action of lithium carbonate. For bipolar disorder, those with at least one copy of the T allele were 3.5x less likely to improve on lithium carbonate therapy.[ref]
Minor allele (T) carriers are less likely to be abdominally obese.[ref]

Check your genetic data for rs2071427 (23andMe v4, v5, AncestryDNA): (T is the minor allele)

The minor allele, T, has associations with a higher risk of obesity and higher BMI.[ref]

Other genes:

FTO is a gene with variants that are associated with an increased risk of obesity (nicknamed the fatso gene). A 2015 study found that FTO-deficient mice had robust circadian locomotor activity rhythms, while “Overexpression of FTO represses the transcriptional activation by CLOCK and BMAL1.”[ref] Other studies have shown that over-expression of FTO leads to increased body fat.[ref]

Lifehacks: Optimizing Circadian Rhythm

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