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In a previous post, I discussed the role that vitamin A plays in generating our circadian rhythm and ensuring good sleep and alertness during the day by interacting with a protein in our retina known as melanopsin. There is a very small but growing body of literature suggesting that variations in the gene for melanopsin underlie how sensitive we are to blue light and how likely we are to go to bed late at night.

In this post, I’ll give you the background necessary to understand the importance of polymorphisms in the melanopsin gene, review the related research, show you how you can use a 23andMe account (regardless of whether you have full access to their pre-FDA dispute health reports) to determine your own genetic status, and offer some practical recommendations for how to use this information to adjust your diet and lifestyle if you suffer from problems getting good sleep and feeling alert during the day.

If you aren’t into geeking out on physiology, skip to the practical recommendations. If you’re all about the geeking out, read on from here.

Prefer to listen? This post has a corresponding podcast.

Reintroducing Our Good Friend Melanopsin

Melanopsin is a protein that is present primarily in cells within the retina known as intrinsically photosensitive retinal ganglion cells (ipRGCs). Melanopsin is closely related to the more well known opsin proteins in the eye: rhodopsin is present in cells known as rods and helps us see the outlines of shapes in dim light; specific red, blue, and green opsins are present in cells known as cones and help us see colors in bright light. One common thread that ties all of these proteins together is that each of them uses vitamin A to detect light. Melanopsin differs from the other opsins in that it translates light into physiological responses that have nothing to do with forming images.

The primary function of melanopsin that we are concerned with here is to respond to blue light (and to a lesser degree to green light) by generating a signal that will let the brain know that it is daytime: time to shut down melatonin and turn on the physiological response associated with being awake and alert. However, melanopsin also plays a role in pupil constriction. Because of this, some of the studies I will review below use the degree of pupil restriction in response to light as an estimate of the sensitivity of a person’s melanopsin system.

Polymorphisms in the Melanopsin Gene And Pupillary Constriction

The studies that have looked at variations – known technically as polymorphisms – in the melanopsin gene as determinants of how sensitive pupillary constriction is to light have used two different approaches.

In the first approach, investigators measure the diameter of the pupil during exposures to different intensities of light. This is called the steady-state pupil response. The strength of this approach is that the context is realistic, while its limitation is that it isn’t entirely specific to melanopsin. It is currently thought that pupillary constriction is mediated partly by melanopsin and partly by the inputs from rods and cones, and probably through direct interaction between the three systems.

In the second approach, investigators measure what is known as the post-illumination pupil response (PIPR). In this test, the wavelength of blue light to which melanopsin is most sensitive is used, and the degree of pupillary constriction after the light is removed is measured. It is currently thought that after the light is removed any remaining constriction in the pupil is mediated almost exclusively by melanopsin with little to no participation of rods and cones. Thus, the strength of this approach is that it is more specific to melanopsin. The limitation of this approach is that the context is less realistic: most of our light exposure occurs for long periods at a time and the short period of transition between lights on and lights off occupies only a tiny portion of our experience.

From a nutritional perspective, it is notable that all of the responses, whether mediated by ipRGCs, by rods, or by cones, are equally dependent on vitamin A.

The Most Relevant Melanopsin Polymorphism

The polymorphism that has most clearly been tied to pupillary response is known as i394T. The majority of people have a “T” at this position, while a minority of people have a “C.” If you are not familiar enough with genetics to know what these letters mean, it is something you can easily gloss over and still understand the concept. In that case, you can just think of the letters as representing one of two different forms of the gene. Each specific form is called an allele, so we refer to people having either the “T” allele or the “C” allele. Since we each get one set of alleles from our mother and one set of alleles from our father, each of us can be homozygous for the T allele (TT), homozygous for the C allele (CC), or heterozygous (CT).

The majority of people in the world are TT. The percentages of people who have at least one C allele are currently estimated as 34% of people with European ancestry, 28% of Chinese, 17% of Japanese, and 14% of Nigerians (according to the discussion of this paper). The percentages of people who are CC are 12% of those with European ancestry, 13% of Chinese, and 2% of Japanese (according to the discussion of this paper).

Studies Using Steady-State Pupil Response

Among just under 75 healthy Japanese university students (reference), those who had one or more C allele had larger pupils under low light and smaller pupils under bright light. They used white light instead of light with a specific wavelength.

Statistically, the greater pupillary constriction was significant at light levels at or above 1000 lux. This is 2 to 3 times what would be found in office lighting, and roughly equivalent to what would be found outside on a cloudy day (see here). However, a close examination of the data suggests that, compared to people with a TT genotype, people with the C allele go from having smaller pupils to having larger pupils somewhere between 10 and 100 lux. This is 10 times as bright as a full moon on a clear night and three times as bright as a clear sky at twilight, but is similar to typical lighting in someone’s living room.

These data suggest that people with a C allele are more sensitive both to darkness and to light. At an illumination level found at night in the absence of artificial lighting, or found in carefully constructed intentional darkness, people with the C allele – according to their pupils, anyway – perceive a greater degree of darkness than people with the TT genotype.  At an illumination level found during daytime, or during virtually any kind of exposure to artificial lighting, people with the C allele perceive a greater degree of brightness than people with the TT genotype.

According to this paper, the statistics suggested no difference between having one C allele and two. However, a close inspection of the data shows that this is not a result of the magnitude of the effect and is rather a result of a high degree of variation among people with the CC genotype. Moreover, the CT genotype was four times as common in this study as the TT genotype. The greater variation and smaller number of subjects would make it more difficult to find statistical significance.  It is a much more sensible conclusion from this study that having one C allele makes you more sensitive to light and having two C alleles doubles this effect, and that the study would have demonstrated this with more robust statistics if it simply had a larger sample size. That said, ideally we should await larger studies before arriving at firm conclusions about the difference between having one C allele and having two.

The same research group conducted another study in an entirely different sample of just under 70 Japanese university students that came to similar conclusions using a different lighting protocol. They showed that the effect was seen for blue and green light, but not for red light. Notably, a given amount of green light produces much more brightness than the same amount of blue light; thus, in dim lighting the blue wavelengths are much more relevant than the green wavelengths.

Studies Using Post-Illumination Pupil Response (PIPR)

One study used the PIPR to blue light (blue PIPR) to study the same phenomenon in 30 subjects ranging from 18 to 65 living in Pennsylvania. The original intention of the study was to obtain insights about seasonal affective disorder (SAD), so the subjects were recruited on the basis of having SAD or serving as controls. Melanopsin does have a connection to SAD, but that part of the study is not relevant to the topic of this blog post, so I am only reporting here their analysis of the relation between the i394T polymorphism and PIPR.

As discussed above, PIPR provides a more highly controlled but less realistic context than the steady-state pupil response, and it’s primary advantage is that it is more specific to melanopsin.

The blue PIPR was dose-dependently associated with the C allele. In fact, the degree of pupillary constriction in the post-blue phase was undetectable (-0.03 mm) in the TT subjects but was robust (0.16 mm) in the CT subjects and was more than 3-fold stronger (0.54 mm) in the CC subjects.

Conclusion From the Pupil Response Studies

Thus, there is agreement between the studies that use steady-state pupil response and those that use PIPR, those conducted in Japan and those conducted in the US, and those conducted in university students and those conducted in a population with a broader age range. The main conclusion is that the minority of people (~30% in populations with European ancestry, less in other populations) who have one or more C allele are more sensitive to lightness and darkness than the majority of people with the TT genotype, and the smaller minority of people who are homozygous for the C allele are most sensitive.

The net result is that having a C allele makes the difference between lightness and darkness more significant to you, and having two C alleles increases this effect.

But does the C allele affect sleep?

PIPR and Sleep Timing

A brand new study that has so far only been published in abstract form (with the full text slated for June) found that, among just over 70 individuals between the ages of 16 and 35, those who had a later sleep time (i.e., fell asleep later, woke up later, and thus had a later mid-point for their sleep) had a greater PIPR. This suggests that greater sensitivity of the melanopsin system can affect sleep timing. One plausible interpretation of this is that greater sensitivity to blue light is making night-time blue light exposure a more significant lifestyle variable and more likely to cause later sleep onset in people with a greater PIPR.

Since we know from the studies reviewed above that a C allele for the i394T melanopsin polymorphism predisposes someone to greater melanopsin sensitivity and greater PIPR, this new study lends further plausibility to hypothesis that people with the C allele are more likely to suffer from poor sleep in response to improper use of artificial light.

What About Vitamin A?

Unfortunately, nothing is known about the molecular mechanism by which the i394T polymorphism affects the function of melanopsin. Since melanopsin uses vitamin A to detect light, the polymorphism could affect how it interacts with vitamin A. No studies have yet investigated whether vitamin A status modifies the effect of the polymorphism. At this point in time, then, we can have reasonable confidence that the C allele increases the likelihood that better controlling light exposure will fix sleep problems, but it remains a wide open question whether the C allele can be used to assess the probability that improvements in vitamin A status would fix sleep problems.

Practical Recommendations

Here are my current thoughts on how we can use this information to get better sleep and better daytime alertness.

How to Use 23andMe to Know Your Own Melanopsin Genetics

In order to follow the directions in this section, you need to get a 23andMe account and send them a saliva sample. This will give you MUCH more information than what I am showing you here. Before doing so, weigh your concerns about self-knowledge and privacy and make your own personal decision about whether participating is consistent with your values. If you have already done this, all you need do is log into your account and follow these instructions.

To the best of my knowledge, 23andMe does not offer a health report about the melanopsin gene. However, you can easily hack this:

• In the upper right corner of the home screen, click on the drop-down arrow by your name, and select “browse raw data.”
• Midway down the new page, you will see two text boxes, “Jump to a gene” and “Jump to an SNP.” Copy and paste “rs1079610” (without the quotes) into the text box to the right of “Jump to an SNP.”
• Press “Go.”
• You should see a new page that says “OPN4” on the left and says your name and genotype on the right. Under your name, see whether it says TT, CT, or CC.
• If you have one or more C alleles, this indicates increased sensitivity to disruptions of the natural light cycle caused by the use of artificial lighting.

If you need extra help with the 23andMe interface, skip to 4:15 in the video below:

What to do With this Information

If you have a C allele, and especially if you have two, and you have any trouble falling or staying asleep and feeling alert during the day, you should make strict control of your light exposure a top priority and consider this more likely to solve your problems than if you did not have this information.

Here is how I would define strict control of light exposure based on my current understanding:

• Light exposure is primarily relevant at the beginning and end of your waking time. As I noted in my previous post on melanopsin, in hunter-gatherers and other groups who live natural lifestyles near the equator, peak sun exposure is around 9 AM and they seek shade from the sun at mid-day. As noted in this extensive review, initial light exposure is relevant to the beginning of your wake cycle and initial darkness is relevant to the end of your wake cycle, but light in the middle of your wake cycle has little effect. So, be liberal about light exposure during the middle of your day but be strict about light exposure in the early morning and at night.
• Get as much light exposure as possible as close to waking as possible. As a rule of thumb, I open my blinds and curtains and turn my lights on as soon as I wake up, and then I try to get a half hour of outdoor sunshine as soon as I am ready to leave my apartment.
• Practice a strict routine of blue light minimization for 2-4 hours before bedtime. I have found that reading paperback fiction by candlelight does NOT qualify for this at all because having enough candlelight to read well gives me insomnia. Unless you want to meditate in pitch blackness or spend your time outside in an area with no artificial light pollution, this means using the following types of tools: blue-blocking glasses (I currently use these); ambient lighting low in blue light (I currently use this light bulb, the night light, and the flash light from lowbluelights.com), f.lux for your computer screen; and NightShift if you have iOS 9.3 or later for iphone 6 or later, which is part of the Displays and Brightness settings.
• It is important to design your routine so you don’t have interruptions in your blue light avoidance. For example, using ambient lighting is way better than the glasses in many ways, but not if you’re sticking your head into your refrigerator and getting blasted with bright blue light while looking for your late-night snack.

Personally, I have the CT genotype, which places me in the top ~30% of light sensitivity for people with European ancestry. But my anecdotal experience suggests I’m in much higher than the 30th percentile for light sensitivity. Perhaps this is partly a result of my very lightly colored eyes, which let in a lot more blue light than darker eyes, and thereby allow that larger dose of blue light to interact with my more sensitive melanopsin.

Personally, I have found the combination of a light-, temperature-, and psychology-based routine to eliminate well over 99% of my sleeping trouble, providing it is practiced on the backdrop of nutritional adequacy. But none of it worked until I made an intensive effort to improve my vitamin A status after having suffered through chronic intolerance of contact lenses that an ophthalmologist told me were due to dry eyes.

For the role of temperature and psychological factors and their interaction with how I manage my light exposure, I recommend reading the practical recommendations of my previous post on melanopsin and listening to Episode 5 of The Daily Lipid Podcast.

I suspect many people that pay some attention to light exposure either don’t take it seriously enough or focus on the wrong things. For example, avoiding “screens” while keeping the living room lights on and reading a book is probably virtually worthless if you have even a fraction of the light sensitivity that I do, and managing your light exposure inconsistently, no matter how strictly you manage it, is not going to effectively entrain a circadian rhythm. The two central pillars of an effective routine are 1) overwhelming consistency and 2) a degree of strictness that is proportional to your own sensitivity to light.

So, while I think that anyone with sleeping trouble should practice good circadian hygiene, I think having the C allele should motivate you to take light exposure as seriously as I describe it above, because the presence of the C allele could be an incredibly helpful indicator that your light routine is really the missing piece of the puzzle if you have persistent sleep or alertness problems.

Do you know your melanopsin genotype? Do you have experience with light hygiene working or not working to solve your sleep problems? It would be great to hear from you in the comments!

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