Being a morning person may be more of a hardwired trait than a product of habit and discipline. At least, that's according to a new, large-scale study from the genetic testing company 23andMe. The 90,000-person study, published in the journal Nature Communications, explored the genetic basis for loving the a.m., thereby advancing research on circadian rhythms and the problems that surface when they're out of sync. It also reignited discussion over the role that consumer data can and should play in shaping what "science says!"
Since late 2007, more than one million customers have sent their saliva to 23andMe to unlock information about their ancestry, as well as learn whether they’ve inherited genes linked to more than 90 traits and medical conditions. But the direct-to-consumer genotyping startup has stirred controversy along the way. Because, at first, 23andMe went after the sort of curious consumer who likes to spend a hundred bucks to discover they have the gene that makes their urine smell when they eat asparagus. But, with time, 23andMe drifted into dicier DIY-diagnostics territory and raised concerns about medical fearmongering.
Genotyping can, after all, reveal both quirky traits and disconcerting predispositions to diseases. When 23andMe results prompt people to get expensive, unnecessary tests and procedures, the thinking goes, public interest suffers. And, during a period between 2013 to 2015, FDA restrictions permitted 23andMe to sell only raw genetic data, rather than data with accompanying health analysis. 23andMe skirted FDA regulations and arguably emerged with something of great value to public interest: a huge bank of genetic data that's varied, versatile and ripe for use in population studies.
23 and Sleep
Recently, 23andMe dipped into its biological bank to explore the genetic basis of chronotypes (whether someone is a morning lark or a night owl). The company has funded a number of studies using genetic, demographic and personal information submitted by customers. In this case, researchers zeroed in on customers who answered “yes” to the question “are you a morning person?” Then, they further pared down that group to include only customers of European descent.
After making sure they only included people who say things like “up and at ‘em” (a.k.a. “standardizing the data”), researchers had 90,000 genomes to scrutinize. They isolated 15 DNA mutations shared by enough of the early-rising participants to constitute statistical significance. Previous studies (from various researchers) had already linked seven of the 15 mutations to sleep-related traits.
In short, they pinpointed what we’ll call “morning genes.”
The study was the first to identify a genetic basis for human chronotypes on such a large scale. As cool as the work is, 23andMe’s research model — scientific advancements courtesy of mass-market spit samples — isn’t traditional. And 23andMe is not solely, or even primarily, focused on population genetics research, nor does it pretend to be. So, we turned to Jonathan Cedernaes, a sleep medicine and neuroscience researcher at Northwestern University, and James Fadden, vice president of the Circadian Sleep Disorders Network. Here’s what they had to say about the findings.
Let’s give credit where it’s due: Smaller studies (involving a few hundred people, max) laid the foundation for 23andMe to get glory.
Jonathan Cedernaes: Other studies have found associations between genetic variants in, for example, core clock genes, a lot of which seem to have been found in the present study as well.
But, the 23andMe study is significant. For starters, it confirmed previous results. In science, replicability (repeating a study and achieving similar enough results) is a big deal.
Cedernaes: It’s easy to miss that [these results] validate a lot of previous findings from smaller studies, which again is important as validation proves that such findings are more likely to be true findings and not, e.g., false positives.
James Fadden: One thing I find interesting is that many of the gene associations found in these large studies point to genes which have known functions involved in the biochemistry of circadian rhythms. This correlation of genes and biochemistry is not always so clear in large genome-wide association studies of other conditions.
Also, when it comes to population genetics, size matters.
Fadden: Previous studies have looked at similar genetic variants at a genome-wide level, and how they are associated with variations in sleep and circadian rhythms...These new studies involved around 89,000-119,00 subjects in each study, giving them considerably more power.
23andMe also linked morning people to gene mutations we didn’t know were relevant to circadian rhythms in humans.
Fadden: The additional genes implicated in these studies which do not have known connections to circadian rhythms also suggest areas for investigation.
Cedernaes: They found genetic variants of several circadian genes to be linked to their question of morningness. One such gene is VIP, which encodes vasoactive intestinal peptide, and which in animal studies have been shown to be essential for the master clock in the brain (the suprachiasmatic nucleus) to function properly and to basically be able to set the sleep-wake cycle.
While 23andMe published the biggest study from a consumer genetic-testing service, it’s not the only big study of this kind.
Fadden: This study is actually one of three large genome studies on chronotypes that were all published within the last week. The two others used data from the UK Biobank. There is considerable overlap in the findings from the three studies, helping to confirm their validity.
The results link people who say they love the morning to other health traits, such as BMI, but don't link any specific gene mutations to those qualities.
Cedernaes: This means that further studies are likely needed to provide causal mechanisms, which may require sleep interventions or analyses of genetic data and subject characteristics (such as BMI) in other large populations.
The results may be more applicable to healthy sleepers than people with circadian rhythm disorders.
Fadden: These findings apply primarily to a normal range of phenotypes. While no doubt some of the subjects have circadian disorders, most presumably do not. The genes involved in the normal range of sleep chronotypes and the genes involved in actual sleep and circadian disorders do seem to have considerable commonality, but there are also differences. So we would be dealing with different types of studies.
Also, the results reflect genomes of 90,000 people with at least 97 percent European ancestry. Even among Europeans, important differences could emerge.
Cedernaes: People from nordic countries have a very different light exposure during most of the year as compared with people in southern Europe, and there are studies suggesting that sleep duration varies geographically. Ideally, people from a narrow geographic location should be studied as such cohorts can be assumed to be more similar to one another, and thus reduce the “noise” or variance in the data.
On the other hand, going Euro-only could mean the findings don’t apply to people who don’t hail from the continent.
Cedernaes: By restricting their analyses to people of European ancestry only, the researchers may have missed associations that are present in other populations, such as variants of other clock genes being linked to morningness, and vice versa.
Fadden: The subjects studied were of European ancestry so there may be other genetic variants involved in circadian function in other populations. For example a smaller Japanese study found a different SNP implicated in diurnal preference, although both the Japanese variant and the findings from these studies do point to the same gene, PER3, as being important, so they aren't totally inconsistent.
The participants also had the money and interest to sign up for 23andMe in the first place, but the study was probably big enough minimize the impact of studying a self-selected pool.
Cedernaes: It could always be speculated that people who are willing to have their genome analyzed by 23andMe would somehow be different from the general population, in terms of their sleep or circadian rhythms. But since 23andMe have genotyped more than 1 million people, their combined dataset should be able to account for even smaller differences.
Fadden: The study population does have some influence on the results, but probably not so large as to call into question the major findings.
This study is good news for night owls looking to blame biology.
Fadden: Even if these studies do not offer an immediate payoff in treatment they are important in another way. Most of us have been called "lazy" or "undisciplined" or in other ways told that our sleep disorders are our own fault. We are offered condescending advice ("just go to bed earlier"). Most of us know from our own experience that the timing of our sleep is not something we can control and that most sleep advice does not apply to us. The fact that sleep timing is now being shown to be under genetic control is very helpful to us.
Shift workers could benefit from this as well.
Cedernaes: Shift work is common today and drugs that could counteract negative effects of either sleep deprivation or circadian misalignment, both of which occur in shift work, would be of great value for the well being of a large proportion of our working force, including those working in health care.
But going forward, we need to experiment with different sleeping conditions and measure circadian rhythms and sleep activity objectively.
Cedernaes: It may be possible to use these findings to stratify people in interventional studies, to more causally examine how specific genetic variants contribute to e.g. sleep duration or sleep timing, or important phenotypes that have been linked to e.g. sleep deprivation or circadian misalignment in humans.
Quotes have been condensed and edited.