243: Genome-wide UVB GxE study finds 162 vitamin D variants

[00:00:00] Speaker A: Foreign. Welcome to Base by Bass, the papercast that brings genomics to you wherever you are. Thanks for listening and don't forget to follow and rate us in your podcast app. [00:00:23] Speaker B: Okay, let's. Let's unpack this. Think about your own experience over the course of a year. Why do we often feel metabolically and even, you know, psychologically different in summer compared to deep winter? And we're not just talking about needing a coat. Is it purely about the amount of sunlight hitting our skin or is there a. A deeper built in biological mechanism that regulates our seasonal biology? [00:00:46] Speaker A: It's a classic question and it ties environment directly to genetics. Yeah, for decades we've known vitamin D status is overwhelmingly determined by solar exposure. But what if your genes, which, you know, we thought had a pretty modest fixed influence, suddenly become much more powerful when the sun shines brightest? [00:01:03] Speaker B: And that is the paradox at the heart of our deep dive today. This new research focused on vitamin D status, or the concentration of 25 hydroxy vitamin D, which we'll just call 25oHD. It reveals that the genetic contribution nearly doubles when sun exposure is high. That's right, the SNP based heritability, it jumped from about 8.48% in the lowest UVB quintile to, well, a remarkable 15.56% in the highest. [00:01:28] Speaker A: That's a huge jump. [00:01:29] Speaker B: It is. It suggests our genes aren't passively waiting. They actively seize control when the environment provides the opportunity. And the massive implication here, this genetic control over vitamin D is entangled with the core machinery of the human circadian clock. [00:01:44] Speaker A: Wow. [00:01:44] Speaker B: It places vitamin D right at the center of seasonal biological timing that is genuinely groundbreaking. [00:01:49] Speaker A: It completely changes how we view vitamin D not just as a nutrient, but will potentially as a powerful seasonal signal. So before we dive into the intricate methodology that allowed scientists to unlock this, we really need to pause and give some special recognition. Today's deep dive celebrates the cutting edge work of Risha Shrem and her colleagues. I mean, this team from multiple institutions like Trinity College Dublin and the University of Edinburgh has truly advanced our understanding of the genetic basis of 25oHD status. [00:02:15] Speaker B: They really did. And to understand why this work is so important, we have to look at the history of this research. The fundamental problem is clear. 25 OHD concentration is strongly regulated by solar ultraviolet b radiation or UVB. Previous genome wide association studies, the GWS, they were good. They identified over 100 variants, but altogether they only explained about 4.2% of the total variance. [00:02:41] Speaker A: Only 4%. Right. [00:02:42] Speaker B: And ambient UVB, by contrast explained three times that amount, about 12.4%. [00:02:48] Speaker A: So the environment was the dominant factor. But that genetic puzzle just felt incomplete. Yeah. And the historical challenge, as you mentioned, was how crudely the environment was measured. [00:03:00] Speaker B: Precisely. The standard approach was simply using season of blood draw as a proxy for sun exposure. [00:03:06] Speaker A: Oh, right. [00:03:06] Speaker B: So if you gave blood in January, you were in the winter group. June, you were in summer. [00:03:10] Speaker A: But the variation within those seasons is just huge, let alone day to day. [00:03:14] Speaker B: It's terribly inaccurate. And here's a vivid example. Think about London, where this research was based. The average daily UVB do in December might be a paltry 0.11 kilojoules per square meter. Fast forward to June and it hits 5.56. [00:03:28] Speaker A: This is a 50 fold difference. [00:03:30] Speaker B: 50 fold. So lumping a sunny day in March and a dreary day in November into one category, it just masks colossal variability. [00:03:38] Speaker A: Which means any real interaction between a gene and the sun would be completely blurred out. [00:03:42] Speaker B: Exactly. If a gene environment interaction, a GXE interaction, is present and you fail to model that environment accurately, well, you're just guaranteed to increase unexplained variants and mask those crucial genetic associations. [00:03:56] Speaker A: So this study set out to fix that. [00:03:58] Speaker B: Yes. The scientific necessity was clear. Precision in the environment leads to immense power in the genetics. [00:04:03] Speaker A: Okay, so here's where the innovation really starts. Because they managed to build an environmental measurement tool that finally respects the biological reality. First, let's talk scale. They used a massive cohort, 338,977 UK Biobank participants, all of white British ancestry. That gives you the statistical power you need. [00:04:23] Speaker B: It does. But the methodological star of the show is this new hyper precise measurement. They developed the cumulative and weighted ambient UVB dose, or CWD uvb. They didn't rely on averages. They calculated a unique precise dose for every single participant. [00:04:40] Speaker A: How on earth did they manage that for hundreds of thousands of people? [00:04:45] Speaker B: They leveraged satellite weather data from something called the TMIS database. And they linked this specific satellite data to the participant's exact residential location and the exact date the blood sample was drawn. So they had the UVB availability in the atmosphere for that specific time and place. [00:05:02] Speaker A: So they knew exactly how much sun was potentially available to you in your neighborhood when you went to the clinic. [00:05:07] Speaker B: That's the first part. The second and perhaps most critical part is the waiting. We know vitamin D doesn't just appear and disappear. It has a half life of about 35 days in the body. [00:05:16] Speaker A: Right. [00:05:16] Speaker B: So they made the CWDUV B dose cumulative over the 135 days prior to sampling. [00:05:23] Speaker A: 135 days. So that's roughly four and a half months. It covers the body's full storage window. [00:05:29] Speaker B: Exactly. But you don't want the sun exposure from four months ago to count as much as the sun exposure from last week. [00:05:34] Speaker A: Sure, that makes sense. [00:05:35] Speaker B: So to reflect the actual biology, they weighted the doses. More recent exposures contributed much more heavily than those from the distant past. It's. You can think of it like a weighted gpa, right? [00:05:46] Speaker A: Your final exams matter more than your first quiz. [00:05:48] Speaker B: Precisely. And this biological rigor just dramatically improved the quality of the environmental model. [00:05:54] Speaker A: That attention to detail must have been the key that unlocked the genetics. So with that refined environmental variable, they applied these advanced analytical models while adjusting for things like age, sex, supplements, all that. [00:06:07] Speaker B: The power of that precision was just stunningly evident in the results. [00:06:11] Speaker A: Absolutely. The most striking quantitative result is just the sheer number of genetic regions they found. The study identified 307 unique independent variants associated with 25oHD. And crucially, 162 of those variants were entirely novel. [00:06:27] Speaker B: 162 never seen before. [00:06:29] Speaker A: They literally doubled the number of known genetic loci influencing vitamin D status purely because they measured the sun better. [00:06:38] Speaker B: And it goes beyond just finding new locations. They found compelling evidence for that GXE interaction itself. 20 specific variants showed significant interaction effects with UVB exposure. [00:06:50] Speaker A: So their impact actually changes depending on sun availability. [00:06:53] Speaker B: Yes. And this was seen in new genes like COPB1 and PSMA1. [00:06:58] Speaker A: And that ties right back to the heritability gradient we mentioned at the start. That doubling of heritability is powerful. But they also showed higher heritability in the subgroup that reported spending three or more hours outdoors. [00:07:10] Speaker B: It's a consistent story. The genes controlling vitamin D are only fully expressive when they have that fuel from the environment. [00:07:17] Speaker A: So if we start connecting these genes to the bigger picture, what does it tell us? [00:07:21] Speaker B: Well, the functional annotations tell a remarkable story about human seasonality. What's fascinating here is the association with core circadian clock genes. The body clock genesis, specifically bmal1, rntl and npas2. These are the fundamental timekeepers of the body regulating biological timing on a 24 hour cycle. [00:07:40] Speaker A: So the genes that regulate our sleep, wake cycle and internal rhythm are linked to the genes that regulate our sun derived vitamin. That can't be a coincidence. [00:07:50] Speaker B: It strongly suggests a mechanism. And what's more, the gene set analysis was heavily dominated by pathways involved in lipid metabolism. [00:07:57] Speaker A: Like cholesterol and triglycerides. [00:07:59] Speaker B: Exactly. Things like LDL hdl, triglycerides, telomicron clearance. This provides a mechanistic basis for the long observed associations between vitamin D and metabolic health. [00:08:10] Speaker A: And you mentioned the UGT genes. That's about excretion, right? Getting rid of things? [00:08:13] Speaker B: It is. It's the major route for converting Active 25 OHD into an inactive excretable form. It's called glucuronidation. [00:08:21] Speaker A: So why is finding more of those genes important? [00:08:24] Speaker B: Because that pathway is highly regulated. And while it's technically excretion, some emerging research suggests these conjugated forms might represent an alternative storage or biological buffer of vitamin D. So if your genetic variability in UGT genes influences how quickly you inactivate or store 25oHD, it has major implications for how quickly you become deficient and how we even define enough. [00:08:45] Speaker A: Let's talk about those broader implications. The discovery of 162 new loci just proves that genetic power was being wasted by imprecise environmental modeling. [00:08:56] Speaker B: It really was. This raises an absolutely vital quotient about human seasonal biology. The deep association between vitamin D genes and core circadian clock genes like BMA1, combined with the increased heritability and high UVB, it suggests that seasonal variation in vitamin D is not just a passive result of sun exposure. [00:09:14] Speaker A: So it's not just a happy accident that we have more vitamin D in summer and less in winter. It's part of a design. [00:09:20] Speaker B: It may play an active mechanistic role in human innate seasonal physiology. Think of melatonin. [00:09:25] Speaker A: Right. It signals nighttime. [00:09:27] Speaker B: Similarly, low 25oHD status in winter may act as a seasonal signal. It could trigger metabolic, immune or behavioral responses. A sort of winter mode that is. [00:09:35] Speaker A: A fundamental reframing of seasonal adaptation. But that leads to a huge clinical challenge. If low vitamin D is an innate signal for winter mode and that mode has been important for survival, what happens when we recommend year round high dose vitamin D supplementation? [00:09:52] Speaker B: Exactly. It raises the question of whether that ubiquitous seasonal supplementation might unintentionally disrupt these innate metabolic rhythms. We need to evaluate the long term impact of maintaining high vitamin D status when the body's internal clock may be expecting that lower winter signal. [00:10:09] Speaker A: On a positive clinical note, though, the study does show great promise for personalization. They developed new genetic risk scores. [00:10:16] Speaker B: Yes. And the clinical difference was stark. They found a substantial 14.01 UNL difference in 25 OHD concentration between the top and bottom decile of the genetic score. [00:10:27] Speaker A: That's a big difference. [00:10:28] Speaker B: It is. And that level of predictive power means these refined scores can directly inform personalized vitamin D dosing. If you know a person's genetics make them intrinsically poor at utilizing the available sun, you can dose them more accurately. [00:10:40] Speaker A: Okay, before we wrap up, we should address the limitations. They always point toward the next steps in research. [00:10:45] Speaker B: Primarily, the study was based on UK biobank participants, who are overwhelmingly of white British ancestry, so generalizability to other ethnicities is limited. Also, the UK's high northerly latitude means overall low UVB variability that likely reduces the power to detect all possible GXE effects you might see globally. [00:11:06] Speaker A: And the final piece of the puzzle that's still missing is the difference between availability and the personal dose received right. [00:11:12] Speaker B: The CWDUVB measures how much sun was in the sky, but you might have been inside or wearing a coat. Sure, future research needs that final leap better personal dosimeters or linked GPS data to capture the actual amount of UVB that hits an individual's skin. [00:11:26] Speaker A: So let's bring it all back home. The central insight is clear by using a uniquely precise measure of solar radiation, scientists have found over 160 new genetic regions influencing vitamin D status. Our genetic makeup exerts far more control over our vitamin D levels when UVB. [00:11:43] Speaker B: Is abundant, and this detailed genetic mapping reveals that the vitamin D pathway is deeply connected to the core machinery of the human circadian clock and lipid metabolism. It strongly suggests vitamin D metabolites may not just be bystanders, but essential mediators of our seasonal rhythms. [00:12:00] Speaker A: That's a powerful takeaway. What does this mean for the future of personalized medicine? Should we adjust vitamin D recommendations based not just on diet and latitude, but also on a person's unique genetic sensitivity to seasonal UVB changes? It makes you wonder if our genes are already perfectly adapted to the fluctuations, and we should pay closer attention to that natural balance. This episode was based on an OpenACGUS article under the CC BY 4.0 license. You can find a direct link to the paper and the license in our episode description if you enjoyed this, follow or subscribe in your podcast app and leave a five star rating. If you'd like to support our work, use the donation link in the description now. Stay with us for an original track created especially for this episode and inspired by the article you just heard about. Thanks for listening and join us next time as we explore more science. Base by base. [00:13:08] Speaker C: I trace the light on a quiet map A pale gold thread through cloud and glass Days add up in a hidden stack what you don't feel still shapes your past A satellite keeps the ledger clean Counting the Sparks that touch the skin while in the blood a steady scream shows what the seasons leave within and every street and every day becomes a number, becomes a wave not just summer not just late but measured fire the body saves are made of clockwork sun lines Gene notes in a changing sky when the daylight arises I can hear it signals turning volume high in the bright the patterns sharpen in the dim they learn to hide I'm made of clockwork sun lines where your DNA meets the tide Some keys are common soft and small Some rare ones hit like heavy rain A million whispers in the wall a few that bend the whole refrain on one long stretch of chromosome the switch is sitting close at rolls like street lights in the midnight zone that flicker when the wind blows and in the liver's quiet room old pathways humming second time lipids drift and shift in bloom cleared and carry line by line. [00:15:18] Speaker B: Now. [00:15:18] Speaker C: Made of clockwork sun lines Gene notes in a changing sky when the daylight rises I can hear it signals turning volume high in the bright the patterns sharpen in the dim they learn to hide I'm made of clockwork sunlight. Your DNA meets the tide BMO1 keeps the ladder lit A metronome behind the bones not proof of cause just pieces fit like constellations half known tones maybe winners Lower Glo is more than lack it's also a sign a coded rhythm telling slow to every cell that keeps its time I made a clockwork sun lines G notes in a changing sky when the daylight rises I can hear it signals turning volume high so take the light and take the measure Let the data guide the ride I made a clock the sunlight. Meets the T. [00:17:12] Speaker A: Ra.