This GWAMA of up to 21,495 European-ancestry participants used the Sniffin' Sticks odour identification test to map genetic variants influencing identification of twelve odours and an identification score. The study reports ten independent loci (seven novel), sex-stratified effects, and a Mendelian randomization finding that Alzheimer's genetic risk negatively affects smell identification.
0:00Welcome to Base by Base, 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. Imagine you're uh, sitting at a kitchen table, right?
0:15And you're peeling a perfectly ripe orange. Instantly, that really sharp, sweet citrusy zest hits the air. Or maybe you're snapping a piece of raw cinnamon bark in half. You personally can identify those smells perfectly without even opening your eyes.
0:30Yeah, you just know instantly what it is Exactly. But the person sitting right next to you takes a deep breath and just they just shrug. They can tell it's, you know, something fragrant, maybe something sued related, but they completely struggle to actually name it.
0:41And most of us just, I mean, we write that off as someone having a quote unquote, good nose versus a bad nose. Like, it's just some quirk of their personality or, you know, their palate. Right. But the reality is actually far more complex, that difference in perception is hardwired into their DNA.
0:56And it is deeply influenced by their biological sex, which raises this immediate, just massive question for you, the listener. What really happens when this genetic wiring breaks down? Yeah, that's the big one.
1:08And how could our ability to identify a simple, everyday scent completely change our understanding of neurodegenerative diseases, like, um, like Alzheimer's? It's mind blowing, really, because it forces us to completely reframe how we look at the human sensory experience.
1:26We aren't just talking about smelling food. We are looking directly at the fundamental genetic architecture of the brain. So to unpack this, today we celebrate the work of friends. First year, Marcus Schultz, Christian Fuchsberger, and they're really vast collaborative teams, across the Chris, life adult, Rhineland and Eric's studies, who have advanced our understanding of the genetics of human olfactory perception.
1:47And we should mention, this monumental deep dive into the research was publishing nature communications on July 1st, 2025. Right. And you called it monumental, which, well, why is this such a big deal compared to, say, our sense of sight or hearing?
2:00So smell is entirely unique among human senses. Like, if we look at the bigger picture of human evolution in neuroscience, your other senses, vision, hearing touch, they all have to pass through this relay station in the brain called the thalamus.
2:17Okay, the 5th Yeah. Think of the thalamus as like a corporate switchboard. Sensory input comes in, the operator processes it, and then routes the call to the logical conscious parts of your brain. But olfaction smell.
2:30It doesn't do that. Wait, it just skips the switchboard. totally skips it. It has a direct, unfiltered, neuronal connection straight to the amygdala. And the amygdala is the emotional center of the brain, right?
2:41Exactly. And it also connects directly to the hippocampus, which is your memory center. From an evolutionary standpoint, this actually makes perfect sense. I mean, if our ancestors smelled a predator or, you know, smoke from a fire or rotting food.
2:55They didn't have time to be put on hold by the brain switchboard. Right, right. They needed an instant visceral reaction to just survive. Which totally explains why a specific smell can act as a like a biological time machine.
3:06You smell rain on hot pavement or um, uh, a specific brand of sunscreen, and you are instantly transported back to this vivid childhood memory, totally bypassing your rational brain. Yeah, it's a direct hit to the memory banks.
3:21But there's a very real clinical problem attached to this direct connection, isn't there? When olfactory dysfunction happens, when that system fails, it severely impacts a person's quality of life. Oh, absolutely.
3:33And the clinical problem goes much, much deeper than just losing the joy of food or the nostalgia of a memory. In patients diagnosed with Alzheimer's disease or Parkinson's disease, the prevalence of olfactory impairment is just staggering.
3:46How staggering are we talking? It is greater than 80%. Wow. Over 80% of those patients lose their sense of smell. Yeah. And what makes that statistic so critical is the timeline. This loss of smell often precedes the actual motor or cognitive symptoms of those neurodegenerative diseases by several years.
4:02So it's an early warning system. Exactly. It operates as this red flag that something is fundamentally failing in the brain circuitry long before the memory loss or the tremors even begin. Okay, so if smell is our early warning system.
4:15We obviously need to understand exactly how it works at a baseline level, which leads to this really fascinating historical and biological observation that the researchers tackled. The sex difference. Yes.
4:26Women generally have a much better sense of smell than men. The data consistently shows that women are better at identifying smells, uh, discriminating between different odors and even detecting them at much lower concentrations.
4:39Yeah, that sexual dimorphism in olfaction has been heavily documented for decades, but the underlying reason for it has been the subject of, well, intense debate. I got to admit, my initial thought goes straight to cultural factors.
4:51Like, there's this long-standing argument that traditional historical roles, you know, food preparation, gathering, simply made women more familiar with culinary smell. Right. The practice makes perfect theory.
5:03Exactly. If you spend more time cooking with diverse ingredients, you naturally develop better identification skills just through sheer practice. If that's true, then this is just a learned behavior. So the big question is, are men and women actually built differently when it comes to the physical hardware of smelling?
5:21And to answer whether this is cultural practice or biological hardware, the researchers utilized a massive genome wide association meta analysis. Yeah, a drama. They basically aggregated the genetic data of nearly 21,500 individuals of European ancestry.
5:40Okay, just to put that into perspective for you listening, that is an incredible amount of data, our DNA is made up of over 3 billion letters. Scanning the genetic code of 21,500 people is essentially looking for a few specific typos in a massive global library.
5:55But wait, how do you even test the sense of smell for that many people consistently? Like, how do you compare it against their genes? So they used a highly standardized screening tool called the Sniff and Sticks test.
6:04Sniff and sticks. Yeah, it's a funny name, but it's very rigorous. The administrators use these devices that look exactly like felt tip pens. But instead of ink, they dispense naturally emulated odors.
6:16There are 12 specific scents used in this test, things like orange, leather, cinnamon, peppermint, banana, lemon, licorice, coffee, cloves, pineapple, rose and fish. Okay, so you uncap the pen, wave it into the person's nose, and they just have to identify it.
6:32But how do you stop people from just guessing? Because if I don't know the smell, I might just panic and throw out a random food name. Well, that's the trick. It is a forced choice test. The participant is given a specific list of 4 options for each pen and they must choose one.
6:46This structure actually allows researchers to build a highly accurate statistical model of a person's olfactory identification ability and a mathematically accounts for random guessing. Oh, that smart.
6:56Yeah. And once they had those identification scores, they took a critical, really novel step. They conducted a sex stratified analysis, they literally split this massive genetic data set by sex to look for S&P by sex interactions.
7:10And a SMP, SMP being a single nucleotide polymorphism. That single letter typo in the DNA we talked about earlier. Exactly right. They were checking to see if specific genes physically behave differently or have a different impact in a male body versus a female body.
7:26But hold on. If you're looking at over 21,000 adult, how do you isolate their genetics from their lifestyle? Like, someone might have a terrible sense of smell because they smoked a pack of cigarettes a day for 30 years or, I don't know, worked in a chemical plant, not because of their DNA.
7:41How do the researchers prove the genes are actually causing the differences and not just a lifetime of environmental factors? And that right there is the eternal struggle of observational biology. To solve it, they used a methodology called Mendelian randomization.
7:56Mendelian randomization. How does that bypass the lifestyle stuff? It acts kind of like nature's own randomized chronical trial. Because you inherit your genes randomly at birth long before you ever pick up a cigarette or choose a specific diet.
8:10Researchers can use those inherited genetic variants as unbiased tools. Oh, I see. Yeah, it allows them to untangle the exact direction of cause and effect. They used it here to test for bidirectional, causal relationships between sex hormones, the ability to smell, and those neurodegenerative diseases we mentioned.
8:28They needed to know definitively does poor smell cause brain disease, or does brain disease cause poor smell? Okay, I am dying to dig into the results here. When they scan those 1000000000s of letters across all those people, did they actually find the genetic hardware for smell?
8:44They absolutely did. They discovered 10 independent genetic losi, which are specific locations on the genome that definitively govern our ability to smell. Yeah, and out of those 10, an incredible 7 of them were completely novel.
8:59They had never before been linked to olfaction. And most of these loci were located within clusters of olfactory receptors, which belonged to a really large family of proteins called G protein coupled refecters.
9:11Hang on a 2nd though. That actually contradicts a major concept in neuroscience, doesn't it? You're thinking of the ototope theory. Yes. The prevailing idea in the field is the ototope theory. I always understood that one single olfactory receptor could bind to multiple structurally similar smells, kind of a master key that can open several different but related locks.
9:33Right. So if I have a genetic mutation at one of these 10 low size. Shouldn't I lose a whole category of smells, like why wouldn't a whole cluster of scents just disappear at once? That is a brilliant observation, and it highlights one of the most surprising findings of this entire paper.
9:47The researchers expected to see exactly what you just described, based on that master key idea, but the data showed the exact opposite. Wait, really? Yeah, every single one of these 10 low sci was exclusively associated with just one specific odor, not a category, not a cluster, one genetic locus, one specific smell.
10:06Oh wow. That implies our genetic coding for smell is incredibly specialized. Yeah, we aren't just inheriting a general good nose. We are inheriting the specific ability to perceive distinct molecular shapes.
10:17It gets even more specific, and honestly, a little bit strange. Okay, lay it on me. The researchers calculated an overall identification score for the entire sniff and sticks test, essentially grading how well people did across all 12 smells globally.
10:31They found that this overall global score was entirely driven by people's genetic ability to smell pineapple. I'm sorry, what pineapple? Yes, which was traced to Locus 8 on the genome. Wait, our entire baseline for genetic smell capability in this massive European study hinged on pineapple.
10:48It did. If you literally remove pineapple from the mathematical equation, the genetic association with the overall global score simply vanishes. It is a completely fascinating anomaly in the data. That is just, that's profound and kind of hilarious.
11:02But let's bring it back to that debate we started with. Culture versus biology and men and women. Did the sex stratified analysis actually prove that men and women have different biological hardware for smelling?
11:12It did, proving once and for all that it's not just a cultural artifact of women spending time in kitchens. Let's look at locust 2, which involves a gene called ADCY2. This gene dramatically increased the odds of a person successfully identifying the smell of an orange, but this genetic advantage existed only in females.
11:31Yeah, it was a completely female specific genetic trait. So a woman with that variant literally possesses a biological key that unlocks that specific citrus perception, and a man with the exact same variant gets absolutely no benefit from it.
11:46Exactly. And we see the reverse effect as well. Look at Locust 9, which is located near a cluster of OR 5 genes. This locust was associated with the ability to smell pineapple. Now, while it helped both sexes, the genetic effect size was significantly higher in males, so it operates as a male differential treat.
12:02Okay, so we have the proof. Biological sex alters the hardware. But what is the actual mechanism there? Like how does being male or female physically change how a gene operates inside a neuron in your nose?
12:13So the researchers analyze these specific candidate genes and found that they contain something called androgen response elements. Androgens are male sex hormones, like testosterone. So the hormones are actually interacting with the genes themselves.
12:28Exactly. These energy response elements are specific sequences of DNA located in the regulatory regions of the genes. Think of them as like physical docking stations. Okay. This means that sex hormones floating in the bloodstream might actually interact directly with the DNA of these smell receptors.
12:44The hormones can physically bind to the DNA docking stations and alter how strongly the gene is expressed. Wow. Yeah, they are fundamentally changing how the 2 sexes perceive odors at a literal molecular level.
12:56The hormones are literally turning the volume dials up or down on specific smells right at the DNA level. That perfectly explains why fluctuating hormone levels like, um, during pregnancy or puberty, can radically change how sensitive someone is to assent.
13:11But if we pull back for a 2nd and look at the clinical implications. How does this all connect to Alzheimer's? We touched on that early warning system earlier. Right, and this was the paradigm shifting inside of the paper.
13:23We discussed how they used Mendelian randomization to figure out the direction of cause and effect, right? Yes, nature's randomized trial. For years, the scientific community has worried that environmental damage to the olfactory system, like, say, breathing in heavy pollution or toxins might allow those toxins to travel up that direct neuronal highway straight into the brain and start the Alzheimer's disease process.
13:46And I mean, that seems pretty logical. If the R factory nerve is a direct unfiltered pathway to the memory center, it could easily be a Trojan horse for environmental damage. It does seem logical, but the Mendelian randomization analysis definitively proved it wrong.
14:02Wait, really? Yeah. The pathway goes the other way. Having a poor sense of smell does not cause Alzheimer's or Parkinson's disease. Instead, a high genetic risk for Alzheimer's, actually causes a decrease in overall odor identification.
14:16Ugh. The disease genetics are driving the sensory loss. So the brain disease starts 1st and the loss of smell is just like collateral damage. Exactly. And they trace this mechanism specifically to a variant in a gene called Tom M 40.
14:30Tom and 40. Okay, let's make sure we understand exactly how that works. How does a mutated Tom M40 gene reach out and destroy a person's ability to smell? So, Tom and 40 codes for a protein that is heavily involved in mitochondrial function.
14:43Imagine a cell is a massive manufacturing city, and the mitochondria are the power plants keeping the whole city running. Standard biology class analogy. I with you. Tom M40 acts like the loading dock doors of that power plant.
14:57It helps import essential proteins and fuel into the mitochondria. If the Tom M 40 gene is mutated, those loading dock doors essentially jam shut. So the power plant can't get the parts it needs. Right.
15:08And that leads to massive mitochondrial dysfunction and neurotoxicity. The power plant just shuts down entirely. And if we think about olfactory sensory neurons. I mean, they are constantly firing, right?
15:19Every single time you take a breath. They're rapidly taking in environmental data and sending it directly to the brain. They must require a huge amount of energy to operate. They are massive energy hogs.
15:29And because the olfactory system is so deeply energy dependent. It is incredibly vulnerable to any drop in power. If we use that power plant analogy. The mitochondrial dysfunction is the fire, and the smell loss is just the smoke.
15:44That's a great way to put it. When the mitochondria start failing due to that Alzheimer's genetic risk, The olfactory neurons simply suffocate. They are among the very 1st cells in the entire body to show the damage.
15:56Which reframes smell loss in a clinical setting entirely. It's not a Trojan horse letting toxins into the brain. It's a shared mechanism. It's a direct early downstream consequence of the exact same cellular power failures that will eventually burn through the memory centers of the brain.
16:12Exactly, which makes it an incredibly valuable biomarker for early detection. But, you know, to maintain our scientific rigor here, we really have to look at the limitations of how they gathered this data.
16:23Right, because the sniff and sticks test, it relies on 12 very specific smells. orange, leather, cinnamon, licorice. Those are heavily tied to European food and culture. Yeah, and that's a tiny microscopic fraction of human capability.
16:37Humans can detect an estimated 10000000000 different sense. Testing only 12 culturally specific odors means we are likely missing massive amounts of genetic data regarding how we perceive the wider olfactory world.
16:50Not to mention the demographic limit. Right. The genetic data was limited exclusively to individuals of European ancestry. And we absolutely cannot extrapolate these specific genetic variants to global populations.
17:02I mean diet, culture, environmental pressures, evolutionary history. All of that differs wildly across the globe. Our genetic hardware for smell was shaped by those distinct environments, and our data needs to actually reflect that diversity.
17:13Which lays out a very clear roadmap for future research. This study beautifully prioritizes the molecular mechanisms we need to investigate specifically how these G protein coupled pathways and those mitochondrial loading docks interact.
17:28But the necessary next steps. They must include broad cross-cultural studies. We need to use entirely different sets of odors, perhaps natural environmental sense, not tied to specific cultural cuisines, just to see how universal these genetic rules truly are.
17:42So to bring it all together, our ability to identify specific odors is uniquely coded in our DNA and interacts deeply with our biological sex, proving that smell isn't just a passive sense, but a highly individualized genetic trait.
17:55Furthermore, this genetic wiring reveals that olfactory loss is a direct downstream consequence of the neurodegenerative pathways leading to Alzheimer's rather than a cause. Yeah, every single time you take a breath, you are not just sampling the air.
18:09You are actively engaging your most ancient genetic and neurological hardware and revealing the underlying health of your brain's circuitry. Which leaves us with his final thought. What does this mean for the future of diagnosing your long-term brain health through a simple, personalized sniff test?
18:24It's a whole new frontier. It really is. This episode was based on an open access article under the CCBY 4.0 license. You can find a direct link to the paper and the license in our episode description.
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