July 28, 2025 • 20 mins
🎙️ Episode 89: Decoding the Genetics of Smell: Sex-Specific Variants in Olfactory Identification
🧬 In this episode of PaperCast Base by Base, we explore how a genome-wide association meta-analysis of olfactory identification across 21,495 individuals reveals novel genetic loci underlying human smell perception.
🔍 Study Highlights:
Using the Sniffin’ Sticks screening test across four European cohorts totaling 21,495 individuals, the authors conducted a genome-wide association meta-analysis of twelve common odorant identifications and an overall identification score. The study discovered ten independent loci reaching genome-wide significance, seven of which were novel and included candidate genes within olfactory receptor clusters as well as GPCR signalling genes such as ADCY2. Sex-stratified analyses identified two female-specific loci and one locus with sex-differential effects implicating androgen response elements in candidate genes. Mendelian randomization analyses revealed a negative causal effect of Alzheimer’s disease risk on overall odor identification while finding no significant causal roles for sex hormones or olfactory performance on neurodegenerative outcomes.
🧠Conclusion:
These discoveries refine our understanding of the genetic architecture of human olfaction and pave the way for targeted molecular investigations into sex-specific sensory mechanisms.
đź“– Reference:
Förster F, Emmert D, Horn K, Pott J, Frasnelli J, Imtiaz MA et al. Genome-wide association meta-analysis of human olfactory identification discovers sex-specific and sex-differential genetic variants. Nat Commun. 2025;16:5434. https://doi.org/10.1038/s41467-025-61330-y
đź“ś License:
This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/
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Transcript
Episode Transcript
Available transcripts are automatically generated. Complete accuracy is not guaranteed.
(00:14):
Welcome to Base by Base, the paper cast that brings genomics
to you wherever you are. Imagine this.
You catch a whiff of freshly baked cookies, and suddenly
you're 7 years old again. Standing in your grandma's
kitchen, or perhaps a particularperfume instantly brings back a
vivid memory, complete with feelings you haven't felt in
years. That's because our sense of
(00:34):
smell isn't just about identifying odors.
It's directly wired to our amygdala, the brains emotional
and memory center. You know, where memories and
emotions get processed. But what if changes in this
incredibly fundamental sense could offer early clues about,
well, serious health issues? Because here's the real world
problem. Olfactory dysfunction, or a loss
of smell isn't just an inconvenience.
(00:55):
It can severely impact quality of life, and it's strongly
linked to serious neurodegenerative diseases like
Parkinson's and Alzheimer's. In fact, for Parkinson's, smell
loss can even precede the motor symptoms by years.
That's that's a powerful signal we often overlook.
So for this deep dive, our mission is to try and uncover
the genetic secrets behind our sense of smell and maybe even
(01:16):
understand why men and women often experience it so
differently. Can genetics really explain
these subtle yet profound differences?
And what does our nose have to tell us about the very earliest
stages of diseases like Alzheimer's?
OK, let's unpack this fascinating mystery.
Today we celebrate the groundbreaking work of France
Fir String colleagues, publishedin Nature Communications on June
19, 2025. This team has really profoundly
(01:39):
advanced our understanding of the genetic basis of human
olfactory perception, taking us a significant step closer to
unlocking the secrets held within our sense of smell.
It's truly a fascinating area, especially given how integral
olfaction is to human experience.
You know, far beyond simply identifying A scent.
That direct neural connection tothe amygdala and the limbic
system? Well, it means smells are deeply
(02:01):
intertwined with our emotional responses, memory formation,
even decision making. Think about it, a negative
association with a smell like something spoiled can lead to a
really powerful avoidance response.
Keeps us safe, right? A primal instinct, almost.
Exactly, and when that sense is impaired it can severely impact
quality of life. Olfactory dysfunction can stem
(02:22):
from various causes, viral infections, head injuries,
sinonasal diseases. But it's most concerning link is
with neurodegenerative conditions.
For example, over 80% of Alzheimer's and Parkinson's
patients experience significant olfactory impairment. 80%,
that's huge. It really is, and what's
particularly striking here is that for Parkinson's, smell loss
frequently appears years before any motor symptoms show up.
(02:45):
Years before, yeah. Making it a critical potential
early marker for the disease. And this leads us to some, well,
truly surprising insights about sex differences, doesn't it?
Oh. Absolutely.
There's this pronounced sexual dimorphism and smell perception.
Generally, women seem to exhibitbetter olfactory identification,
better odor discrimination. Yeah, and they can detect odors
(03:06):
at lower concentrations too, right?
That's right. And existing hypothesis for this
range from, you know, traditional gender roles like
women's historical involvement in food prep to biological
factors like fluctuating sex hormones during the menstrual
cycle. But until now, the idea of gene
by sex interactions, how specific genes might influence
these differences between males and females, that's largely been
(03:28):
unexplored territory. Pretty much, yes.
It's been a gap in our understanding.
And just to set the stage, our ability to smell relies heavily
on olfactory receptors, or ORS. These are a massive family of
genes, actually the largest genefamily in humans with hundreds
of functional receptors. Hundreds.
Wow. Yeah.
They are absolutely crucial for how we perceive smell, acting as
(03:49):
the the initial detectors for the vast array of odors all
around us. So the ambition of the study was
enormous to conduct a comprehensive genome wide
association meta analysis or drama.
This is essentially a massive genetic search across many, many
individuals to pinpoint the specific genetic underpinnings
of human olfactory perception. And crucially, they focus not
(04:11):
just on overall effects, but specifically on sex specific and
sex differential genetic variants.
Meaning how genes might behave differently depending on whether
you're male or female. Exactly.
A really key distinction. This wasn't a small undertaking
either. It was the largest duama of
individual smell identification to date.
We're talking up to 21,495 individuals of European ancestry
(04:34):
across four major cohorts. That's a huge data set to work
with. OK, 21,000 people.
That's impresses kale, and theirprimary tool for measuring smell
was something called the Sniff and Sticks screening test.
Tell us a bit about that. How's it work?
Yes, the sniff and sticks. It's actually quite clever.
It involves a forced choice identification of 12 common
odors, things like orange, cinnamon, pineapple, fish,
(04:58):
pretty recognizable smells. Participants smell a stick and
then have to choose from a list of options what they think the
odor is. It also provides an overall
identification score based on the total number of correct
answers. So.
It gives a quantitative measure.Precisely.
It's a standardized way to quantify someone's ability to
identify specific smells that. Sounds like a robust test.
(05:18):
But beyond the sheer scale of participants, what made this
particular deep dive so powerful?
How did their methodology, you know, push the boundaries to
really unlock these genetic secrets?
Well. They really did innovate first,
as you mentioned, there was thatsheer scale of the meta
analysis, pooling data from multiple studies to get a sample
size never really seen before inthis area.
(05:38):
But beyond that, they introducedthe crucial addition of sex
stratified analysis sex. Stratified, meaning they split
the data. Exactly.
They didn't just look at men andwomen lump together.
They analyzed the genetic data for each sex separately.
This allowed them to investigatehow genetic effects might
actually differ between males and females, a significant leap
(05:58):
from previous studies that oftenjust looked at combined
populations. OK, that.
Makes sense and. They also used advanced
bioinformatic annotation and Co localization analysis, right?
Fancy computer work? Yeah, you could say that these
are sophisticated computational tools that help researchers
identify the specific candidate genes most likely responsible
for the genetic effects they observe.
(06:20):
And it helps explore those elusive Gene Bisex interactions,
too. And perhaps most innovatively,
they used Mendelian randomization or MIS art.
This sounds like a genetic detective to me.
What exactly did it allow them to investigate That's.
A great analogy. Mendelian randomization is
incredibly powerful because it helps distinguish genuine
causation from mere correlation.The classic causation versus
(06:43):
correlation problem. Exactly, which is often a huge
challenge in these complex biological systems.
By using genetic variants as sort of natural randomizations,
they could investigate causal relationships, relationships
between things like sex hormones, olfactory perception,
and those neurodegenerative diseases like Alzheimer's and
Parkinson's. So it helps ask does A cause B
(07:07):
or does B cause A? Or is there maybe something else
connecting them? Precisely, it gets us closer to
understanding the direction of the arrow, so to speak.
So, diving into the key findingsthe study truly delivered, they
discovered 10 independent genetic loci associated with
odor identification 10. New genetic locations.
Well, ten independent loci. And what's remarkable is that
(07:28):
seven of these were entirely novel, never before linked to
Smell 7. Brand new ones, yeah.
These associations involved 5 specific odors and even more
impressively, seven of these loci met a stricter study wide
significance threshold. Meaning the evidence is really
strong. Very strong, yes.
High confidence in those seven and the locations of these
(07:49):
genetic signals make strong biological sense too.
They were predominantly found within clusters of olfactory
receptor genes, the OR genes we mentioned.
Right, that fits perfectly it. Reinforces the idea that these
receptors are absolutely centralto our ability to perceive
specific odors. So what does this all mean for
the mysterious sex differences in smell?
(08:11):
This is where the results becometruly fascinating, right
offering a brand new perspective.
Absolutely, this is a major stepforward.
For the first time, they identified 2 genetic loci that
were distinctly female specific.Female specific, so the effect
only showed up in women. Exactly the genetic effect was
significant only in females. For instance, 1 genetic variant
(08:31):
linked to orange identification showed a 2.88 odds ratio in
females an. Odds ratio of almost three.
What does that mean in simple terms it.
Means women with this specific genetic were almost three times
more likely to correctly identify the smell of orange
compared to women without it. And importantly, this
significant genetic effect was completely absent in males.
(08:51):
No effect whatsoever. Incredible.
And was there anything for males?
Yes. Conversely, 1 locus showed a sex
differential effect. Here.
The genetic impact was notably larger in males, specifically
for identifying the smell of pineapple at locus 9, So.
Not just present absent, but a stronger effect in one sex.
Exactly. So it's clear that genetic
(09:12):
influences on smell are definitely not uniform across
the sexes. That's a huge revelation.
So what's the proposed mechanism?
How could genes have these sex specific effects?
Well, the potential mechanism they propose is quite
compelling. They found that candidate genes
near these sex specific or sex differential loci often contain
something called androgen response elements or AR ES.
(09:34):
Androgen response elements. Androgens are like testosterone,
right? Correct.
These AR ES are specific DNA sequences that can bind to
androgen hormones like testosterone.
This suggests a direct way that sex hormones might influence
gene expression, how active a gene is, and by extension, our
sense of smell. So.
It's like a genetic switch that can be flipped or be turned up
or down by hormones. That's a.
(09:55):
Great way to think about it. Yes, a hormone modulated switch.
OK. Now about those big questions of
cause and effect, hormones, neurodegenerative diseases.
What did Mendelian randomizationthat genetic detective
ultimately reveal? Right, this is where the MRI
analysis gave us some surprisingand actually very important
negative results first. Negative results can be just as
(10:18):
informative, sometimes more so. Absolutely.
The study found no convincing support for a causal influence
of sex hormones like testosterone or estradiol on
overall smell identification. So hormone levels themselves
don't seem to cause the general differences in smell ability at.
Based on this analysis, no causal link was found for
overall identification ability, and crucially, it also found no
(10:41):
support for a causal impact of olfactory impairment on
neurodegenerative diseases like Alzheimer's or Parkinson's.
Wait, so losing your sense of smell doesn't cause Alzheimer's
or Parkinson's? This study provides strong
evidence against that causal direction.
It directly challenges the idea that smell loss itself triggers
these diseases, but. There's a significant causal
(11:01):
link in the other direction, right?
That's a critical distinction. Yes, absolutely.
And this is a key finding. What was robustly and
significantly detected was a negative causal effect of
Alzheimer's disease on overall odor identification.
OK. Break that down.
What does that mean? It means that having a higher
genetic risk for Alzheimer's disease directly contributes at
(11:21):
having poorer smell identification.
The disease process seems to impact smell, not the other way
around. For example, the specific
statistic, the beta coefficient for AD using the standard
definition on the identificationscore was medic in .07 with a
highly significant adjusted P value of 0.009.
So a higher genetic risk for AD leads to a lower smell score.
(11:45):
Precisely, for every increase ingenetic risk for Alzheimer's,
the smell identification score decreased by a notable
statistically significant amount.
This highlights a direct negative impact of AD risk on
smell and. This held true for both sexes.
Yes, this effect was consistent even when looking just at
females, and they even pinpointed a key gene
potentially driving this AD smell Link a variant in the Tom
(12:07):
M40 gene Tom. M40 What does that gene do?
Tom M40 codes for a Translo case.
It's basically a protein involved in importing other
proteins into the mitochondria. Mitochondria that sells
powerhouses. Exactly so the hypothesis here
is that neurodegeneration causedby mitochondrial dysfunction,
perhaps related to this Tom M40 variant, triggers both olfactory
dysfunction and Alzheimer's disease development.
(12:29):
Ah. So it suggests a shared
underlying biological mechanism,not one causing the other, but
both resulting from a common root problem.
That's the strong implication, yes, A shared pathology, rather
than a simple cause and effect chain between smell loss and AD
itself. So what does this all mean for
our understanding of smell and its ties to health?
(12:50):
This study seems to dramaticallyreshape some long held ideas.
It truly does. These findings offer several
important insights. Firstly, they kind of challenge
what's known as the Ototope theory, the.
Ototope theory. Yeah, it suggested that
recognizing an odor relies on a broad activation pattern across
multiple olfactory receptors. The implication was that a
(13:10):
single mutation might affect many odors.
However, most of the genetic loci identified in this study
affected single odors, not multiple ones.
It suggests a much more nuanced,maybe more precise, genetic
control over our smell perception than previously
thought. Even the overall identification
score seemed largely driven by the strong signal from just one
(13:32):
odor, pineapple, not a compositeof many different odors.
That's. A fascinating paradigm shift.
So what does this new understanding tell us about the
tools we use to study smell? Like the sniff and sticks test
you mentioned. Well, it certainly highlights
some limitations. While useful, the sniff and
sticks test itself represents only a tiny, tiny fraction of
the vast human odor spectrum. How vast are we talking?
(13:55):
Some estimates suggest we might distinguish over a trillion
different stimuli A. Trillion.
Wow. OK, 12 is definitely a small
sample then. Exactly.
And the test is also culturally biased, designed primarily for
European populations and it tends to over represent
nutrition related smells. This might explain why genes
involved in maybe more general odor perception like a gene
(14:16):
called ADCY 3 involved in broad cellular signaling weren't
strongly detected here. So.
We might need larger studies with a much broader, more
diverse set of odors to find those more universal genetic
links. That seems likely, yes.
The candidate genes they did identify broadly fall into about
three groups. You have the olfactory receptors
themselves, which makes sense. Then you have genes involved in
(14:38):
what's called GPC or downstream signaling pathways like Adcy 2,
and finally genes affecting higher neuronal function or
neurogenesis, things like brain development and neural growth
such as GSX 2 and FBXL 17. But the strongest effects were
in the O Rs. Yes, the strongest effects, as
you might anticipate, were foundin those OR clusters, confirming
(14:58):
their central role. And Speaking of those sex
specific findings, especially with the androgen response
elements, the AR ES, how do we move forward?
How can we understand those better and really grasp these
sex differences at a deeper level?
That's a key question. The presence of these sex
differential and sex specific variants strongly suggests that
genetic mechanisms are significant contributors to the
(15:19):
observed sex differences in smell.
The fact that AR ES were found near candidate genes like
ORS&ADCY 2 is a plausible explanation.
A good hypothesis, but we reallyneed experimental confirmation.
So lab work basically. Exactly functional assays using
cell cultures for example, you could expand these to include
varying levels of sex hormones, testosterone, estrogen, and
(15:42):
actually observe their direct impact on receptor activity or
expression in a controlled environment.
See if the hormones flip those switches and.
What about genes further down the processing chain, like a DC
Y2 or GSX 2? Yeah, for those investigating
their roles would likely requirein vivo models, probably animal
studies. Although it's worth noting that
cross species translation from say, mice to humans is pretty
(16:04):
complex for smell because there are significant evolutionary
divergences. So that's always a challenge,
right? So this raises an important
question. If the Mendelian randomization
analysis indicated that general sex hormone levels don't cause
the overall smell differences, these hormone response elements
are present near important smellgenes.
What's really happening? Is it less about the level of
(16:24):
hormones circulating and more about how individual genes
respond to them? That's a great.
Point, and it highlights the complexity.
While the Mr. analysis found no causal link between general
hormone levels and overall smellidentification, there are
caveats for estrogen in women. For instance, the study had
limitations because many participants were postmenopausal
(16:45):
and had undetectable estrogen levels.
So. That might have masked some
effects it might have. Yes, future studies really need
to address this, maybe by focusing specifically on
premenopausal women or stratifying by hormone levels
more carefully to fully explore estrogens role.
It suggests the interaction might be more complex than just
a simple direct dose response across the whole population.
(17:06):
It could be about timing or tissue specific responses, or
how sensitive an individual's receptors are.
OK. And.
Turning back to the Alzheimer's smell link, what are the next
steps there? Well, definitely.
Aiming to replicate that robust causal effect of AD risk on
olfaction, especially exploring how this manifests in
individuals with mild cognitive impairment or MCIMCI being a.
(17:28):
Potential preclinical stage for Alzheimer's?
Exactly. Understanding it at that early
stage is crucial. And then more molecular research
on Tom M40 and the role of mitochondrial dysfunction in the
shared pathology of smell loss in Alzheimer's is absolutely
vital. If we can understand that shared
mechanism better, it could unlock completely new
therapeutic targets for potentially treating or
(17:50):
preventing both issues. And it's always important.
To acknowledge a study's limitations, what were some of
the key areas where this research could be expanded in
the future, besides needing moresmells?
Well, as you said. The relatively small number of
odors tested due to cost and complexity that definitely
limited statistical power, especially for those really
specific sex. Stratified analysis and the
(18:12):
focus on European ancestry is a big one.
Cultural background influences smell, exposure and maybe even
perception. So we need studies and more
diverse population makes sense. Also the lack of gene
environment interaction data is another area ripe for future
exploration. How does our environment,
pollutants, diet, infections interact with our genes to
affect our sense of smell? We don't know much about that
(18:32):
yet. OK, so to.
Sum it up all up then. This monumental deep dive into
the genetics of smell has truly expanded our understanding,
hasn't it? It uncovered 7 entirely novel
genetic variants tied to how we perceive specific odors.
And for the first time, it showed us clear sex specific and
sex differential genetic effects.
Possibly links to how our bodiesrespond to hormones like
(18:54):
testosterone. It really reshapes our
understanding of how granular and precise our genetic control
over smell truly is. More specific than we thought?
Absolutely. And perhaps most importantly,
while it didn't find evidence that our sense of smell causes
neurodegenerative diseases like Alzheimer's, it strongly
confirmed a robust causal link in the other direction.
(19:15):
Having a genetic predisposition to Alzheimer's disease appears
to directly impact your overall ability to identify odors.
This point strongly towards a shared underlying mechanism,
likely involving mitochondrial dysfunction, that researchers
can now focus on and potentiallytarget In both conditions, it's
a really powerful genetic clue. So what does?
This mean for how we might one day use simple smell tests,
maybe not just as a diagnostic flag for potential
(19:37):
neurodegenerative disease, but perhaps as a window into the
underlying biological processes of these really complex
conditions. Definitely something to Mull
over until our next deep dive. 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. If you enjoy this analysis, the
(19:57):
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your favorite podcast app and leave us a five star rating.
It only takes a few seconds but makes a huge difference in
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Thanks for listening and join usnext time as we explore more
science base by Base.
Welcome to Base by Base, the paper cast that brings genomics
to you wherever you are. Imagine this.
You catch a whiff of freshly baked cookies, and suddenly
you're 7 years old again. Standing in your grandma's
kitchen, or perhaps a particularperfume instantly brings back a
vivid memory, complete with feelings you haven't felt in
years. That's because our sense of
(00:34):
smell isn't just about identifying odors.
It's directly wired to our amygdala, the brains emotional
and memory center. You know, where memories and
emotions get processed. But what if changes in this
incredibly fundamental sense could offer early clues about,
well, serious health issues? Because here's the real world
problem. Olfactory dysfunction, or a loss
of smell isn't just an inconvenience.
(00:55):
It can severely impact quality of life, and it's strongly
linked to serious neurodegenerative diseases like
Parkinson's and Alzheimer's. In fact, for Parkinson's, smell
loss can even precede the motor symptoms by years.
That's that's a powerful signal we often overlook.
So for this deep dive, our mission is to try and uncover
the genetic secrets behind our sense of smell and maybe even
(01:16):
understand why men and women often experience it so
differently. Can genetics really explain
these subtle yet profound differences?
And what does our nose have to tell us about the very earliest
stages of diseases like Alzheimer's?
OK, let's unpack this fascinating mystery.
Today we celebrate the groundbreaking work of France
Fir String colleagues, publishedin Nature Communications on June
19, 2025. This team has really profoundly
(01:39):
advanced our understanding of the genetic basis of human
olfactory perception, taking us a significant step closer to
unlocking the secrets held within our sense of smell.
It's truly a fascinating area, especially given how integral
olfaction is to human experience.
You know, far beyond simply identifying A scent.
That direct neural connection tothe amygdala and the limbic
system? Well, it means smells are deeply
(02:01):
intertwined with our emotional responses, memory formation,
even decision making. Think about it, a negative
association with a smell like something spoiled can lead to a
really powerful avoidance response.
Keeps us safe, right? A primal instinct, almost.
Exactly, and when that sense is impaired it can severely impact
quality of life. Olfactory dysfunction can stem
(02:22):
from various causes, viral infections, head injuries,
sinonasal diseases. But it's most concerning link is
with neurodegenerative conditions.
For example, over 80% of Alzheimer's and Parkinson's
patients experience significant olfactory impairment. 80%,
that's huge. It really is, and what's
particularly striking here is that for Parkinson's, smell loss
frequently appears years before any motor symptoms show up.
(02:45):
Years before, yeah. Making it a critical potential
early marker for the disease. And this leads us to some, well,
truly surprising insights about sex differences, doesn't it?
Oh. Absolutely.
There's this pronounced sexual dimorphism and smell perception.
Generally, women seem to exhibitbetter olfactory identification,
better odor discrimination. Yeah, and they can detect odors
(03:06):
at lower concentrations too, right?
That's right. And existing hypothesis for this
range from, you know, traditional gender roles like
women's historical involvement in food prep to biological
factors like fluctuating sex hormones during the menstrual
cycle. But until now, the idea of gene
by sex interactions, how specific genes might influence
these differences between males and females, that's largely been
(03:28):
unexplored territory. Pretty much, yes.
It's been a gap in our understanding.
And just to set the stage, our ability to smell relies heavily
on olfactory receptors, or ORS. These are a massive family of
genes, actually the largest genefamily in humans with hundreds
of functional receptors. Hundreds.
Wow. Yeah.
They are absolutely crucial for how we perceive smell, acting as
(03:49):
the the initial detectors for the vast array of odors all
around us. So the ambition of the study was
enormous to conduct a comprehensive genome wide
association meta analysis or drama.
This is essentially a massive genetic search across many, many
individuals to pinpoint the specific genetic underpinnings
of human olfactory perception. And crucially, they focus not
(04:11):
just on overall effects, but specifically on sex specific and
sex differential genetic variants.
Meaning how genes might behave differently depending on whether
you're male or female. Exactly.
A really key distinction. This wasn't a small undertaking
either. It was the largest duama of
individual smell identification to date.
We're talking up to 21,495 individuals of European ancestry
(04:34):
across four major cohorts. That's a huge data set to work
with. OK, 21,000 people.
That's impresses kale, and theirprimary tool for measuring smell
was something called the Sniff and Sticks screening test.
Tell us a bit about that. How's it work?
Yes, the sniff and sticks. It's actually quite clever.
It involves a forced choice identification of 12 common
odors, things like orange, cinnamon, pineapple, fish,
(04:58):
pretty recognizable smells. Participants smell a stick and
then have to choose from a list of options what they think the
odor is. It also provides an overall
identification score based on the total number of correct
answers. So.
It gives a quantitative measure.Precisely.
It's a standardized way to quantify someone's ability to
identify specific smells that. Sounds like a robust test.
(05:18):
But beyond the sheer scale of participants, what made this
particular deep dive so powerful?
How did their methodology, you know, push the boundaries to
really unlock these genetic secrets?
Well. They really did innovate first,
as you mentioned, there was thatsheer scale of the meta
analysis, pooling data from multiple studies to get a sample
size never really seen before inthis area.
(05:38):
But beyond that, they introducedthe crucial addition of sex
stratified analysis sex. Stratified, meaning they split
the data. Exactly.
They didn't just look at men andwomen lump together.
They analyzed the genetic data for each sex separately.
This allowed them to investigatehow genetic effects might
actually differ between males and females, a significant leap
(05:58):
from previous studies that oftenjust looked at combined
populations. OK, that.
Makes sense and. They also used advanced
bioinformatic annotation and Co localization analysis, right?
Fancy computer work? Yeah, you could say that these
are sophisticated computational tools that help researchers
identify the specific candidate genes most likely responsible
for the genetic effects they observe.
(06:20):
And it helps explore those elusive Gene Bisex interactions,
too. And perhaps most innovatively,
they used Mendelian randomization or MIS art.
This sounds like a genetic detective to me.
What exactly did it allow them to investigate That's.
A great analogy. Mendelian randomization is
incredibly powerful because it helps distinguish genuine
causation from mere correlation.The classic causation versus
(06:43):
correlation problem. Exactly, which is often a huge
challenge in these complex biological systems.
By using genetic variants as sort of natural randomizations,
they could investigate causal relationships, relationships
between things like sex hormones, olfactory perception,
and those neurodegenerative diseases like Alzheimer's and
Parkinson's. So it helps ask does A cause B
(07:07):
or does B cause A? Or is there maybe something else
connecting them? Precisely, it gets us closer to
understanding the direction of the arrow, so to speak.
So, diving into the key findingsthe study truly delivered, they
discovered 10 independent genetic loci associated with
odor identification 10. New genetic locations.
Well, ten independent loci. And what's remarkable is that
(07:28):
seven of these were entirely novel, never before linked to
Smell 7. Brand new ones, yeah.
These associations involved 5 specific odors and even more
impressively, seven of these loci met a stricter study wide
significance threshold. Meaning the evidence is really
strong. Very strong, yes.
High confidence in those seven and the locations of these
(07:49):
genetic signals make strong biological sense too.
They were predominantly found within clusters of olfactory
receptor genes, the OR genes we mentioned.
Right, that fits perfectly it. Reinforces the idea that these
receptors are absolutely centralto our ability to perceive
specific odors. So what does this all mean for
the mysterious sex differences in smell?
(08:11):
This is where the results becometruly fascinating, right
offering a brand new perspective.
Absolutely, this is a major stepforward.
For the first time, they identified 2 genetic loci that
were distinctly female specific.Female specific, so the effect
only showed up in women. Exactly the genetic effect was
significant only in females. For instance, 1 genetic variant
(08:31):
linked to orange identification showed a 2.88 odds ratio in
females an. Odds ratio of almost three.
What does that mean in simple terms it.
Means women with this specific genetic were almost three times
more likely to correctly identify the smell of orange
compared to women without it. And importantly, this
significant genetic effect was completely absent in males.
(08:51):
No effect whatsoever. Incredible.
And was there anything for males?
Yes. Conversely, 1 locus showed a sex
differential effect. Here.
The genetic impact was notably larger in males, specifically
for identifying the smell of pineapple at locus 9, So.
Not just present absent, but a stronger effect in one sex.
Exactly. So it's clear that genetic
(09:12):
influences on smell are definitely not uniform across
the sexes. That's a huge revelation.
So what's the proposed mechanism?
How could genes have these sex specific effects?
Well, the potential mechanism they propose is quite
compelling. They found that candidate genes
near these sex specific or sex differential loci often contain
something called androgen response elements or AR ES.
(09:34):
Androgen response elements. Androgens are like testosterone,
right? Correct.
These AR ES are specific DNA sequences that can bind to
androgen hormones like testosterone.
This suggests a direct way that sex hormones might influence
gene expression, how active a gene is, and by extension, our
sense of smell. So.
It's like a genetic switch that can be flipped or be turned up
or down by hormones. That's a.
(09:55):
Great way to think about it. Yes, a hormone modulated switch.
OK. Now about those big questions of
cause and effect, hormones, neurodegenerative diseases.
What did Mendelian randomizationthat genetic detective
ultimately reveal? Right, this is where the MRI
analysis gave us some surprisingand actually very important
negative results first. Negative results can be just as
(10:18):
informative, sometimes more so. Absolutely.
The study found no convincing support for a causal influence
of sex hormones like testosterone or estradiol on
overall smell identification. So hormone levels themselves
don't seem to cause the general differences in smell ability at.
Based on this analysis, no causal link was found for
overall identification ability, and crucially, it also found no
(10:41):
support for a causal impact of olfactory impairment on
neurodegenerative diseases like Alzheimer's or Parkinson's.
Wait, so losing your sense of smell doesn't cause Alzheimer's
or Parkinson's? This study provides strong
evidence against that causal direction.
It directly challenges the idea that smell loss itself triggers
these diseases, but. There's a significant causal
(11:01):
link in the other direction, right?
That's a critical distinction. Yes, absolutely.
And this is a key finding. What was robustly and
significantly detected was a negative causal effect of
Alzheimer's disease on overall odor identification.
OK. Break that down.
What does that mean? It means that having a higher
genetic risk for Alzheimer's disease directly contributes at
(11:21):
having poorer smell identification.
The disease process seems to impact smell, not the other way
around. For example, the specific
statistic, the beta coefficient for AD using the standard
definition on the identificationscore was medic in .07 with a
highly significant adjusted P value of 0.009.
So a higher genetic risk for AD leads to a lower smell score.
(11:45):
Precisely, for every increase ingenetic risk for Alzheimer's,
the smell identification score decreased by a notable
statistically significant amount.
This highlights a direct negative impact of AD risk on
smell and. This held true for both sexes.
Yes, this effect was consistent even when looking just at
females, and they even pinpointed a key gene
potentially driving this AD smell Link a variant in the Tom
(12:07):
M40 gene Tom. M40 What does that gene do?
Tom M40 codes for a Translo case.
It's basically a protein involved in importing other
proteins into the mitochondria. Mitochondria that sells
powerhouses. Exactly so the hypothesis here
is that neurodegeneration causedby mitochondrial dysfunction,
perhaps related to this Tom M40 variant, triggers both olfactory
dysfunction and Alzheimer's disease development.
(12:29):
Ah. So it suggests a shared
underlying biological mechanism,not one causing the other, but
both resulting from a common root problem.
That's the strong implication, yes, A shared pathology, rather
than a simple cause and effect chain between smell loss and AD
itself. So what does this all mean for
our understanding of smell and its ties to health?
(12:50):
This study seems to dramaticallyreshape some long held ideas.
It truly does. These findings offer several
important insights. Firstly, they kind of challenge
what's known as the Ototope theory, the.
Ototope theory. Yeah, it suggested that
recognizing an odor relies on a broad activation pattern across
multiple olfactory receptors. The implication was that a
(13:10):
single mutation might affect many odors.
However, most of the genetic loci identified in this study
affected single odors, not multiple ones.
It suggests a much more nuanced,maybe more precise, genetic
control over our smell perception than previously
thought. Even the overall identification
score seemed largely driven by the strong signal from just one
(13:32):
odor, pineapple, not a compositeof many different odors.
That's. A fascinating paradigm shift.
So what does this new understanding tell us about the
tools we use to study smell? Like the sniff and sticks test
you mentioned. Well, it certainly highlights
some limitations. While useful, the sniff and
sticks test itself represents only a tiny, tiny fraction of
the vast human odor spectrum. How vast are we talking?
(13:55):
Some estimates suggest we might distinguish over a trillion
different stimuli A. Trillion.
Wow. OK, 12 is definitely a small
sample then. Exactly.
And the test is also culturally biased, designed primarily for
European populations and it tends to over represent
nutrition related smells. This might explain why genes
involved in maybe more general odor perception like a gene
(14:16):
called ADCY 3 involved in broad cellular signaling weren't
strongly detected here. So.
We might need larger studies with a much broader, more
diverse set of odors to find those more universal genetic
links. That seems likely, yes.
The candidate genes they did identify broadly fall into about
three groups. You have the olfactory receptors
themselves, which makes sense. Then you have genes involved in
(14:38):
what's called GPC or downstream signaling pathways like Adcy 2,
and finally genes affecting higher neuronal function or
neurogenesis, things like brain development and neural growth
such as GSX 2 and FBXL 17. But the strongest effects were
in the O Rs. Yes, the strongest effects, as
you might anticipate, were foundin those OR clusters, confirming
(14:58):
their central role. And Speaking of those sex
specific findings, especially with the androgen response
elements, the AR ES, how do we move forward?
How can we understand those better and really grasp these
sex differences at a deeper level?
That's a key question. The presence of these sex
differential and sex specific variants strongly suggests that
genetic mechanisms are significant contributors to the
(15:19):
observed sex differences in smell.
The fact that AR ES were found near candidate genes like
ORS&ADCY 2 is a plausible explanation.
A good hypothesis, but we reallyneed experimental confirmation.
So lab work basically. Exactly functional assays using
cell cultures for example, you could expand these to include
varying levels of sex hormones, testosterone, estrogen, and
(15:42):
actually observe their direct impact on receptor activity or
expression in a controlled environment.
See if the hormones flip those switches and.
What about genes further down the processing chain, like a DC
Y2 or GSX 2? Yeah, for those investigating
their roles would likely requirein vivo models, probably animal
studies. Although it's worth noting that
cross species translation from say, mice to humans is pretty
(16:04):
complex for smell because there are significant evolutionary
divergences. So that's always a challenge,
right? So this raises an important
question. If the Mendelian randomization
analysis indicated that general sex hormone levels don't cause
the overall smell differences, these hormone response elements
are present near important smellgenes.
What's really happening? Is it less about the level of
(16:24):
hormones circulating and more about how individual genes
respond to them? That's a great.
Point, and it highlights the complexity.
While the Mr. analysis found no causal link between general
hormone levels and overall smellidentification, there are
caveats for estrogen in women. For instance, the study had
limitations because many participants were postmenopausal
(16:45):
and had undetectable estrogen levels.
So. That might have masked some
effects it might have. Yes, future studies really need
to address this, maybe by focusing specifically on
premenopausal women or stratifying by hormone levels
more carefully to fully explore estrogens role.
It suggests the interaction might be more complex than just
a simple direct dose response across the whole population.
(17:06):
It could be about timing or tissue specific responses, or
how sensitive an individual's receptors are.
OK. And.
Turning back to the Alzheimer's smell link, what are the next
steps there? Well, definitely.
Aiming to replicate that robust causal effect of AD risk on
olfaction, especially exploring how this manifests in
individuals with mild cognitive impairment or MCIMCI being a.
(17:28):
Potential preclinical stage for Alzheimer's?
Exactly. Understanding it at that early
stage is crucial. And then more molecular research
on Tom M40 and the role of mitochondrial dysfunction in the
shared pathology of smell loss in Alzheimer's is absolutely
vital. If we can understand that shared
mechanism better, it could unlock completely new
therapeutic targets for potentially treating or
(17:50):
preventing both issues. And it's always important.
To acknowledge a study's limitations, what were some of
the key areas where this research could be expanded in
the future, besides needing moresmells?
Well, as you said. The relatively small number of
odors tested due to cost and complexity that definitely
limited statistical power, especially for those really
specific sex. Stratified analysis and the
(18:12):
focus on European ancestry is a big one.
Cultural background influences smell, exposure and maybe even
perception. So we need studies and more
diverse population makes sense. Also the lack of gene
environment interaction data is another area ripe for future
exploration. How does our environment,
pollutants, diet, infections interact with our genes to
affect our sense of smell? We don't know much about that
(18:32):
yet. OK, so to.
Sum it up all up then. This monumental deep dive into
the genetics of smell has truly expanded our understanding,
hasn't it? It uncovered 7 entirely novel
genetic variants tied to how we perceive specific odors.
And for the first time, it showed us clear sex specific and
sex differential genetic effects.
Possibly links to how our bodiesrespond to hormones like
(18:54):
testosterone. It really reshapes our
understanding of how granular and precise our genetic control
over smell truly is. More specific than we thought?
Absolutely. And perhaps most importantly,
while it didn't find evidence that our sense of smell causes
neurodegenerative diseases like Alzheimer's, it strongly
confirmed a robust causal link in the other direction.
(19:15):
Having a genetic predisposition to Alzheimer's disease appears
to directly impact your overall ability to identify odors.
This point strongly towards a shared underlying mechanism,
likely involving mitochondrial dysfunction, that researchers
can now focus on and potentiallytarget In both conditions, it's
a really powerful genetic clue. So what does?
This mean for how we might one day use simple smell tests,
maybe not just as a diagnostic flag for potential
(19:37):
neurodegenerative disease, but perhaps as a window into the
underlying biological processes of these really complex
conditions. Definitely something to Mull
over until our next deep dive. 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. If you enjoy this analysis, the
(19:57):
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Thanks for listening and join usnext time as we explore more
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