About a month ago, after some back-and-forth with several people about their experiences (including on lesswrong), I hypothesized that I don’t feel the emotions signalled by oxytocin, and never have. (I do feel some adjacent things, like empathy and a sense of responsibility for others, but I don’t get the feeling of loving connection which usually comes alongside those.)
Naturally I set out to test that hypothesis. This note is an in-progress overview of what I’ve found so far and how I’m thinking about it, written largely to collect my thoughts and to see if anyone catches something I’ve missed.
Under the hypothesis, this has been a life-long thing for me, so the obvious guess is that it’s genetic (the vast majority of other biological state turns over too often to last throughout life). I also don’t have a slew of mysterious life-long illnesses, so the obvious guess is that’s it’s pretty narrowly limited to oxytocin—i.e. most likely a genetic variant in either the oxytocin gene or receptor, maybe the regulatory machinery around those two but that’s less likely as we get further away and the machinery becomes entangled with more other things.
So I got my genome sequenced, and went looking at the oxytocin gene and the oxytocin receptor gene.
The receptor was the first one I checked, and sure enough I have a single-nucleotide deletion 42 amino acids in to the open reading frame (ORF) of the 389 amino acid protein. That will induce a frameshift error, completely fucking up the rest of protein. (The oxytocin gene, on the other hand, was totally normal.)
So that sure is damn strong evidence in favor of the hypothesis! But, we have two copies of most genes, including the oxytocin receptor. The frameshift error is only on one copy. Why isn’t the other copy enough for almost-normal oxytocin signalling?
The frameshift error is the only thing I have which would obviously completely fuck up the whole protein, but there are also a couple nonsynonymous single nucleotide polymorphisms (SNPs) in the ORF, plus another couple upstream. So it’s plausible that one of the SNPs messes up the other copy pretty badly; in particular, one of them changes an arginine to a histidine at the edge of the second intracellular loop. (Oxytocin receptor is a pretty standard g-protein coupled receptor, so that’s the mental picture here.) I did drop the sequences into alphafold, and I don’t see any large structural variation from the SNPs, but (a) that histidine substitution would most likely change binding rather than structure in isolation, and (b) this is exactly the sort of case where I don’t trust alphafold much, because “this is one substitution away from a standard sequence, I’ll just output the structure of that standard sequence” is exactly the sort of heuristic I’d expect a net to over-rely upon.
It’s also possible-in-principle that the second receptor copy is fine, but the first copy frameshift alone is enough to mess up function. I think that’s unlikely in this case. The mRNA for the frameshifted version should be removed pretty quickly by nonsense-mediated decay (I did double check that it has a bunch of early stop codons, NMD should definitely trigger). So there should not be a bunch of junk protein floating around from the frameshifted gene. And the frameshift is early enough that the messed up proteins probably won’t e.g. form dimers with structurally-non-messed-up versions (even if oxytocin receptor normally dimerizes, which I’d guess it doesn’t but haven’t checked). At worst there should just be a 2x lower concentration of normal receptor than usual, and if there’s any stable feedback control on the receptor concentration then there’d be hardly any effect at all.
Finally, there’s the alternative hypothesis that my oxytocin signalling is unusually weak but not entirely nonfunctional. I do now have pretty damn strong evidence for that at a bare minimum, assuming that feedback control on receptor density doesn’t basically counterbalance the fucked up receptor copy.
Anyway, that’s where I’m currently at. I’m curious to hear others’ thoughts on what mechanisms I might be missing here!
The receptor was the first one I checked, and sure enough I have a single-nucleotide deletion 42 amino acids in to the open reading frame (ORF) of the 389 amino acid protein. That will induce a frameshift error, completely fucking up the rest of protein.
I’m kind of astonished that this kind of advance prediction panned out!
I admit I was somewhat surprised as well. On a gut level, I did not think that the very first things to check would turn up such a clear and simple answer.
I’m insufficiently knowledgeable about deletion base rates to know how astonished to be. Does anyone have an estimate of how many Bayes bits such a prediction is worth?
FWIW, GPT-5T estimates around 10 bits, double that if it’s de novo (absent in both parents).
This might be a bad idea right now, if it makes John’s interests suddenly more normal in a mostly-unsteered way, eg because much of his motivation was coming from a feeling he didn’t know was oxytocin-deficiency-induced. I’d suggest only doing this if solving this problem is likely to increase productivity or networking success; else, I’d delay until he doesn’t seem like a critical bottleneck. That said, it might also be a very good idea, if depression or social interaction are a major bottleneck, which they are for many many people, so this is not resolved advice, just a warning that this may be a high variance intervention, and since John currently seems to be doing promising work, introducing high variance seems likely to have more downside.
I wouldn’t say this to most people; taking oxytocin isn’t known for being a hugely impactful intervention[citation needed], and on priors, someone who doesn’t have oxytocin signaling happening is missing a lot of normal emotion, and is likely much worse off. Obviously, John, it’s up to you whether this is a good tradeoff. I wouldn’t expect it to completely distort your values or delete your skills. Someone who knows you better, such as yourself, would be much better equipped to predict if there’s significant reason to believe downward variance isn’t present. If you have experience with reward-psychoactive chemicals and yet are currently productive, it’s more likely you already know whether it’s a bad idea.
Seems like that depends on details of the problem. If the receptor has zero function, then yes. If functionality is significantly reduced but nonzero… maybe.
Perhaps Gurkenglas meant this is as a ~confirmatory test that John is actually oxytocin-insensitive because the test results (IIUC) are compatible with only one gene copy being screwed up.
I ordered this one off of amazon. AFAICT it does nothing for me. But that’s a pretty minor update, because even those who use it say the effects are “subtle”, and frankly I think snorting oxytocin is probably bullshit and does nothing beyond placebo even for normal people. I did have a couple other people try the one I bought, and their results indeed sounded like a nothingburder.
<a href="https://One other thing - labs typically filter reportable genome results by the phenotype you give them. I don’t know how this guy did the genome, but if he were to put something like “social deficits”, “emotional dysregulation” or something else about his lack of emotional range, the lab would definitely report the variant plus their research on it and recommendations.">this one</a>
BTW, has anyone on LW tried oxytocin and is willing to report on the experience?
Not directly related to your query, but seems interesting:
The receptor was the first one I checked, and sure enough I have a single-nucleotide deletion 42 amino acids in to the open reading frame (ORF) of the 389 amino acid protein. That will induce a frameshift error, completely fucking up the rest of protein.
Which, in turn, is pretty solid evidence for “oxytocin mediates the emotion of loving connection/aching affection” (unless there are some mechanisms you’ve missed). I wouldn’t have guessed it’s that simple.
Generalizing, this suggests we can study links between specific brain chemicals/structures and cognitive features by looking for people missing the same universal experience, checking if their genomes deviate from the baseline in the same way, then modeling the effects of that deviation on the brain. Alternatively, the opposite: search for people whose brain chemistry should be genetically near-equivalent except for one specific change, then exhaustively check if there’s some blatant or subtle way their cognition differs from the baseline.
Doing a brief literature review via GPT-5, apparently this sort of thing is mostly done with regards to very “loud” conditions, rather than in an attempt to map out the brain in general. I could imagine that it won’t turn out that simple in practice, but the actual bottleneck is probably researchers with a good enough theory-of-mind to correctly figure out the subtle ways the subjects’ cognition differs (easy for “severe autism”, much harder for “I feel empathy and responsibility, but not loving connection”).
~Surely there’s a lot of other things involved in mediating this aspect of human cognition, at the very least (/speaking very coarse-grainedly), having the entire oxytocin system adequately hooked up to the rest of everything.
IE it is damn strong evidence that oxytocin signalinf is strictly necessary (and that there’s no fallback mechanisms wtc) but not that it’s simple.
Did your mother think you were unusual as a baby? Did you bond with your parents as a young child? I’d expect there to be some symptoms there if you truly have an oxytocin abnormality.
For my family this is much more of a “wow that makes so much sense” than a “wow what a surprise”. It tracks extremely well with how I acted growing up, in a bunch of different little ways. Indeed, once the hypothesis was on my radar at all, it quickly seemed pretty probable on that basis alone, even before sequencing came back.
A few details/examples:
As a child, I had a very noticeable lack of interest in other people (especially those my own age), to the point where a school psychologist thought it was notable.
I remember being unusually eager to go off to overnight summer camp (without my parents), at an age where nobody bothered to provide overnight summer camp because kids that young were almost all too anxious to be away from their parents that long.
When family members or pets died, I’ve generally been noticeably less emotionally impacted than the rest of the family.
When out and about with the family, I’ve always tended to wander around relatively independently of the rest of the group.
Those examples are relatively easy to explain, but most of my bits here come from less legible things. It’s been very clear for a long time that I relate to other people unusually, in a way that intuitively matches being at the far low end of the oxytocin signalling axis.
Though beyond a certain level of development we have numerous other drives beyond the oxytocin-related ones. Hence why you-as-a-baby might be particularly telling. From what I understand, oxytocin is heavily involved in infant-caregiver bonding and is what enables mothers to soothe their babies so effectively (very much on my mind right now as I am typing this comment while a baby naps on me haha).
Whereas once you’re above a certain age, the rational mind and other traits probably have an increasingly strong effect. For example, if you’re very interested in your own thoughts and ideas, this might overwhelm your desire to be close to family members.
Anyway, it seems likely that your oxytocin hypothesis is correct either way. Cool finding!
I have a similar intuition about how some other people are missing a disgust response that I have. Seems like a biological thing that some people have much less of than others and it has a significant effect on how we relate to others.
Is that frame-shift error or those ~6 (?) SNPs previously reported in the literature for anything, or do they seem to be de novos? Also, what WGS depth did your service use? (Depending on how widely you cast your net, some of those could be spurious sequencing errors.)
Depth is tagged on each individual variation; the frame shift has depth 41, the others have depth anywhere from 40 to 60.
I have not found the frameshift mutation in dbSNP, but I’m not confident that I’ve understood the UI or intended usage patterns, so I’m not confident it’s not in there. The SNPs I haven’t looked for in there yet.
Really interesting post—this actually connects to some research I’ve been looking into recently around oxytocin and attachment patterns.
There’s this psychologist Adam Lane Smith who’s built on neurobiological work by researchers like Carolyn Zahn-Waxler and Ruth Feldman—they’ve found that under high stress conditions when younger, or absence of secure attachment figures, cortisol-induced stress actually strengthens cortisol and dopamine pathways for reward while inhibiting the oxytocin and serotonin pathways. The end result (avoidant attachment) sounds remarkably similar to what you’re describing: people who clearly care about others and feel responsibility, but don’t experience that warm “loving connection” feeling that most people seem to get from relationships.
What struck me about your situation is that you’ve essentially got the genetic version of what this research suggests can happen environmentally. Both paths seem to lead to the same place—having to navigate social connection through pattern recognition and cognitive analysis rather than emotional intuition, because your brain is essentially running on dopamine-driven systems instead of oxytocin-based ones.
Makes me wonder if there’s a whole spectrum of people out there—some genetic, some developmental—who are all essentially operating with similar neurochemical profiles but don’t realize they’re part of the same phenomenon. Your case might be the key to understanding how this actually works at a biological level.
Do you find you’ve gotten really good at reading people through behavioral patterns rather than gut feelings?
this is exactly the sort of case where I don’t trust alphafold much, because “this is one substitution away from a standard sequence, I’ll just output the structure of that standard sequence” is exactly the sort of heuristic I’d expect a net to over-rely upon.
Yep. AlphaMissense, also from DeepMind, is tailored to pathogenicity prediction. You can find its pathogenicity scores in the annotations tab for any (at least I think any) human protein on AFDB.
As a non-subject matter expert in all of the above, I decided to consult my swear-word-adverse relative that recently graduated genetic counseling school. Here is her response:
The logic is sound (if a little colorful haha 😅). It sounds like this guy functionally only has 1 copy of the OXTR gene, and spot on in hypothesis of nonsense-mediated decay.
How the OXTR gene is regulated, I don’t know and haven’t looked into. It would be weird (but possible) for a decrease in OXTR expression to only affect emotions—oxytocin is also important for other brain functions/development, so a genetic change should also impact embryological development of the brain. So if I were to suggest next steps, it would be doing functional studies of the brain (like an MRI) to further evaluate.
One other thing—labs typically filter reportable genome results by the phenotype you give them. I don’t know how this guy did the genome, but if he were to put something like “social deficits”, “emotional dysregulation” or something else about his lack of emotional range, the lab would definitely report the variant plus their research on it and recommendations.
Huh interesting. I might get myself full genome sequenced at some point. I already got myself 23andme sequenced, downloaded the raw data, and put it into promethease a while ago. I did find out I’m AG at rs53576 which is slightly linked to lower empathy, but is also extremely common. I don’t think this is enough to explain a large proportion of my personality, the way your OXTR deletion might be.
(There was something quite amusing to check my SNPs checking whether to start early anti-balding interventions, and have result number 1 be “Low Empathy”. As a further datapoint, I mentioned this to my mum and she basically said “Yeah but what did you expect with me and [dad] as parents?”)
Seeing this
A few details/examples:
As a child, I had a very noticeable lack of interest in other people (especially those my own age), to the point where a school psychologist thought it was notable.
I remember being unusually eager to go off to overnight summer camp (without my parents), at an age where nobody bothered to provide overnight summer camp because kids that young were almost all too anxious to be away from their parents that long.
When family members or pets died, I’ve generally been noticeably less emotionally impacted than the rest of the family.
When out and about with the family, I’ve always tended to wander around relatively independently of the rest of the group.
Made me think I should take a deeper look. This all sounds pretty familiar, and I don’t think the AG in rs53576 is strong enough to shift me off-distribution to the degree that I am.
If the one clearly fucked up receptor copy is sufficient for your “symptoms”, it seems pretty likely that one of your parents should have them too. I think there is no reason to expect a denovo mutation to be particularly likely in your case (unlike in cases that lead to severe disfunction). And of course you can check for that by sequencing your parents.
So my money would be on the second copy also being sufficiently messed up that you have basically no fully functioning oxytocin receptors. If you have siblings and you are the only odd one in the family, you could make a pretty strong case for both copies being messed up, by showing that you are the only one with the combination of frameshift in one copy and particular SNPs in the other. (If you are not the only odd one you can make an even stronger case).
I did drop the sequences into alphafold, and I don’t see any large structural variation from the SNPs, but (a) that histidine substitution would most likely change binding rather than structure in isolation, and (b) this is exactly the sort of case where I don’t trust alphafold much, because “this is one substitution away from a standard sequence, I’ll just output the structure of that standard sequence” is exactly the sort of heuristic I’d expect a net to over-rely upon.
Even if the structure is correct and does look the same, the binding properties of the receptor could still be different if the histidine is in the part that’s relevant for the receptor binding.
The thing you want is a tool that tells you how the receptor binding properties change through the mutation not the AlphaFold that just gives you the 3D structure. A quick question at GPT-5, suggests that there are freely available tools that tell you how the receptor binding properties change via a single point mutation.
About a month ago, after some back-and-forth with several people about their experiences (including on lesswrong), I hypothesized that I don’t feel the emotions signalled by oxytocin, and never have. (I do feel some adjacent things, like empathy and a sense of responsibility for others, but I don’t get the feeling of loving connection which usually comes alongside those.)
Naturally I set out to test that hypothesis. This note is an in-progress overview of what I’ve found so far and how I’m thinking about it, written largely to collect my thoughts and to see if anyone catches something I’ve missed.
Under the hypothesis, this has been a life-long thing for me, so the obvious guess is that it’s genetic (the vast majority of other biological state turns over too often to last throughout life). I also don’t have a slew of mysterious life-long illnesses, so the obvious guess is that’s it’s pretty narrowly limited to oxytocin—i.e. most likely a genetic variant in either the oxytocin gene or receptor, maybe the regulatory machinery around those two but that’s less likely as we get further away and the machinery becomes entangled with more other things.
So I got my genome sequenced, and went looking at the oxytocin gene and the oxytocin receptor gene.
The receptor was the first one I checked, and sure enough I have a single-nucleotide deletion 42 amino acids in to the open reading frame (ORF) of the 389 amino acid protein. That will induce a frameshift error, completely fucking up the rest of protein. (The oxytocin gene, on the other hand, was totally normal.)
So that sure is damn strong evidence in favor of the hypothesis! But, we have two copies of most genes, including the oxytocin receptor. The frameshift error is only on one copy. Why isn’t the other copy enough for almost-normal oxytocin signalling?
The frameshift error is the only thing I have which would obviously completely fuck up the whole protein, but there are also a couple nonsynonymous single nucleotide polymorphisms (SNPs) in the ORF, plus another couple upstream. So it’s plausible that one of the SNPs messes up the other copy pretty badly; in particular, one of them changes an arginine to a histidine at the edge of the second intracellular loop. (Oxytocin receptor is a pretty standard g-protein coupled receptor, so that’s the mental picture here.) I did drop the sequences into alphafold, and I don’t see any large structural variation from the SNPs, but (a) that histidine substitution would most likely change binding rather than structure in isolation, and (b) this is exactly the sort of case where I don’t trust alphafold much, because “this is one substitution away from a standard sequence, I’ll just output the structure of that standard sequence” is exactly the sort of heuristic I’d expect a net to over-rely upon.
It’s also possible-in-principle that the second receptor copy is fine, but the first copy frameshift alone is enough to mess up function. I think that’s unlikely in this case. The mRNA for the frameshifted version should be removed pretty quickly by nonsense-mediated decay (I did double check that it has a bunch of early stop codons, NMD should definitely trigger). So there should not be a bunch of junk protein floating around from the frameshifted gene. And the frameshift is early enough that the messed up proteins probably won’t e.g. form dimers with structurally-non-messed-up versions (even if oxytocin receptor normally dimerizes, which I’d guess it doesn’t but haven’t checked). At worst there should just be a 2x lower concentration of normal receptor than usual, and if there’s any stable feedback control on the receptor concentration then there’d be hardly any effect at all.
Finally, there’s the alternative hypothesis that my oxytocin signalling is unusually weak but not entirely nonfunctional. I do now have pretty damn strong evidence for that at a bare minimum, assuming that feedback control on receptor density doesn’t basically counterbalance the fucked up receptor copy.
Anyway, that’s where I’m currently at. I’m curious to hear others’ thoughts on what mechanisms I might be missing here!
I’m kind of astonished that this kind of advance prediction panned out!
I admit I was somewhat surprised as well. On a gut level, I did not think that the very first things to check would turn up such a clear and simple answer.
I’m insufficiently knowledgeable about deletion base rates to know how astonished to be. Does anyone have an estimate of how many Bayes bits such a prediction is worth?
FWIW, GPT-5T estimates around 10 bits, double that if it’s de novo (absent in both parents).
well, what happens when you take oxytocin?
This might be a bad idea right now, if it makes John’s interests suddenly more normal in a mostly-unsteered way, eg because much of his motivation was coming from a feeling he didn’t know was oxytocin-deficiency-induced. I’d suggest only doing this if solving this problem is likely to increase productivity or networking success; else, I’d delay until he doesn’t seem like a critical bottleneck. That said, it might also be a very good idea, if depression or social interaction are a major bottleneck, which they are for many many people, so this is not resolved advice, just a warning that this may be a high variance intervention, and since John currently seems to be doing promising work, introducing high variance seems likely to have more downside.
I wouldn’t say this to most people; taking oxytocin isn’t known for being a hugely impactful intervention[citation needed], and on priors, someone who doesn’t have oxytocin signaling happening is missing a lot of normal emotion, and is likely much worse off. Obviously, John, it’s up to you whether this is a good tradeoff. I wouldn’t expect it to completely distort your values or delete your skills. Someone who knows you better, such as yourself, would be much better equipped to predict if there’s significant reason to believe downward variance isn’t present. If you have experience with reward-psychoactive chemicals and yet are currently productive, it’s more likely you already know whether it’s a bad idea.
Didn’t want to leave it unsaid, though.
if the problem is with the receptor, taking more won’t make a difference
Sounds like a great empirical test!
Seems like that depends on details of the problem. If the receptor has zero function, then yes. If functionality is significantly reduced but nonzero… maybe.
Perhaps Gurkenglas meant this is as a ~confirmatory test that John is actually oxytocin-insensitive because the test results (IIUC) are compatible with only one gene copy being screwed up.
I ordered this one off of amazon. AFAICT it does nothing for me. But that’s a pretty minor update, because even those who use it say the effects are “subtle”, and frankly I think snorting oxytocin is probably bullshit and does nothing beyond placebo even for normal people. I did have a couple other people try the one I bought, and their results indeed sounded like a nothingburder.
Your link is broken. The raw HTML is:
<a href="https://One other thing - labs typically filter reportable genome results by the phenotype you give them. I don’t know how this guy did the genome, but if he were to put something like “social deficits”, “emotional dysregulation” or something else about his lack of emotional range, the lab would definitely report the variant plus their research on it and recommendations.">this one</a>BTW, has anyone on LW tried oxytocin and is willing to report on the experience?
Fixed, thanks.
Not directly related to your query, but seems interesting:
Which, in turn, is pretty solid evidence for “oxytocin mediates the emotion of loving connection/aching affection” (unless there are some mechanisms you’ve missed). I wouldn’t have guessed it’s that simple.
Generalizing, this suggests we can study links between specific brain chemicals/structures and cognitive features by looking for people missing the same universal experience, checking if their genomes deviate from the baseline in the same way, then modeling the effects of that deviation on the brain. Alternatively, the opposite: search for people whose brain chemistry should be genetically near-equivalent except for one specific change, then exhaustively check if there’s some blatant or subtle way their cognition differs from the baseline.
Doing a brief literature review via GPT-5, apparently this sort of thing is mostly done with regards to very “loud” conditions, rather than in an attempt to map out the brain in general. I could imagine that it won’t turn out that simple in practice, but the actual bottleneck is probably researchers with a good enough theory-of-mind to correctly figure out the subtle ways the subjects’ cognition differs (easy for “severe autism”, much harder for “I feel empathy and responsibility, but not loving connection”).
… and so at long last John found the answer to alignment
The answer was Love
and it had always has been
(hopes this is a joke)
~Surely there’s a lot of other things involved in mediating this aspect of human cognition, at the very least (/speaking very coarse-grainedly), having the entire oxytocin system adequately hooked up to the rest of everything.
IE it is damn strong evidence that oxytocin signalinf is strictly necessary (and that there’s no fallback mechanisms wtc) but not that it’s simple.
Did your mother think you were unusual as a baby? Did you bond with your parents as a young child? I’d expect there to be some symptoms there if you truly have an oxytocin abnormality.
For my family this is much more of a “wow that makes so much sense” than a “wow what a surprise”. It tracks extremely well with how I acted growing up, in a bunch of different little ways. Indeed, once the hypothesis was on my radar at all, it quickly seemed pretty probable on that basis alone, even before sequencing came back.
A few details/examples:
As a child, I had a very noticeable lack of interest in other people (especially those my own age), to the point where a school psychologist thought it was notable.
I remember being unusually eager to go off to overnight summer camp (without my parents), at an age where nobody bothered to provide overnight summer camp because kids that young were almost all too anxious to be away from their parents that long.
When family members or pets died, I’ve generally been noticeably less emotionally impacted than the rest of the family.
When out and about with the family, I’ve always tended to wander around relatively independently of the rest of the group.
Those examples are relatively easy to explain, but most of my bits here come from less legible things. It’s been very clear for a long time that I relate to other people unusually, in a way that intuitively matches being at the far low end of the oxytocin signalling axis.
Interesting. That seems like reasonable evidence.
Though beyond a certain level of development we have numerous other drives beyond the oxytocin-related ones. Hence why you-as-a-baby might be particularly telling. From what I understand, oxytocin is heavily involved in infant-caregiver bonding and is what enables mothers to soothe their babies so effectively (very much on my mind right now as I am typing this comment while a baby naps on me haha).
Whereas once you’re above a certain age, the rational mind and other traits probably have an increasingly strong effect. For example, if you’re very interested in your own thoughts and ideas, this might overwhelm your desire to be close to family members.
Anyway, it seems likely that your oxytocin hypothesis is correct either way. Cool finding!
I have a similar intuition about how some other people are missing a disgust response that I have. Seems like a biological thing that some people have much less of than others and it has a significant effect on how we relate to others.
Is that frame-shift error or those ~6 (?) SNPs previously reported in the literature for anything, or do they seem to be de novos? Also, what WGS depth did your service use? (Depending on how widely you cast your net, some of those could be spurious sequencing errors.)
Depth is tagged on each individual variation; the frame shift has depth 41, the others have depth anywhere from 40 to 60.
I have not found the frameshift mutation in dbSNP, but I’m not confident that I’ve understood the UI or intended usage patterns, so I’m not confident it’s not in there. The SNPs I haven’t looked for in there yet.
Really interesting post—this actually connects to some research I’ve been looking into recently around oxytocin and attachment patterns.
There’s this psychologist Adam Lane Smith who’s built on neurobiological work by researchers like Carolyn Zahn-Waxler and Ruth Feldman—they’ve found that under high stress conditions when younger, or absence of secure attachment figures, cortisol-induced stress actually strengthens cortisol and dopamine pathways for reward while inhibiting the oxytocin and serotonin pathways. The end result (avoidant attachment) sounds remarkably similar to what you’re describing: people who clearly care about others and feel responsibility, but don’t experience that warm “loving connection” feeling that most people seem to get from relationships.
What struck me about your situation is that you’ve essentially got the genetic version of what this research suggests can happen environmentally. Both paths seem to lead to the same place—having to navigate social connection through pattern recognition and cognitive analysis rather than emotional intuition, because your brain is essentially running on dopamine-driven systems instead of oxytocin-based ones.
Makes me wonder if there’s a whole spectrum of people out there—some genetic, some developmental—who are all essentially operating with similar neurochemical profiles but don’t realize they’re part of the same phenomenon. Your case might be the key to understanding how this actually works at a biological level.
Do you find you’ve gotten really good at reading people through behavioral patterns rather than gut feelings?
Yep. AlphaMissense, also from DeepMind, is tailored to pathogenicity prediction. You can find its pathogenicity scores in the annotations tab for any (at least I think any) human protein on AFDB.
https://alphafold.ebi.ac.uk/entry/P30559?activeTab=annotations
(You may have to click on a different tab and return to the annotations tab for the heatmap and structure viewer to load).
As a non-subject matter expert in all of the above, I decided to consult my swear-word-adverse relative that recently graduated genetic counseling school. Here is her response:
The logic is sound (if a little colorful haha 😅). It sounds like this guy functionally only has 1 copy of the OXTR gene, and spot on in hypothesis of nonsense-mediated decay.
How the OXTR gene is regulated, I don’t know and haven’t looked into. It would be weird (but possible) for a decrease in OXTR expression to only affect emotions—oxytocin is also important for other brain functions/development, so a genetic change should also impact embryological development of the brain. So if I were to suggest next steps, it would be doing functional studies of the brain (like an MRI) to further evaluate.
One other thing—labs typically filter reportable genome results by the phenotype you give them. I don’t know how this guy did the genome, but if he were to put something like “social deficits”, “emotional dysregulation” or something else about his lack of emotional range, the lab would definitely report the variant plus their research on it and recommendations.
Amazing, is this the future of psychotherapy?
“Doctor, I have a problem...” “Stop talking, just give me a blood sample. Okay, your problem is X.”
Huh interesting. I might get myself full genome sequenced at some point. I already got myself 23andme sequenced, downloaded the raw data, and put it into promethease a while ago. I did find out I’m AG at rs53576 which is slightly linked to lower empathy, but is also extremely common. I don’t think this is enough to explain a large proportion of my personality, the way your OXTR deletion might be.
(There was something quite amusing to check my SNPs checking whether to start early anti-balding interventions, and have result number 1 be “Low Empathy”. As a further datapoint, I mentioned this to my mum and she basically said “Yeah but what did you expect with me and [dad] as parents?”)
Seeing this
Made me think I should take a deeper look. This all sounds pretty familiar, and I don’t think the AG in rs53576 is strong enough to shift me off-distribution to the degree that I am.
If the one clearly fucked up receptor copy is sufficient for your “symptoms”, it seems pretty likely that one of your parents should have them too. I think there is no reason to expect a denovo mutation to be particularly likely in your case (unlike in cases that lead to severe disfunction). And of course you can check for that by sequencing your parents.
So my money would be on the second copy also being sufficiently messed up that you have basically no fully functioning oxytocin receptors. If you have siblings and you are the only odd one in the family, you could make a pretty strong case for both copies being messed up, by showing that you are the only one with the combination of frameshift in one copy and particular SNPs in the other. (If you are not the only odd one you can make an even stronger case).
Even if the structure is correct and does look the same, the binding properties of the receptor could still be different if the histidine is in the part that’s relevant for the receptor binding.
The thing you want is a tool that tells you how the receptor binding properties change through the mutation not the AlphaFold that just gives you the 3D structure. A quick question at GPT-5, suggests that there are freely available tools that tell you how the receptor binding properties change via a single point mutation.