Preprint Complex Genetics and Regulatory Drivers of Hypermobile Ehlers-Danlos Syndrome: Insights from [GWAS] Meta-analysis, 2025, Petrucci-Nelson et al

Maybe it never affected reproduction rate much and it was partially advantageous to be bendy to shoot an arrow?
I thought most of the connective tissue conditions worsened most bio-mechanical processes that aim to produce power? Stability and resilience would also be a massive issue.

Sure, being bendy might mean that you’re able to do a deep lunge to strike your melee opponent from a greater distance, but I’m not sure that would make up for the risk of injury long term?
 
I thought most of the connective tissue conditions worsened most bio-mechanical processes that aim to produce power? Stability and resilience would also be a massive issue.

Sure, being bendy might mean that you’re able to do a deep lunge to strike your melee opponent from a greater distance, but I’m not sure that would make up for the risk of injury long term?
I think it's pretty hard to have meaningful arguments about reproduction rates when there isn't data for anything. I think anybody could just hypothesise whatever they want, but maybe I'm wrong about that. But if your suggestion is that people with hEDS have worsened bio-mechnical processes and a group of people with such issues are seemingly being picked up by this study but seemingly not really by other studies, isn't that quite an inconsistent explanation if one would want to explain the results to be driven by confounding factors?
 
I struggle to make sense of such an argument in the context of hEDS. Maybe it never affected reproduction rate much and it was partially advantageous to be bendy to shoot an arrow?
I suspect these evolutionary pressures long predate the time of arrows. And because hEDS is said to be a disabling disease appearing in adolescence it would in many cases have reduced fitness. So the idea is that strong effects like the one found here would normally have been filtered away if they are so clearly associated with a (not so rare) disease.
The fact that this loci had an OR of 1.8 in "MUSC1" and 1.4 in the "All of us" could suggest that maybe you can pick up something that isn't necessarily genuine, but I still find it hard to construct a story about a somewhat systemic confounder when at least one cohort seems to be rather different (in age, sex, recruitment handling, socioeconomic background, race and ethnicity).
I don't know either (just guessing) but it could perhaps be an issue with matching cases and controls or quality control? Suspect we'll have to wait for a bigger replication study to know the answer.
 
1- it seems unplausible that self-reported hEDS would stand for much, contrary to ME/CFS
2- DecodeME data strongly suggests that self-reported symptoms and self-reported diagnosis of ME/CFS (verified by self-reported symptoms) identify a group of people suffering from a distinct pathology

I actually think these two statements give a slightly wrong impression of our past discussions.

hEDS does stand for something fairly specific biologically - bendiness. But it is so ill defined that it can be expected to gather together all sorts of different processes leading to bendiness.

Note that in my statement:
Almost nothing is known about mechanisms involved in ME/CFS but recent genetic studies show that the syndrome picks out a specific biological process, or cluster of processes, with a profile of genetic risk factors not found in other conditions. (One gene may overlap for chronic pain.)

I allow for ME/CFS also covering a cluster of processes. The statement could reasonably be taken to mean that ME/CFS is as bioogically real as bendiness. Bendiness is a distinct biology, whether or not it is a pathology.

I do have concerns about an hEDS cohort being biased by all sorts of irrelevant factors, which may well include medical prejudice in favour of diagnosing women with hEDS for instance. But I think it is highly likely that if you take a group of people who are at least a bit bendier than average and have acquired this diagnosis that you will find fairly strong links to genes that make people a bit more bendy. There are likely to be hundreds of those, only one or two of which might turn up on a fairly small study.

The real problem with grouping bendy people is that bendiness itself depends on a variety of different things for different joints. For instance, the ability to hyperextend the elbow (scores on Beighton) is probably largely dependent on bone congruence, which is different in males and females (who also have a 'carrying angle'). But knee hyperextension is dependent on ligament and musculotendinous extensibility. The bones do not lock in any position. Spinal mobility probably depends on disc deformability - another tissue again.
 
I actually think these two statements give a slightly wrong impression of our past discussions.

hEDS does stand for something fairly specific biologically - bendiness. But it is so ill defined that it can be expected to gather together all sorts of different processes leading to bendiness.

Note that in my statement:
Almost nothing is known about mechanisms involved in ME/CFS but recent genetic studies show that the syndrome picks out a specific biological process, or cluster of processes, with a profile of genetic risk factors not found in other conditions. (One gene may overlap for chronic pain.)

I allow for ME/CFS also covering a cluster of processes. The statement could reasonably be taken to mean that ME/CFS is as bioogically real as bendiness. Bendiness is a distinct biology, whether or not it is a pathology.

I do have concerns about an hEDS cohort being biased by all sorts of irrelevant factors, which may well include medical prejudice in favour of diagnosing women with hEDS for instance. But I think it is highly likely that if you take a group of people who are at least a bit bendier than average and have acquired this diagnosis that you will find fairly strong links to genes that make people a bit more bendy. There are likely to be hundreds of those, only one or two of which might turn up on a fairly small study.

The real problem with grouping bendy people is that bendiness itself depends on a variety of different things for different joints. For instance, the ability to hyperextend the elbow (scores on Beighton) is probably largely dependent on bone congruence, which is different in males and females (who also have a 'carrying angle'). But knee hyperextension is dependent on ligament and musculotendinous extensibility. The bones do not lock in any position. Spinal mobility probably depends on disc deformability - another tissue again.
I think those are very fair points. The results could easily be related to bendiness without being related to anything else. In that case think point 1. would be more accurately be reflected by something along the lines of "1- it seems unplausible that self-reported hEDS would stand for a specific disease, contrary to ME/CFS". In which case 1 and 2 wouldn't be in contradiction to each other.
 
I don't know either (just guessing) but it could perhaps be an issue with matching cases and controls or quality control? Suspect we'll have to wait for a bigger replication study to know the answer.
Yes, it looks like the approach to controls seems to be quite different here to that of DecodeME? I was under the impression that DecodeME just wanted to get the largest set of possible controls, with the priority being to reduce false positives and not minding the possibility of increasing likelihood of false negatives, whilst here they pretty much did the opposite (by ruling out certain conditions in the controls)? I guess that makes it more likely that the genes picked out here are related to general bendiness rather than hEDS-bendiness (because "bendiness genes" become underrepresented in your controls if you exclude Marfan, EDS and the other things that were excluded)?
 
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I think it's pretty hard to have meaningful arguments about reproduction rates when there isn't data for anything.
I’m not sure what you mean by reproduction rate. Does that refer to the probability of passing on your genetic material to the next generation?
But if your suggestion is that people with hEDS have worsened bio-mechnical processes and a group of people with such issues are seemingly being picked up by this study but seemingly not really by other studies, isn't that quite an inconsistent explanation if one would want to explain the results to be driven by confounding factors?
My point was that if people are more severely more bendy and have other tissue issues, then their bio-mechanics are much more vulnerable, and if that’s linked to a very few genes then those genes would have a lower chance of surviving.

That appears to be the case with the EDS genes, they are exceedingly rare.

What we see here are genes that are not tied to most of the other issues that supposedly are common among pwhEDS.

So what does the genes signify, and are they even relevant for the disability that the pwhEDS faces?

Assuming the results are valid (I don’t have the knowledge to check) I think it’s plausible that they have just picked out people that are more likely to be a bit bendy, and maybe more specifically women that are a bit bendy because hEDS is supposedly female dominated.

If that ties them together with a unified pathology behind their disability is a different issue, and probably less likely?
 
hEDS is almost certainly a meaningful diagnostic concept. Whether it’s called EDS or not shouldn’t matter that much. The label stuck because in some cases it does resemble other forms of EDS (it does in my case). The difference is/might be that it’s largely polygenic, not monogenic. Acting like the name “EDS” is inherently wrong or shouldn't be used is nevertheless a bit overstated. And if it's only because changing the name now would be a bad idea for similar reasons like changing the name for ME/CFS would be.

hEDS probably represents an earlier stage of diagnostic definition, much like Oxford or Fukuda once did for ME/CFS. Over time, refinement of criteria, ideally alongside biomarker stratification and genetic insights will hopefully bring more clarity. Dismissing hEDS as “mere bendiness” (which by itself can carry serious consequences) ignores both patient reality and published findings (e.g. Colombi), though.

My guess is that participation in hEDS studies is skewed toward those who are both hypermobile AND have multisystem symptoms (delayed gut emptying, dysautonomia, etc.) that remain otherwise unexplained. Those who are “only bendy” are likely underrepresented rather than overrepresented in research cohorts? Much larger (and better-biomarker-characterized) cohorts are urgently needed to clarify whether and how hypermobility might be causally related to these additional systemic issues, of course.
 
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hEDS is almost certainly a meaningful diagnostic concept.

How can something where there is 500-fold disagreement about what it includes be useful?
Also, EDS is a concept around geneticdifferences in connective tissue. hEDS includes that you have symptoms, when nobody knows whether or not those symptomms have anything to do with the bendiness. I have worked alongside the people who have promoted this ide all my life. It is purely designed to make certain physicians seem clever and convince patients to pay money as far as I can see.It is about as meaningful as 'being tall disease'.
 
How can something where there is 500-fold disagreement about what it includes be useful?
Also, EDS is a concept around geneticdifferences in connective tissue. hEDS includes that you have symptoms, when nobody knows whether or not those symptomms have anything to do with the bendiness. I have worked alongside the people who have promoted this ide all my life. It is purely designed to make certain physicians seem clever and convince patients to pay money as far as I can see.It is about as meaningful as 'being tall disease'.

Like ME/CFS is a 'being tired, deconditioned and lazy disease' (all part of 'normal distribution' after all!), you mean? Like the 500-fold (?!) disagreement about definitions for ME/CFS? Your views on this matter are well-known, they are partly correct and what is, is hardly any news to anyone working on this - very few would dispute most of what you say.

Taking your points into consideration, only figuring out the (various polygenic combinations of) 'bendiness' would be a worthy cause. You are way too hung up on whether this is actually 'EDS', I believe. Nobody really cares about that.

Personally, I believe to think that this 'bendiness' could not have other interesting upstream or downstrean implications for 'systemic issues' and that it shouldn't be studied more in that context is very difficult to take seriously.
 
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Like ME/CFS is a 'being tired, deconditioned and lazy disease' (all part of 'normal distribution' after all!), you mean?

No, more like the ICC which invent a multisystem disease like hEDS that muddles up allsorts of unsubstantiated causal links.

Studying bendiness is a perfectly worthwhile activity but it will get nowhere much if the people studying it are completely confused about what they want to prove. There are likely to be a hundred different genes that cause different degrees of bendiness in different places. Each one is likely to be associated with a different group of symptoms, if any at all.

The Kallikrein genes picked up in these recent studies are interesting and likely relevant to a rare cause of bendiness but not as a contributor to a non-existent syndrome.
 
No, more like the ICC which invent a multisystem disease like hEDS that muddles up allsorts of unsubstantiated causal links.

Studying bendiness is a perfectly worthwhile activity but it will get nowhere much if the people studying it are completely confused about what they want to prove. There are likely to be a hundred different genes that cause different degrees of bendiness in different places. Each one is likely to be associated with a different group of symptoms, if any at all.

The Kallikrein genes picked up in these recent studies are interesting and likely relevant to a rare cause of bendiness but not as a contributor to a non-existent syndrome.

Is that so much worse than “making up PEM as a core feature,” which after all is not substantiated by any (diagnostic) biomarker?

Also interesting re: rare causes of bendiness - how were these rare potential causes identified? By using some “somewhat arbitrary cutoff/criteria” for inclusion. Which is, to some degree, always the case in ill-defined syndromes and a starting point.

And while hEDS is certainly not well defined or fully characterized, its diagnostic criteria are already based on more than just bendiness.
 
Is that so much worse than “making up PEM as a core feature,” which after all is not substantiated by any (diagnostic) biomarker?

Yes, because it is arguing backwards. You start with a clinical feature and try to find markers that might explain it. You do not start with an assumption that symptoms are due to bendiness due to genes and give it a name without knowing whether it is the case.
And while hEDS is certainly not well defined or fully characterized, its diagnostic criteria are already based on more than just bendiness.

Which is why it is such a bad category - as per above. It is bad in the way ICC is bad because it assumes you have to have symptoms due to nervous and immune system changes - backwards again.
 
Yes, because it is arguing backwards. You start with a clinical feature and try to find markers that might explain it. You do not start with an assumption that symptoms are due to bendiness due to genes and give it a name without knowing whether it is the case.
It occurs to me that a parallel might be made red hair being associated with increased risk of some symptoms, such as increased pain sensitivity, and conditions such as skin cancer, endometriosis and Parkinsons' disease. None of these is called red hair disease. They are named according to symptoms and signs. So you start with the symptoms and see whether there's a higher proportion of pw red hair and whether there is any genetic and physiological link.

Similarly, you can start with symptoms and conditions such as pain and IBS, and see if there's a higher prevalence of bendy people. But you don't diagnose them as having bendy disease, but as having IBS or whatever.
 
Yes, because it is arguing backwards. You start with a clinical feature and try to find markers that might explain it. You do not start with an assumption that symptoms are due to bendiness due to genes and give it a name without knowing whether it is the case.


Which is why it is such a bad category - as per above. It is bad in the way ICC is bad because it assumes you have to have symptoms due to nervous and immune system changes - backwards again.

I would like to push back a bit on this but currently lack the energy, I might follow up, but in short:

Bendiness is the clinical feature, though, and if you get a lot of people with let's say bendiness plus cigarette paper scarring or visceroptosis (or whatever,…) and these patients are what you believe a significantly large sub-population and these extra features are extremely rare in the general population vs the bendiness population then it could make sense to subgroup them further. That's what hEDS is and it could make sense to differentiate it from hypermobility syndrome in that way.
 
That's what hEDS is and it could make sense to differentiate it from hypermobility syndrome in that way.

What makes you think that such a group can usefully be identified? (And from what I have seen hEDS is defined in all sorts of other ways - including symptoms).

I have run a hypermobility clinic and seen scores of patients. In my general rheumatology clinic I have seen thousands. Have you? I also know that the physicians who claim these things talk and write fairy tales. Each one makes slightly different stuff up, showing that none of them are actually talking about a single reality.
 
What makes you think that such a group can usefully be identified? (And from what I have seen hEDS is defined in all sorts of other ways - including symptoms).

I have run a hypermobility clinic and seen scores of patients. In my general rheumatology clinic I have seen thousands. Have you? I also know that the physicians who claim these things talk and write fairy tales. Each one makes slightly different stuff up, showing that none of them are actually talking about a single reality.


What makes me think that people with the same or similar features are more likely to have the same or similar underlying genetic issues? What kind of ridiculous question is that?

As stated earlier, there are obviously many issues with definitions, and with mixing traits with features/signs/symptoms but the way you portray this specifically makes me think you are heavily biased. It's just not completely random or arbitrary and hence potentially useful. It might not be.

Whether or not you have seen thousands of hypermobile patients, how does that relate to the logic behind subgrouping them in principle? I don't care much about your issues with your former colleagues tbh, these are just random misgivings to me, you either can explain what is you think they do wrong in more detail or it's just a waste of time to even discuss it.

I have spoken to hundreds of people with hEDS, read and seen thousands of comments, and reviewed most of the literature. This is similar to how you define your ME/CFS expertise, if I remember correctly. You have never seen or treated ME/CFS patients, right? I have hEDS, and I am interested in understanding the complex genetic underpinnings of this.

Please explain how you would approach this if not in the way it is currently done via hEDS. Genuinely interested. I doubt you will come up with a better idea, especially given the current constraints. In such a scenario, there will always be pros and cons to looking at specific families versus population-size cohorts. Both approaches are needed, and to get sizeable cohorts you need certain definitions that will always be somewhat arbitrary. It's absolutely obvious to everyone involved that this is not a monogenic (in the one gene for the cohort sense mostly) issue and polygenic in a complex fashion, that doesn't mean there is no overlap and/or useful signal. And while it can be, it's not automatically a mistake to mix traits with symptoms for definitions. There are trade-offs for everything.

By the way, what is PEM? You think that’s not a “symptom”? The entire definition of ME/CFS is based on it! The whole of ME/CFS is basically nothing but symptoms/features currently and you advocated (rightly so) for a GWAS!

Here are the criteria:

The Ehlers Danlos Society https://share.google/MUl3XFvXhBKf0WOS

Not that many symptoms, right? Maybe 'random' traits and features, but not that many symptoms. One thing you are definitely doing is conflating bad research based on unproven causality re symptoms using diagnostic criteria with the diagnostic criteria themselves and it will be very difficult for you to argue otherwise. Based on what you have said here I doubt you have even read the criteria.

(I will not be back online for a while.)
 
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