[ME/CFS Research Foundation] International ME/CFS Conference 2026 7–8 May


  • Pipper-Krampl began by saying that ME/CFS is a complex multisystem disease with increasing evidence for cardiometabolic abnormalities and impaired vascular regulation. One important aspect is arginine and its connection to nitrous oxide. However, the metabolites associated with this have not been well-studied in ME/CFS, so they decided to see if they have any significance in ME/CFS and if they differ between male and female patients.
  • Using the UK ME/CFS Biobank, they analyzed arginine- and polyamine-related metabolites. In the female cohort , there was no significant differences between healthy controls and ME/CFS patients. However, in the male cohort, there were significant metabolic alterations between healthy controls and ME/CFS patients.
  • Their results suggest that there may be an imbalance in arginine usage and uptake in the NO and polyamine pathways which could impact vascular and metabolic function. They also support a sex-dependent role of the arginine-NO axis in ME/CFS.
  • One participant asked if it would be helpful to directly measure NO. Pipper-Krampl said they studied that in a past paper that they can learn more about from the QR code on their poster. Martina Seifert asked if they had the chance to link the metabolites to the known cardiovascular parameters of the patients. Pipper-Krampl responded by saying that is a great idea that she will hopefully see when the whole paper is published soon since the presentation is just a small sneak-peak.
 
 
SugarSquared said:
I also have no idea. Maybe if @Chris Ponting has some time, he could answer us on here?
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Apologies for the delay in responding, but I've been away. Yes, "direct genetic evidence" for an immune-related pathogenesis could be provided by an HLA association. "Indirect genetic evidence" is an association to a gene with known immune function such as BTN2A1, whose association has both common variation and rare variation evidence. Nevertheless, despite a known function of BTN2A1 being immunological, we cannot rule out this gene/protein having other, non-immunological functions, especially as it is expressed in non-immune cells, e.g. neurons.
Also, to clarify, DecodeME tested for a significant sex-bias of the genetic associations at the 8 loci, but drew a blank. This is the basis to the conclusion that there is no statistical evidence for sex-bias of genetic effects. The strong female bias in prevalence may have a genetic contribution, but none that we've yet found.
 
Chris Ponting said:
The strong female bias in prevalence may have a genetic contribution, but none that we've yet found.
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Pardon me, @Chris Ponting , but surely you did find it - you found the women had two X chromosomes. I agree that you do not know which bit produced the prevalence bias but it must have been the two X rather than XY and it surely could not have been present on the autosomes, since sets of these are randomly associated with an X or a Y at meiosis? No autosomal SNP variants are going to segregate with sex so are not going to be responsible for the sex bias?
 
Chris Ponting said:
Yes, "direct genetic evidence" for an immune-related pathogenesis could be provided by an HLA association. "Indirect genetic evidence" is an association to a gene with known immune function such as BTN2A1, whose association has both common variation and rare variation evidence.
Chris Ponting said:
Nevertheless, despite a known function of BTN2A1 being immunological, we cannot rule out this gene/protein having other, non-immunological functions, especially as it is expressed in non-immune cells, e.g. neurons.
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And I think this is splitting hairs a bit. Class I HLA genes are expressed on all cells too. They may have unknown functions. We do not even know that the classic HLA-B associated disease, ankylosing spondylitis, is 'immune'. Fifty years on the reason for the link to B27 is still unknown. BTN2A1 might be seen as signalling cell housekeeping status in a more general way than HLA-B but we know that HLA-B signals in two quite different ways, reflecting various sorts of housekeeping.
 
Jonathan Edwards said:
No autosomal SNP variants are going to segregate with sex so are not going to be responsible for the sex bias?
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Maybe a way would be something like a genetic variant on an autosome which can cause ME/CFS, but it depends on high levels of estrogen to have an effect. A GWAS would find a stronger association in females than males, and it would provide a clue to the basis of the sex bias.
 
forestglip said:
A GWAS would find a stronger association in females than males, and it would provide a clue to the basis of the sex bias.
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It might do, It would provide a clue to part of the way the two XX conferred bias, yes. But that is a different issue. It would not be responsible for the sex bias. Finding a discrepancy between SNP variant distribution between sexes, or not, does not alter the fact that two XX are responsible for the bias. There is a faint possibility that the bias is due to psychosocial factors impacting on females rather than males, but the two X are still the critical factor in the causal chain for each individual.
 
Jonathan Edwards said:
It might do, It would provide a clue to part of the way the two XX conferred bias, yes. But that is a different issue. It would not be responsible for the sex bias. Finding a discrepancy between SNP variant distribution between sexes, or not, does not alter the fact that two XX are responsible for the bias. There is a faint possibility that the bias is due to psychosocial factors impacting on females rather than males, but the two X are still the critical factor in the causal chain for each individual.
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I think Chris was just saying that nothing specific, like a link to estrogen, has been found. Being female vs male is clearly a genetic trait, but how much does it help to say that's the cause of the sex bias? It's almost a truism. Like if a research group was tasked with identifying why women tend to have different careers than men, and the conclusion they come back with is that it's genetic: women have two X chromosomes so this is the critical step that must lead to the discrepancy. That doesn't seem like it provides any usable information.

Also, why not lack of Y chromosome as the risk factor?
 
forestglip said:
Being female vs male is clearly a genetic trait, but how much does it help to say that's the cause of the sex bias? It's almost a truism.
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Well yes, that is my point. But Chris seemed to doubt it:
Chris Ponting said:
The strong female bias in prevalence may have a genetic contribution, but none that we've yet found.
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They said they checked the karyotpes, so they did find it. XX. That is not as tight as a splurge of SNPs in linkage disequilibrium but it is a chunk of DNA (two chunks).
 
forestglip said:
Like if a research group was tasked with identifying why women tend to have different careers than men, and the conclusion they come back with is that it's genetic: women have two X chromosomes so this is the critical step that must lead to the discrepancy. That doesn't seem like it provides any usable information.
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Only because we already knew it. Like Chris already knows it - it's genetic and XX.

There is an interesting debate about whether the bias is due to two doses of X or the absence of Y, which we have explored quite a lot. I take that as being part of the detail to further explore. Strictly speaking the cause of bias is having XX rather than XY - which I think is how I phrased it originally.
 
forestglip said:
I think Chris was just saying that nothing specific, like a link to estrogen, has been found. Being female vs male is clearly a genetic trait, but how much does it help to say that's the cause of the sex bias? It's almost a truism.
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I agree you can look at calling it 'genetic' or not as semantics, and if you look at it just as a single piece of data, it's a truism.

What I was scratching my head about was that it seemed liked the direct effects of X vs Y were skipped over. When someone asked about the sex bias in the talk Chris mentioned that there is no sex-bias of the variants found on the autosomes, and then, to explain the sex bias we see in ME/CFS cases, offered the environment and X-chromosome inactivation. Maybe it's not standard terminology in genetics to call the cascade of changes kicked off by the SRY gene on the Y chromosome a genetic effect, but surely it's still one of the preliminary hypotheses for the different rates of ME/CFS we see in men and women?
 
Jonathan Edwards said:
Well yes, that is my point. But Chris seemed to doubt it:

They said they checked the karyotpes, so they did find it. XX. That is not as tight as a splurge of SNPs in linkage disequilibrium but it is a chunk of DNA (two chunks).
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ScoutB said:
What I was scratching my head about was that it seemed liked the direct effects of X vs Y were skipped over. When someone asked about the sex bias in the talk Chris mentioned that there is no sex-bias of the variants found on the autosomes, and then, to explain the sex bias we see in ME/CFS cases, offered the environment and X-chromosome inactivation. Maybe it's not standard terminology in genetics to call the cascade of changes kicked off by the SRY gene on the Y chromosome a genetic effect, but surely it's still one of the preliminary hypotheses for the different rates of ME/CFS we see in men and women?
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Yes, I think I see what you're saying.

Chris said this in the talk:
So either there is no genetic predisposition and that it all comes from the environment towards females over males or perhaps more likely what we see in DecodeME is just the tip of the iceberg, above the water line. And there's a lot more genetic variation that explains ME that we haven't yet seen. And it will be that unexplained genetics that will be sex biased.
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So it sounds like Chris is saying something like that it's possible that different environments experienced by people of the sexes lead to the sex bias. Which Jonathan would counter that this is still genetically linked, as the genetics led to the different environments.

And another rebuttal would be that even with regard to the more "genetic" sex-related causes, he still does not give enough focus to the simple difference in sex chromosomes and instead is focused on variation between cases and controls, which may or may not produce significant findings related to sex bias, even if it was the case that, for example, just having one fewer Y chromosome led to less of a protein being made which is protective against ME/CFS.

I think I'd agree with the second point. With regard to the first environment point, I think I could see an argument for saying it's not genetic though. For example, we can imagine a case where a government decided to discriminate against women and enforce lower pay. Would we say the sex bias in pay is caused by having XX vs XY, or caused by government policies?
 
forestglip said:
For example, we can imagine a case where a government decided to discriminate against women and enforce lower pay. Would we say the sex bias in pay is caused by having XX vs XY, or caused by government policies?
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But that is the BPS ploy of separating psychosocial from biology. We should treat everything as biology. What if eccentric medium spiny neurons have synapses that under the influence of a gene variant tend to produce a certain sort of behaviour. God forbid it might even be perfectionist. That leads to the idividual interacting with other humans in ways that set the up to get ME/CFS. So all the 8 hits we have could be just as psychosocial.

This exposes the complete con of estimating proportion of genetic and environmental components (leaving aside forgetting about the stochastic) for disease causation. It is all totally dependent on 'what might otherwise have happened, which changes over history, with the arrival of new viruses, with different political systems and on and on.

Yes, we can end up floundering in semantics. It is just that I am surprised about the way Chris has presented this. Why do we want to invoke the tip of an iceberg (I am not even sure what that is an analogy for) rather than say that very likely it is down to TLR8 or BTK on X or a controller gene on Y.
 
Jonathan Edwards said:
But that is the BPS ploy of separating psychosocial from biology. We should treat everything as biology.
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Ok, but what about the specific example I gave? I think it's unlikely to be a major component, but it's a plausible that discriminatory policies could lead to poor health. Should we be focusing on which neurons in women are responsible for them being discriminated against?

I'm just giving a counterexample. I think the sex bias is more likely to come from biology.
 
forestglip said:
Ok, but what about the specific example I gave? I think it's unlikely to be a major component, but it's a plausible that discriminatory policies could lead to poor health. Should we be focusing on which neurons in women are responsible for them being discriminated against?
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In that instance it wouldn’t be any neurons that are responsible, because the discrimination happens due to gender. So the genetic cause would be their chromosomes, and psychosocial circumstances would be laws and regulations.

From a practical standpoint it would be easier to fix the laws than to change someone’s chromosome, so that’s what you’d focus on.

But none of that is really relevant to ME/CFS.
 
forestglip said:
I think the sex bias is more likely to come from biology.
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I agree. I am not suggesting otherwise. I am simply trying to to make the point that to me Chris's way of expressing the possibilities makes things more difficult than it need be. We have every reason to think that there are some sex chromosome based genes that determine the sex bias through good old-fashioned signalling pathways.
 
Chris Ponting said:
despite a known function of BTN2A1 being immunological, we cannot rule out this gene/protein having other, non-immunological functions, especially as it is expressed in non-immune cells, e.g. neurons
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Dumb questions from someone who hasn’t been able to follow all the genetic discussions closely and is looking for a brainfog compatible explanation

It seems to me that most or all of the genes people have been looking at are expressed in multiple tissues and have multiple functions and possibly unknown ones as well

So how do you tease apart which tissues and/or functions are the problem ones? Why has everyone landed on neurons (not suggesting that’s wrong, just trying to understand)? Why are we not looking at all the functions of a gene, in neurons and elsewhere, together? Is it because neurons express those genes most strongly?

If so, is strength of expression necessarily relevant? Does strength of expression reflect how critical a process is, or just how much of it typically happens? Couldn’t something going just slightly wrong in some obscure tissue or pathway cause just as much trouble if it happens to be particularly sensitive to minor changes?

I’ll stop here before I think of even more possibly unanswerable questions :muted:;)

I like your videos by the way Chris, very helpful
 
Ravn said:
It seems to me that most or all of the genes people have been looking at are expressed in multiple tissues and have multiple functions and possibly unknown ones as well
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This is an important point and I think all those doing the analyses take it seriously. To me, it is the weight of lots of bits of data that makes the pointer to neurons pretty convincing. And we do have some very neuron specific roles for some of these genes. BTN2A1 may be on all cells but is likely to be recognised by cells with 'immune' roles like NK cells or T cells. CA10 has a specific role in controlling synaptic re-modelling.

Trying to focus in on specific brain areas or cell types may well fall foul of your arguments. Quantitative comparisons of expression are likely to be misleading, I think many would agree. But we have other evidence that tends to point to hypothalamus and related areas like ventral striatum.

The cautionary tale in RA is that the key gene variant was DR4, which is used by B cells and macrophages to pass antigens to T cells. That has raised the hare that it is a T cell disease for about 40 years now when it is almost certainly a sign that it is a B cell disease. But other evidence was available to lead to a useful model and treatment.
 
Ravn said:
Dumb questions from someone who hasn’t been able to follow all the genetic discussions closely and is looking for a brainfog compatible explanation

It seems to me that most or all of the genes people have been looking at are expressed in multiple tissues and have multiple functions and possibly unknown ones as well

So how do you tease apart which tissues and/or functions are the problem ones? Why has everyone landed on neurons (not suggesting that’s wrong, just trying to understand)? Why are we not looking at all the functions of a gene, in neurons and elsewhere, together? Is it because neurons express those genes most strongly?

If so, is strength of expression necessarily relevant? Does strength of expression reflect how critical a process is, or just how much of it typically happens? Couldn’t something going just slightly wrong in some obscure tissue or pathway cause just as much trouble if it happens to be particularly sensitive to minor changes?

I’ll stop here before I think of even more possibly unanswerable questions :muted:;)

I like your videos by the way Chris, very helpful
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Thanks! We have not reported on neurons (a cell type, although @tralfamadorian97 has: https://trafalmadorian97.github.io/...nalysis/ME_CFS/DecodeME/h_MAGMA-HBA-DecodeME/). The August 2025 preprint used MAGMA to show that ME/CFS genetic heritability is significantly enriched in brain tissues. This result showed that the set of genes expressed in any of these brain tissues is more likely to be located near the DecodeME genetic signals. Hope this helps.
 
The last of the scheduled uploads has been posted from the ME/CFS Research Foundation. Thankfully, I feel a bit better than when I last posted about the videos, I don't think I'll get back to my summaries. Just not as interested and life is going to get busy soon. However, I still want to post the links to all of the videos to finish what I started. So, here they are!
 
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