Preprint Initial findings from the DecodeME genome-wide association study of myalgic encephalomyelitis/chronic fatigue syndrome, 2025, DecodeMe Collaboration

chillier said:
Does a pathogen, probably a virus, ever actually infect a neuron directly? We have non immunological genes affecting neurons, immunological genes that don't necessarily affect neurons, probably explicitly immune related genes that specifically affect neurons too - but i suppose that doesn't have to mean a neuron is dealing with a pathogen directly. I know S4ME is not very keen on the viral reservoir idea aka a brain infection but why is that?
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Yes there are neurotropic viruses definitely. I think there a couple points of evidence against persistent infection, but they're not conclusive.

1) If there was a persistent viral infection, you'd expect that nearly all of the trials using immunosuppressants would lead to dramatic worsening of disease as the virus is able to replicate utterly unchecked. There might be some obscure reason why this doesn't happen, I suppose. But highly unlikely.

2) The type of virus that causes a long term illness like ME/CFS but doesn't result in progressive deterioration and mortality would probably have to be a latent virus. Even hepatitis, which has a very slow course, has a progressive pattern.
It is unlikely that we're all suffering from the same virus, meaning that it would have to be a non-pathogen-specific effect of latent viral infection. If it is a set of different latent viruses, the question then becomes how does a virus in the latent state induce persistent issues in some but not others. Nearly half of adults have latent herpres virus in their nervous system and are fine. So if viral persistence is relevant in ME/CFS, it has to be viral reservoir + something else important.
 
Chris Ponting said:
Hi. I've posted this elsewhere on Science for ME, but think it's important to leave here too.
About the "only a 1% difference between [the frequencies of] those with ME and controls". This small "effect size" does not matter if you're focused on drug discovery. This is because the success rate from clinical development to approval "is largely unaffected by genetic effect size", see https://www.nature.com/articles/s41586-024-07316-0. The reason for this is subtle but important. Even when DNA variation tweaks biology only slightly, this variation highlights what biological aspects need changing via drugs. And these drugs can be made to alter biology to a far, far greater extent than the genes can.
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Simon M said:
(This as the answer to the question about how can small genetic differences between cases controls produce valuable information )

Is it also true that somebody who doesn't have a relevant genetic difference in a particular gene can benefit from any such drug targeting the biology behind the gene?

In other words, can information from genetic study help all those people with the illness who don't have relevant genetic differences?
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ME/CFS Science Blog said:
I've been trying to understand this through a made-up analogy. Thought I might share it to see if it holds and if others find it useful or not.

Suppose an illness is caused by a structure somewhere in the body that lets cells through that it should hold back, like a dam that is breaking. There is one gene X that helps to create a simple protein that acts as one of many support structures in the dam.

One variant of the gene creates a slightly stronger protein than the other variant to support the dam. The difference between the two proteins is minor and this protein is only a minuscule part of what holds the dam. There are many other mechanisms involved in the strength of the dam that involves feedback loops and complex interactions. These are much more important but gene X is simple and straightforward. It only has one job.

In GWAS of the illness, gene X might show up with a very small effect size. The others don't show up because the mechanisms are too complex and intertwined or there is a signal but it's ambiguous and hard to interpret. Luckily gene X points to the problem: the dam is breaking! And luckily scientists know a lot of biology so that they can do much more to support the dam than gene X could by coding its protein. They can create drugs that ensure the dam no longer breaks.

So in this analogy, the dam might be breaking even in those with the stronger protein from gene X. And fixing the dam might cause physiological changes and benefits that are out of proportion to the effect size of gene X.

Now I only hope that real life works like this as well!
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Not to echo or parrot, but does this mean that the tissues affected by the genes found in MECFS are good targets for future research (both diagnostic and treatments)? Specifically they have found areas of the brain to look at, as well as areas in the immune system, and the mitochondria..... These are promising targets for future research and are likely to be involved in the disease process.... yes?

I'm a bit brain fogged pls so let me know if this is accurate summary or how I can improve the wording.

Thanks to all you science experts explaining this to me :)
 
jnmaciuch said:
1) If there was a persistent viral infection, you'd expect that nearly all of the trials using immunosuppressants would lead to dramatic worsening of disease as the virus is able to replicate utterly unchecked. There might be some obscure reason why this doesn't happen, I suppose. But highly unlikely.
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Not necessarily, especially if we are looking at highly specific viral reservoirs.
jnmaciuch said:
) The type of virus that causes a long term illness like ME/CFS but doesn't result in progressive deterioration and mortality would probably have to be a latent virus. Even hepatitis, which has a very slow course, has a progressive pattern.
It is unlikely that we're all suffering from the same virus, meaning that it would have to be a non-pathogen-specific effect of latent viral infection. If it is a set of different latent viruses, the question then becomes how does a virus in the latent state induce persistent issues in some but not others. Nearly half of adults have latent herpres virus in their nervous system and are fine. So if viral persistence is relevant in ME/CFS, it has to be viral reservoir + something else important.
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It could be a combination of agents, and why some get sick and others do not goes back to the right combination.

These are great points @jnmaciuch. I also agree we are looking at several different pathogens among our community as at least triggering events, but the idea of sanctuary reservoirs may hold some merit.

ETA: I see you've considered reservoirs.
 
duncan said:
It could be a combination of agents, and why some get sick and others do not goes back to the right combination.
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Perhaps, though if we're looking at latent viruses (which we pretty much have to, because every other case of active viremia in a sanctuary site that I can think of also presents with pretty clear signs of inflammation and progressive tissue damage), the options are much more limited.

And the interesting thing is that viruses tend to actually knock each other out of latency--there have been documented cases in HIV and EBV, for example. If it does require a particular cocktail of latent viruses than can co-exist and accumulate over a long period, I think you'd still see cases of ME/CFS clustering moreso than you do now. Small towns where all the kids go to school together for their whole lives, families that live together, etc. There would be confounders that make it so that not everyone in a tight-knit community gets all the members of the cocktail, but it would still happen often enough that it would have been a pretty obvious epidemiological clue.

All of it points back to the same story--there may well be a viral reservoir involved in ME/CFS. But if there is, it's almost certainly one that is also present in healthy people, so the viral reservoir doesn't explain what we actually care about.
 
jnmaciuch said:
Yes there are neurotropic viruses definitely. I think there a couple points of evidence against persistent infection, but they're not conclusive.

1) If there was a persistent viral infection, you'd expect that nearly all of the trials using immunosuppressants would lead to dramatic worsening of disease as the virus is able to replicate utterly unchecked. There might be some obscure reason why this doesn't happen, I suppose. But highly unlikely.

2) The type of virus that causes a long term illness like ME/CFS but doesn't result in progressive deterioration and mortality would probably have to be a latent virus. Even hepatitis, which has a very slow course, has a progressive pattern.
It is unlikely that we're all suffering from the same virus, meaning that it would have to be a non-pathogen-specific effect of latent viral infection. If it is a set of different latent viruses, the question then becomes how does a virus in the latent state induce persistent issues in some but not others. Nearly half of adults have latent herpres virus in their nervous system and are fine. So if viral persistence is relevant in ME/CFS, it has to be viral reservoir + something else important.
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Thank you those are good arguments. A rebuttal I could imagine being made to the argument about half of all adults having herpes virus in their nervous system would be - where the reservoir is and how much of it there is could make a difference (eg in brain stem or hypothalamus).

'is a neuron ever infected with a virus' - what I'm also getting with that is whether during the infection that kicks off the illness there is virus getting into neurons or otherwise the CNS when it shouldn't be and if an event like that is necessary to develop ME/CFS. I think the implication in Jo's hypothesis is that it wouldn't be that but instead the IFNg response that kicks things off.
 
jnmaciuch said:
All of it points back to the same story--there may well be a viral reservoir involved in ME/CFS. But if there is, it's almost certainly one that is also present in healthy people, so the viral reservoir doesn't explain what we actually care about.
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Yes, one viral reservoir. But multiples that cause the tumblers to lock into place? Pathogen tandems that not just trigger the cascade of symptoms that is ME/CFS, but may help perpetuate it?

If DecodeME offers insight into who might be susceptible to being hit by the ME/CFS car, I still want to know who is driving.
 
I would agree with @jnmaciuch that the specifics of our viral reservoirs are unlikely to be a key to any sort of solution or even understanding. If there was no speck of dirt we would have nothing to grow food in. A world devoid of background mess is not an option. I don't see any reason to even talk about pathogens or tandems. Nothing indicates any sort of specificity, except perhaps the global presence of EBV and its effects on B cells.
 
Jonathan Edwards said:
I don't see any reason to even talk about pathogens or tandems.
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There are many highly regarded ME/CFS experts that would disagree with you. There are a lot of infectious disease specialists that would disagree with you.

I'm thinking the way to flesh out these ideas, and maybe even resolve these differences in beliefs, at the very least involves talking abut them.
 
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chillier said:
'is a neuron ever infected with a virus' - what I'm also getting with that is whether during the infection that kicks off the illness there is virus getting into neurons or otherwise the CNS when it shouldn't be and if an event like that is necessary to develop ME/CFS. I think the implication in Jo's hypothesis is that it wouldn't be that but instead the IFNg response that kicks things off.
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I think the circumstances under which that could happen are hard to argue for. A virus pretty much already has to be neurotropic in order to get into the CNS at all. Developing the capability to enter into a new cell type is an extraordinarily rare occurrence even for viruses that mutate extremely rapidly.

Perhaps there might be a difference in terms of how much actually gets to the brain, but in that case it would be an issue of severity rather than location specificity since viruses are detectable across the whole brain within 72 hours (at least all the ones I’m familiar with). Plus there are several cardiovascular and neurovascular disorders which seem to be associated with increased blood brain barrier permeability, but those conditions don’t seem to really predispose to ME/CFS or LC.

So that means that if this idea has any merit, it would have to be a neurotropic virus with latency capabilities that probably also enters the brain of people without ME/CFS, and the weird thing that they cause neurons to do in latency only becomes “activated” upon other infections, some of which don’t reach the brain themselves so it would have to be due to the global immune response. And it would have to be a “something weird” which only happens in ME/CFS, so that likely means an additional stochastic event of homeostatic dysregulation.

Maybe there’s something that fits that very specific bill, I can’t fully discount it. My sense is just that it’s a pretty unlikely possibility to begin with and there’s no mechanistic understanding of how any of that would actually lead to the symptoms of ME/CFS that would justify prioritizing it as a research avenue.
 
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