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

[Jonathan Edwards]

Hi @mariovitali ,

To me those responses are just a rehash of all the trendy stuff constantly recycled by people thinking inside a box with no real understanding of global biodynamics. There is no actual explanatory model, just buzzwords.

I think asking @jnmaciuch or @Snow Leopard and a few others here, some with little or no technical training in the field but a good dose of common sense, is likely to provide a more interesting answer.

 

[mariovitali]

Hi @mariovitali ,

To me those responses are just a rehash of all the trendy stuff constantly recycled by people thinking inside a box with no real understanding of global biodynamics. There is no actual explanatory model, just buzzwords.

I think asking @jnmaciuch or @Snow Leopard and a few others here, some with little or no technical training in the field but a good dose of common sense, is likely to provide a more interesting answer.

Thank you for your reply. Actually the responses are not included in my message (=the hypotheses) . One hypothesis text for example states the following :

ME/CFS arises when a genetically primed bottleneck in endosomal/ER trafficking and ER‑phagy (RABGAP1L, ARFGEF2, CCPG1) meets oxidative–lipid stress on mitochondria and endothelium (FBXL4, PRDX6, PEBP1, HFE), tipping immune checkpoints toward non‑resolving activation (BTN2A2, TNFSF4/RC3H1, TRIM38) and culminates in microvascular hypoperfusion (SERPINC1, PTGIS) and dysautonomia (CA10, PEBP1), with epigenetic locking (SUDS3) that sustains the state after diverse triggers (viral or toxicants such as organophosphates).

How the GWAS hits define the core failure points
- Vesicle and receptor trafficking bottleneck
- RABGAP1L and ARFGEF2 (BIG2): control Rab/ARF-dependent endosomal and Golgi trafficking. A deficit here impairs antigen processing, cytokine receptor recycling, and GPCR trafficking (including adrenergic/muscarinic receptors), prolonging or distorting signaling and antigen persistence.
- CCPG1: an ER‑phagy receptor that clears stressed ER. Lower ER‑phagy capacity makes secretory/immune and barrier cells intolerant to acute ER stress (infection, toxins), amplifying the unfolded protein response and DAMP signaling.
- Energetics and oxidative resilience
- FBXL4: maintains mitochondrial DNA and biogenesis; even partial impairment lowers ATP reserve and raises ROS under stress.
- Immune co-regulation and mucosal priming
- BTN2A2: butyrophilin family co-regulatory molecule shaping T cell responses (including γδ T cells); variants can skew immune tone toward either overactivation or poor resolution.
- OLFM4 (Tier 2 but a GWAS hit): neutrophil/intestinal stem cell protein modulating innate responses; links mucosal barrier events to systemic inflammation.
- Neuro–autonomic vulnerability
- CA10: brain/synaptic carbonic anhydrase–like protein (noncatalytic) that modulates synaptic architecture and excitability; variants can destabilize central autonomic networks and sensory processing.
- Transcriptional set-point
- SUDS3: SIN3–HDAC scaffold; shifts gene-expression programs (metabolic and immune), facilitating a chronic “stuck” state.

How Tier 1 genes reinforce these modules
- Immune activation and off-switches
- TNFSF4 (OX40L) and RC3H1 (Roquin-1): coherent pair—RC3H1 normally destabilizes OX40/ICOS mRNAs; variants combined with higher OX40L tilt toward sustained T cell help, autoimmunity, and poor resolution.
- TRIM38, ZNFX1: tune innate RNA-sensing and type I IFN—risk of a chronic, smoldering antiviral program even after acute infection clears.
- BTN3A3 (with BTN2A2): further modulates γδ T cell circuitry.
- Trafficking, degradation, and stress responses
- KLHL20, CSE1L, STAU1, DDX27: ubiquitin/trafficking, RNA handling, ribosome biogenesis—together lower the ceiling for rapid recovery from cellular stress.
- Redox–lipid injury and ferroptosis susceptibility
- PRDX6 (peroxidase/iPLA2), PEBP1 (RKIP; also scaffolds 15‑LOX to peroxidize phosphatidylethanolamine), HFE (iron handling): converge on lipid peroxidation control and ferroptosis threshold.
- B4GALT5: glycosphingolipid biosynthesis that tunes membrane microdomains in platelets/endothelium and immune cells.
- Microvascular tone and thromboregulation
- SERPINC1 (antithrombin) and PTGIS (prostacyclin synthase): prothrombotic/vasoconstrictive tilt → microclots and impaired perfusion.

Tier 2 proximity-only genes (lower confidence, but consistent with the model)
- FBXL4 (also a top GWAS hit, so still high importance), OLFM4, CCPG1: while they lacked eQTL colocalization in this analysis, their known functions fit the core axes above (mitochondria, innate/mucosal immunity, ER‑phagy).

 

[Evergreen]

Regarding pain, being discussed by @voner, @Simon M and others above, here's an excerpt of table 4 from Pendergrast et al. 2016. Scroll down for pain.



For what it's worth, I had little or no new pain for the first 5 years, with the exception of when I did GET (joint pain bad enough to see a specialist, vanished when I stopped GET). The only real pain I had when I was mild and mild-moderate was if I really and truly overdid it to a daft degree, and it receded within a few days. And sometimes feeling in my quads as if I had been exercising heavily the day before (more like muscle fatigue), despite not having done anything that should have made quads tired. A lot of pain now.

 

[Kitty]

And sometimes feeling in my quads as if I had been exercising heavily the day before (more like muscle fatigue), despite not having done anything that should have made quads tired.

That describes part of my pain very well, I've had it throughout the illness except for a couple of remissions. But when I relax the quads they burn too, and that's the worst of it. I've never had pain in any other muscle group.

I was diagnosed in the late 90s (after years of illness), and I remember reading something produced by the MEA. It said quads and intercostals were the most common pain sites.

 

[Evergreen]

That describes part of my pain very well, I've had it throughout the illness except for a couple of remissions. But when I relax the quads they burn too, and that's the worst of it. I've never had pain in any other muscle group.

I was diagnosed in the late 90s (after years of illness), and I remember reading something produced by the MEA. It said quads and intercostals were the most common pain sites.

Yeah, it's interesting that the aftermath you've described in other posts seems to be the opposite of the aftermath for me. I absolutely have to lie down and rest them and that eases the fatigue/burn (somewhat). But it seems like the central issue is the same.

 

[chillier]

A couple more thoughts and open questions

- cell type most clearly implicated is the neuron

- Which type of neurons are affected and where? Peripheral ones or Central ones, acetycholinergic ones or glutamatergic ones? Or any type anywhere. GWI might suggest acetylcholinergic, and the HOMER-SHANK-DLGAP complex that came up in Zhang et al's WGS study might suggest glutamatergic, but I get the feeling from decode that it's probably pan neuronal.

- 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?

- What effect do the variants we see have on the neuron? I think the genes might suggest a dysfunction in the ability to form, maintain or regulate synapses in some way, but how exactly? Would it be excess synapse formation leading to excess firing or an inability to form them leading to a loss of connection. Or would the affect result in a change in scaling, synapses being more prone to scaling either up or down but not the other way. Perhaps the situation is more complex and leads to an inflexibility to change in either direction, or poorly constructed synapses lead to neurotransmitter spillover and more sketchy unstable firing patterns in some form. This is surely the kind of thing we could have a guess at with the evidence we have, and would otherwise be testable in cell culture.

 

[Nightsong]

Re pain in ME/CFS: muscle & joint pain was highly prevalent in the 1999 Jason community sample (link), and in the 2011 Nacul primary-care sample (link) - Nacul et al reported "joint (76% to 91%) and muscle pain (74% to 95%)". There was also a 2010 paper based on interviews with 50 pwME, including 10 severely affected, that attempted to characterise the types of pain they experienced.

There was also this from IOM:

Recent preliminary data from the Centers for Disease Control and Prevention’s (CDC’s) Multi-Site Clinical Study of CFS indicate that 80 percent of patients enrolled had experienced pain in the past week (Unger, 2013). Muscle aches and pains were the most common pain complaint (reported by 72 to 79 percent of patients), followed by joint pain (reported by 58 to 60 percent of patients) and headaches (reported by 48 to 56 percent of patients). Less common pain complaints included tender lymph nodes (37 to 39 percent), abdominal pain (32 percent), sore throat (25 to 28 percent), eye pain (23 percent), and chest pain (15 percent).1,2

Historical surveys also showed significant proportions of pwME experiencing pain - AfME's 2001 membership survey reported that "77% experienced severe pain because of the illness", for instance.

 

[Simon M]

cell type most clearly implicated is the neuron

How sure of this can we be at this stage? The two specific bits of evidence I'm aware of, the most relevant CA 10 for pain, which is directly affects neuron. However, there's also a microglial gene. Microglial are glia not neurons. Then there are the 13 tissues where candidate ME/CFS genes are overexpressed – all brain regions. But I don't think we know if they are glial cells or neurones. Or have I missed something?.

 

[Simon M]

Luckily gene X points to the problem: the dam is breaking!

Good analogy

One variant of the gene creates a slightly stronger protein than the other variant to support the dam

I'm pretty sure genes identified by GWAS make identical proteins, and variants instead alter gene regulation, usually not by very much. That's one reason why effect sizes are small.

So it may be that the dam is stronger because a bit more of this protein is produced. But the point is the same, this could still point to a good target for an effective drug

ADDED
I recently saw a pre-print or paper (sorry, can't find link) that found 92% of gene variants identified by GWAS were non-coding.

 

[chillier]

I'm sure of this can we be at this stage? The two specific bits of evidence that's the most relevant CA 10 for pain, which is directly affects neuron. However, there's also a microglial gene. Microglial are glia not neurons. Then there are the 13 tissues where candidate ME/CFS genes are over expressed – all brain regions. But I don't think we know if they are glial cells or neurones. Or have I missed something?.

That's fair. I'm using a lot of the single cell type annotations from proteinatlas.org as a bit of a guide, and then some of the descriptions of the genes. ARFGEF2 for example supposedly has a role in GABA receptor recycling from endosome to membrane, which would suggest a neuronal function to me. Others have evidence that suggest a role in neurite development (like KHLH20) or neuropeptide (PEBP), but it's true these roles don't need to be carried by the neurons themselves, but could be by supporting glia to affect the function of the neuron.

I'm also factoring in a bit the SHANK complex found in zhang et al WGS, which is post synaptic density on glutamatergic neurons. Could be a good exercise to examine which cell types each of the decode genes most likely point to.

 

[Mij]

I thought pain was really common. It doesn’t have to be extreme pain, and some of it might also be more aches, stiffness and soreness.

I've never had pain related to M.E in 34 years. I have experienced deep bone aching/soreness during the early PVFS stage and only during immune events like viral reactivations. I never described it as pain and it doesn't require medications.

I've never had inflammation markers based on my test results, so the term M.E doesn't fit my experience.

 

[Hoopoe]

I know S4ME is not very keen on the viral reservoir idea aka a brain infection but why is that?

The thinking is that in the terminal stage of the illness, the immune suppression of the virus would fail. Since symptoms and signs of brain infection don't seem to be a common phenomenon in terminal cases, brain infection doesn't seem convincing. There are going to be patients who also have some persistent infection or difficulty controlling infection but it seems to be small minority so there's no clear link.

I know there's some evidence that viruses can produce ongoing responses even while fully suppressed. Van Elzakker was interested in this idea.

 

[duncan]

Does a pathogen, probably a virus, ever actually infect a neuron directly?

My understanding is viruses and bacteria can infect neurons directly. Herpes and borrelia, respectively, would be examples.

 

[jnmaciuch]

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?

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.

 

[ElephantNerd]

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.

(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?

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!

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

 

[duncan]

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.

Not necessarily, especially if we are looking at highly specific viral reservoirs.

) 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.

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.

 

[jnmaciuch]

It could be a combination of agents, and why some get sick and others do not goes back to the right combination.

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.

 

[chillier]

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.

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.

 

[Jonathan Edwards]

One argument against persistent virus is that MECFS seems to have one pattern of presentation (broadly) but the persistent viruses we know of all produce very different disease. MECFS could be due to one specific hidden virus despite being triggbred by lots but it gets a bit complicated.

 

[duncan]

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.

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.