Preprint Biological Insights from Genome-Wide Association Studies and Whole Genome Sequencing of [ME/CFS], 2026, Maccallini et al

[forestglip]

Yes, this dendrogram is based on genetic data. More precisely, I used the genes found by PrecisionLife using the DecodeME cohort plus the genes found by Mark Snyder from WGS of 200 or so ME/CFS patients. I then collected genes form the latest GWAS and rare variants studies for other 27 common diseases.

Might it make sense to make a dendrogram using the raw SNP p values from the whole genome? I don't know how to do it, but it seems like it could be less affected by differences in how studies pick genes (e.g. PrecisionLife's method vs other GWAS using nearest gene).

 

[duncan]

It is simply not possible to tell from observing your symptoms that you have a degenerative disease.

Over 30 years? Sure it is. I've steadily seen my IQ drop over the years. The last I checked, it was down 20 points over premorbid levels. Now, it may be fair to claim those are objective tests, but I can feel my Stupid, much as I can the sense of poison that courses through me that no one can capture in any objective lab.

But if you know where to look, and have the right technology, can you actually demonstrate it in pwME? I think you can, but you better be looking hard for it. How many have access to a Tesla 5 or 7? I did, through the NIH, and it repeatedly revealed brain atrophy, albeit subtle. Fortunately, they were looking for something, they just didn't know what. And my results took them off guard.

How many of us recover to healthy status? 5%? Less? We haven't merely deteriorated, we've loss a varying degree of function - forever.

And for a portion of us, that degree, with speed bumps, only worsens over time. It's just the rate that varies when you've that brand.

Fortunately, that is a small portion of pwME.

I deteriorate with the flu. ME/CFS for me was degenerative.

ETA: My wife has ATS. She has seen only one neurologist in the least 30 years. She has forever refused to read the studies, or look at the science. She doesn't want to know. Do you imagine she doesn't for a second know that her body is slowly failing her in a degenerative fashion?

 

[Verity]

Over 30 years? Sure it is. I've steadily seen my IQ drop over the years. The last I checked, it was down 20 points over premorbid levels. Now, it may be fair to claim those are objective tests, but I can feel my Stupid, much as I can the sense of poison that courses through me that no one can capture in any objective lab.

But if you know where to look, and have the right technology, can you actually demonstrate it in pwME? I think you can, but you better be looking hard for it. How many have access to a Tesla 5 or 7? I did, through the NIH, and it repeatedly revealed brain atrophy, albeit subtle. Fortunately, they were looking for something, they just didn't know what. And my results took them off guard.

How many of us recover to healthy status? 5%? Less? We haven't merely deteriorated, we've loss a varying degree of function - forever.

And for a portion of us, that degree, with speed bumps, only worsens over time. It's just the rate that varies when you've that brand.

Fortunately, that is a small portion of pwME.

I deteriorate with the flu. ME/CFS for me was degenerative.

But you could say these sorts of things about illnesses that we know are not degenerative. I’m not seeing the connection. I was in graduate school when I got sick and have felt very stupid compared to my past self for years! But I started Ritalin recently and regained lot of cognitive function.

I am not sure how interpretable one test showing brain atrophy is. Someone else can weigh in if they think it’s really definitive.

(I think we’d better take this to a different thread if we want to discuss whether ME is degenerative because it may be getting off track here.)

 

[wallfish]

View attachment 32485

Is my interpretation correct that the closeness between Obesity and Sleep Disorder can be attributed to something like Obstructive Sleep Apnea, while the closeness between MECFS and Sleep Disorder is likely due to a different kind of relationship?

Obesity and MECFS are clustered together, but maybe deceptively so?

I might be wrong, I am not familiar with the data or the process. Only glanced the figure. I ask because I struggled in the past to create meaningful dendrograms (in the sense of identifying some known relationship instead of false friends) from text embeddings.

 

[duncan]

But you could say these sorts of things about illnesses that we know are not degenerative. I’m not seeing the connection. I was in graduate school when I got sick and have felt very stupid compared to my past self for years! But I started Ritalin recently and regained lot of cognitive function.

I am not sure how interpretable one test showing brain atrophy is. Someone else can weigh in if they think it’s really definitive.

(I think we’d better take this to a different thread if we want to discuss whether ME is degenerative because it may be getting off track here.)

What percent of us return to our premorbid levels? We don't.

So perhaps the initial insult caused mci, or other damage, and then we level set. Maybe.

But I feel worse, and that's my metric after studying all these studies about so many of us and folk like us for far too many years.

BTW. I've three MRIs that show atrophy.

 

[MrMagoo]

Yes, I’ve also heard that for some, but at the same time there are also people like this.

We’d have to be able to explain both.

What would be degenerating? We haven’t found it yet at least.

I absolutely feel that mine started years before. But I also was running regular 10k, working, studying at night, travelling the world and considering whether to try and do a marathon when I became ill. Not long before I won a prize for most regular attendance at my gym. I had also been struggling with getting more frequent colds/bugs, every few months I’d feel like I was hit by a virus…sound familiar?

 

[Axel]

The link with diabetes is unclear to me. Same applies to obesity. One may argue that if you are sedentary because of ME/CFS, you are susceptible to obesity and diabetes.

Behaviour doesn’t alter genes; that’s what makes these comparisons and parallels so interesting. ME/CFS turns out to be on an unexpected side that will provide further clues.

 

[duncan]

Now, it may be fair to claim those are objective tests, but I can feel my Stupid, much as I can the sense of poison that courses through me that no one can capture in any objective lab.

I have to admit to both @Verity and @Utsikt that's a dubius scientific method I am embracing.

 

[SugarSquared]

Going off of @Axel and @Violeta's thoughts, I wonder if there is some connection to diabetes and obesity through metabolism. Polyendocrine metabolic ovarian syndrome (PMOS, previously PCOS) is strongly linked to type 2 diabetes and obesity due to insulin resistance. Without proper management, it can lead to prediabetes and even go further into type 2 diabetes. I feel like I also remember hearing about non-alcoholic fatty liver disease when learning about PMOS (quick Google search gave me this: Vassilatou, (2014), Nonalcoholic fatty liver disease and polycystic ovary syndrome).

I'm curious where PMOS would end up on the graph (though I don't know what the feasibility of adding it would be). Also, these are my ideas based off of having both PMOS and ME/CFS. I don't know how many people are in my same boat.

I would not be surprised if ME/CFS is not only neurological and immunological, but also metabolic.

 

[MrMagoo]

I have to admit to both @Verity and @Utsikt that's a dubius scientific method I am embracing.

One which many “researchers” would do well to check themselves for…

 

[MrMagoo]

Going off of @Axel and @Violeta's thoughts, I wonder if there is some connection to diabetes and obesity through metabolism. Polyendocrine metabolic ovarian syndrome (PMOS, previously PCOS) is strongly linked to type 2 diabetes and obesity due to insulin resistance. Without proper management, it can lead to prediabetes and even go further into type 2 diabetes. I feel like I also remember hearing about non-alcoholic fatty liver disease when learning about PMOS (quick Google search gave me this: Vassilatou, (2014), Nonalcoholic fatty liver disease and polycystic ovary syndrome).

I'm curious where PMOS would end up on the graph (though I don't know what the feasibility of adding it would be). Also, these are my ideas based off of having both PMOS and ME/CFS. I don't know how many people are in my same boat.

I would not be surprised if ME/CFS is not only neurological and immunological, but also metabolic.

Wouldn’t that make it highly unusual and difficult to detect?

 

[AliceLily]

For myself I don't feel like there is brain atrophy for the reason that when I had Covid in 2024 my brain felt clear for that first week. About the 8th-10th day I felt the heaviness of the brain fog shifting back in, and it was heavy.

It feels to me that something tripped me into brain fog and locked the door until something like a cold/Covid unlocks temporarily and then the trip happens again back to brain fog.

 

[Violeta]

My brain battery is running on low, let me ask @mariovitali what he found in this study that had to do with the liver and ME/CFS. (He mentioned it in his Twitter account.)

Replicated blood-based biomarkers for myalgic encephalomyelitis not explicable by inactivity​

Replicated blood-based biomarkers for myalgic encephalomyelitis not explicable by inactivity - EMBO Molecular Medicine

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a common female-biased disease. ME/CFS diagnosis is hindered by the absence of biomarkers that are unaffected by patients’ low physical activity level. Our analysis used semi-parametric efficient estimators, an initial Super Learner...

link.springer.com

From the study:
"Biomarkers are indicative of chronic inflammation, insulin resistance and liver disease."

Are there any studies that match genes to biomarkers?

 

[mariovitali]

I spoke with a patient just yesterday. He mentioned that he has elevated ALP (Liver-related enzyme). Another patient -a psychiatrist- , got COVID19 then LongCOVID and now he has symptoms similar to Fibromyalgia. He contacted me because he found to have elevated blood ammonia (=impacts the liver). He also has Gilbert's.

Question : Should elevated ammonia be dismissed as an offending factor, simply because not every patient has it? This is what we are discussing here.

Do I believe that the liver is the only responsible factor ? absolutely not. But it should not be dismissed out of the picture because "many people have liver problems and they do not have ME/CFS"

We could see insulin resistance and liver disease that @Chris Ponting' s study identified as factors that set the stage along with other factors. And I believe that synapses are one of them and this is where @paolo study excelled. So we have a kind of a perfect storm taking place : metabolic+immune+neural.

Also, we should not dismiss findings of the DecodeME study so easily and what could they suggest. They imply issues with vesicle trafficking, ER-golgi transport, organelle quality control and autophagy among others. Question : Do these concepts connect with synaptic function? If yes, what are the implications on the synapses if we have failure of these concepts upstream ?

Are we sure that we have checked everything ? Did we have an efferocytosis assay done for ME/CFS after all of these years?

Jack Hadflield, previously CEO of Amatica Health posts about a test that costs more than 1K dollars (yes I know what people think about their methodology). At the same time, he has elevated liver enzymes ever since he got COVID19 :

 

[Jonathan Edwards]

Question : Should elevated ammonia be dismissed as an offending factor, simply because not every patient has it? This is what we are discussing here.

In simple terms, yes it should.

In looking for "ME/CFS" we are looking for some common element to pathogenesis that justifies having this syndrome name, which is there because we suspect such a common element.

If elevated ammonia is not this common element, or part of a common sequence of elements, it is not 'the offending factor'. It might be one of several ways to feed in to such an offending factor but it is not the offending factor we are looking for.

Statistical shifts in values are never going to give us 'offending fctors' if many of the values are in the normal range. They may provide invaluable indirect or circumstantial eviedence of an offending factor nearby but no more than that.

 

[mariovitali]

In simple terms, yes it should.

In looking for "ME/CFS" we are looking for some common element to pathogenesis that justifies having this syndrome name, which is there because we suspect such a common element.

If elevated ammonia is not this common element, or part of a common sequence of elements, it is not 'the offending factor'. It might be one of several ways to feed in to such an offending factor but it is not the offending factor we are looking for.

Statistical shifts in values are never going to give us 'offending fctors' if many of the values are in the normal range. They may provide invaluable indirect or circumstantial eviedence of an offending factor nearby but no more than that.

Elevated ammonia should be dismissed as the universal offending factor in ME/CFS. But it should not be dismissed as biologically irrelevant in a subgroup. Are you suggesting this may not be the case?

if elevated ammonia is not present in most patients, then it is probably not the common causal element that defines ME/CFS but It may be one of several routes feeding into a more central pathology. In complex diseases, many important mechanisms are not present as abnormal lab values in every patient, correct?

In other words, ammonia is unlikely to be the universal cause of ME/CFS, but elevated ammonia or related urea-cycle/liver/nitrogen-handling abnormalities could be a subgroup signal or a clue to a common recovery-failure pathway that is responsible for PEM.

In relation to DecodeME, the same logic applies. RABGAP1L, KLHL20, ARFGEF2-like trafficking biology, autophagy, Golgi/endosome transport, immune signaling, and synaptic development are not “the biomarker” either. But they may point toward a network-level vulnerability. Are we able to dismiss this possibility and focus just to neurons?

 

[Jonathan Edwards]

Elevated ammonia should be dismissed as the universal offending factor in ME/CFS. But it should not be dismissed as biologically irrelevant in a subgroup.

I think those were the points I was making @mariovitali.
But we are looking for the universal offending factor. If there isn't one then the name ME/CFS was a mistake.

And to be honest I doubt that more than 1% of people with ME/CFS have a clinically relevant elevation in ammonia. 5% will have a statistically 'raised' level just because that is how it is defined. I have seen no evidence for even a trend on published studies.

 

[mariovitali]

I think those were the points I was making @mariovitali.
But we are looking for the universal offending factor. If there isn't one then the name ME/CFS was a mistake.

Is it reasonable to look for a universal offending factor in a polygenic disease (I believe Chris Ponting mentioned that many times)? Unless the results of this analysis suggest that ME/CFS is not a polygenic disease.

Talking about names, I really do not care whether we have been calling it in a wrong way and I believe that many patients feel the same. If the common offending factor is metabolic disruption that takes place via different routes be it a viral infection, chemical exposure to organophosphates or even intense stress then we could name it "Post-metabolic disruption syndrome".

Let's end the discussion here for the sake of this thread, I am sure that readers by now get the point.