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

ME/CFS Science Blog said:
He also refers to Paolo Maccalini's meta-analysis of DecodeME with results from other genetic databases. Not sure if we discussed this before. Looks like impressive work from Paolo.
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The meta-analysis only has three significant hits left, but includes one on chromosome 2 that we haven't discussed much because it only reached 10^-6 levels in DecodeME.

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Potential genes are:

UGP2: converts glucose into UDP-glucose. The short form is primarily located in the brain.
VPS54: handles retrograde transport of proteins: it catches vesicles coming back from the cell's outer layers and docks them at the Golgi apparatus for recycling.
 
Paolo's meta-analysis also found glutamatergic synapses to be significant
MAGMA-proprietary gene-set analysis identifies the Gene Ontology (cellular-component level) term GLUTAMATERGIC_SYNAPSE as significant after Bonferroni correction. The term POSTSYNAPTIC_MEMBRANE is almost significant
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A recent study on long COVID found an increased density of AMPA receptors (Fujimoto Y et al. 2025), which may be an adaptation to reduced glutamatergic signalling. In a survey on 150 ME/CFS patients, 66% reported being less able to tolerate alcohol compared to their pre-illness state (Lily C et al. 2019). This could be explained by the inhibitory effect of alcohol on NMDA receptors: under the hypothesis of deficient glutamatergic transmission, alcohol would be expected to exacerbate the disease.
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Nicki Lake

'The first presentation at the Berlin conference was by Prof. Chris Ponting from Edinburgh University on the big genetic study called DecodeME. He made a strong statement that ME/CFS heritability is...
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'The first presentation at the Berlin conference was by Prof. Chris Ponting from Edinburgh University on the big genetic study called DecodeME.
He made a strong statement that ME/CFS heritability is exclusively enriched in neural tissues.

Ponting said that the genetic analysis of ME/CFS has substantial overlap with fibromyalgia and that for both, the genetic risk is focused on the brain, and neurons in particular.

There’s no direct genetic evidence for immune-related pathogenesis outside neural tissue. They hoped to have found a genetic association in the HLA region because that would have been a strong signal that ME/CFS has autoimmunity, but they did not find that.

Someone asked if the genetics highlights certain cell-types in the nervous system: is it more microglia or more synaptic function? Ponting answered that they are doing this analysis right now, but “everything we have right now says it’s neurons, not glia. There are indications for synaptic protein genes being involved.”
DecodeME also did an analysis where they compared patients with high and low symptom burden based on 67 questionnaire responses, but did not find a significant difference in the genetics. Genes that came close to significance are RORA, SPP2/TRPM8, and RARRES2.

Ponting also explained why DecodeME hasn't published yet. They want to do additional analysis (HLA, fine-mapping, gene-based analysis, genetic correlations, comorbidity genetics, etc). These are all nearly done except the analysis of the X chromosome, which is still ongoing.

Lastly, he pleaded for long-read sequencing of the HLA region to get a better resolution and analysis of rare genetic variants.

This will be done in SequenceME, which is looking for additional funding so that it can read all the DecodeME samples with higher resolution.

Interestingly, an analysis of rare variants from the UK biobank already pointed to mutations of the gene BTN2A1, which is involved in T-cell activation. It also came up in DecodeME, so it could be an important lead for research on the immune system in ME/CFS.'

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Amw66 said:
There’s no direct genetic evidence for immune-related pathogenesis outside neural tissue.
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This seems a slightly odd statement, even if it doesn't matter much.
There is no direct genetic evidence even for neurons and the BTN2A genes are quite clearly related to 'immune' responses if that means lymphocyte signalling. They do not necessarily point to micro-organisms or foreign antigen, for sure, but from the disease dynamics point of view I think the possible implication in shifts in lymphocyte populations is key and comes under 'immune-related pathogenesis'.
 
Amw66 said:
He made a strong statement that ME/CFS heritability is exclusively enriched in neural tissues.
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I don’t know how accurately Chris has been quoted but, in addition to Jonathan’s comment about BTN2A above, would it not be more accurate to say that the data from DecodeME only provides evidence of heritability in XYZ?

In other words, the summary above suggests that Chris was saying that the data shows that heritability is confined to genes associated with neural tissues, but my understanding is that it only provides evidence of heritability in those genes (and BTN2A), which is quite different. As far as I understand, WGS could well show that other variants associated with different systems increase probability of ME/CFS.

However, my understanding is very limited so please correct me if I’m wrong.
 
Robert 1973 said:
However, my understanding is very limited so please correct me if I’m wrong.
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No, I think that is right. We don't know that the 8 sites found in DecodeME are responsible for most of what heritability there is. Most of it may be somewhere else, not accessible to the GWAS approach.

Moreover, most of the genes linked to brain and synapses do other things elsewhere, so I think Chris is just talking about the weight of clues rather than anything definitive.

It is also worth remembering that genes may contribute either to the likelihood of an ME/CFS process being set in chain and the susceptibility of target tissues (which could be brain) to the effects of that process. The process might be somewhere else entirely but genetics might have more influence on susceptibility.

Having said all that, biomedical science always has to move forward on the basis of where the weight of clues leans you. If the purpose of speculating is to home in on some region to do more research on then I would agree with Chris entirely.
 
Jonathan Edwards said:
It is also worth remembering that genes may contribute either to the likelihood of an ME/CFS process being set in chain and the susceptibility of target tissues (which could be brain) to the effects of that process.
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I had been thinking about this before you posted, so I’m pleased you’ve mentioned it. I was also wondering if there may be ways to infer whether the identified genes are contributing to the process being set in chain or the susceptibility of target tissues.

I’ve not been able to follow discussions in detail so I apologise if this has already been discussed but I’m wondering if the distributions of variants between different severities could give us any clues.

For example if a variant increased the probability of the process being set in chain then I’m thinking that one would not necessarily expect any difference in distribution between severities (because the process needs to started irrespective of severity). But if it was affecting susceptibility of tissue to the effects of that process then I’m guessing that one might expect to see higher frequency of that variant in people who are more severe.

I’m just thinking aloud and would need to think about this more when my brain is working better but it seems at least conceivable that it might be possible to make some inferences from the existing data.

I’m also wondering if there could be a third variable to which the genes are contributing. If whatever process is being set in chain produces something (eg auto-antibodies) which is then acting on target tissues, presumably the genes could affect the quantity, and perhaps the quality, of whatever is being produced?
 
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Robert 1973 said:
I was also wondering if there may be ways to infer whether the identified genes are contributing to the process being set in chain or the susceptibility of target tissues.
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Interesting question. Off the top of my head, we might some clues from how many diseases the risk gene goes with. An end organ susceptibility gene might perhaps be expected to turn up in a whole range of rather disparate diseases affecting that tissue. A process gene might have a narrower linkage. It may be that cross comparing with lots of other diseases - as people are currently doing, will produce some useful pointers.
 
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