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

voner said:
was anyone else besides me surprised that 86.1% of the cohort reported "muscle pain"? many years of following ME/CFS forums, webinars, conferences led me to believe the number would be much lower. I’m not saying this number is good or bad or inaccurate, just that it surprised me.
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Does not surprise me, it really seems like a big part of me/cfs. Its one of my most disabling symptoms.
 
Utsikt said:
I have aches, soreness, stiffness, tingling, twitching and various forms of ‘regular’ (sharp, burning, pulsing) pain in my muscles. I’d cross of on pain for everything but the tingling and twitching.
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Same symptoms above. The only other pain I get is severe headaches, sinus facial pain, neck and also there is a localized area which happened when I got an infection when 20 years old that suddenly changed homeostasis permanently where I can experience severe pain but that last one happened before ME kicked in.
 
forestglip said:
@ME/CFS Science Blog you were wondering which SNPs were imputed. The imputed.info.gz file might have that.
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Thanks, and big thanks to the DecodeME team for uploading all this info!

This is all quite new to me so apologies for any errors or dumb questions. I think the INFO score give an indication if the imputation went well by comparing the variance of the dosage (expected number of alternative alleles) to the expected variance using the Hardy-Weinberg Equilibrium.

I would think that the genotyped SNPs are the ones with an INFO score of exactly 1 but there are only 408,031 of those in the dataset while the array (Thermo Fisher UKB AxiomTM array) should have around 820.000.

Anyone who has more experience with this who could help explain these things? Perhaps some of the measured SNPs had a INFO score slightly below 1? This all doesn't matter that much but curious to know how the actual procedure went.
 
Utsikt said:
I thought pain was really common.
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I thought it was pretty much universal, at least in women. Not the pain of a torn muscle, or an overworked and stiff one the day after unaccustomed exercise—ever-present discomfort, and a characteristic burning after movement that I never experienced before ME/CFS. Enough to stop me sleeping at night, not enough to make me wish I had a physio handy for a deep tissue massage.

I think every woman I've known in person or chatted to in-depth online has talked about muscle pain. I wouldn't be surprised to hear it was less common in men, though, I've seen posts from several saying they'd never had an issue with it.
 
Kitty said:
I thought it was pretty much universal, at least in women. Not the pain of a torn muscle, or an overworked and stiff one the day after unaccustomed exercise—ever-present discomfort, and a characteristic burning after movement that I never experienced before ME/CFS. Enough to stop me sleeping at night, not enough to make me wish I had a physio handy for a deep tissue massage.

I think every woman I've known in person or chatted to in-depth online has talked about muscle pain. I wouldn't be surprised to hear it was less common in men, though, I've seen posts from several saying they'd never had an issue with it.
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Interesting. Because the only pain I get is rare but really sharp pain. Almost like a painful long lasting cramp. Occurs always in my right hamstring for some reason. (Same hamstring that got grafted for a knee surgery, maybe thats why, but the pain only started once I slipped into extremely severe). (am biologically male)
 
Kitty said:
I thought it was pretty much universal, at least in women.
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I think it's one of the many symptoms that doesn't affect everyone just like some pwME don't experience GI issues or a sore throat. I sometimes have muscle pain when I'm in PEM and it's usually in my neck/shoulders. At the beginning I thought I had slept in a weird position and didn't associate with ME/CFS.
 
I have a question about the gene sequencing reference used in the study. I thought the GRCh37 (hg19) reference was used to interpret the GWAS gene array data in the original UK Biobank work. The DecodeME study uses the same technology so that comparison to the original data for controls is valid.

However the gene reference to the variants listed in the paper seems to be using the GRCh38 (hg38) reference. That means if we want to compare a variant location using the UK Biobank online tool we have to map the coordinates. For example, OLFM4 variant 13-53194927-GT-G is a GRCh38 reference that maps to 13-53769062-GT-G in GRCh37. That seems to map to rs35306732.

When I search for that variant in the CFS phenotype in the UK Biobank it doesn't show any results for that variant. Am I going wrong somewhere? Surely it should be in the original database?

Search | GeneATLAS

geneatlas.roslin.ed.ac.uk geneatlas.roslin.ed.ac.uk
 
wigglethemouse said:
Has there been any comment of the previous finding of SLC25A15 in women in the UK Biobank ME/CFS dataset highlighted in the Joshua Dibble thesis, a member of Chris Pontings team. I couldn't find a reference in the new paper. Would be interesting to know the p-value in this study.
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I checked the summary stats for the variant from the thesis for SLC25A15, rs7337312, which has the ID 13:40779161:G:A. The p-value for this in DecodeME is 0.713705.

Dibble found another novel association in males with the gene PDE10A, with the SNP rs76346913, which has the ID 6:165736174:C:T, but that variant doesn't seem to be one of the variants they tested. I think you would then do something like look up which SNPs are in LD with this SNP to see if any of them are in DecodeME to see if they are significant, but I don't know enough to know how to do that right.

Edit: The thesis does provide a SNP in strong LD with the PDE10A SNP, rs78375762:
However, to support this as a true association, it is encouraging that there are two other neighbouring SNPs on chromosome 6 with p-values near the suggestive threshold for this phenotype in males: rs1013902 and rs78375762. rs1013902 has the more notable p-value (p = 2.20 × 10−6 ), but is not in LD with rs76346913 (D0 = 0.0203). However the second SNP (rs78375762, p = 6.70 × 10−6 ) is in strong linkage disequilibrium with rs76346913 (D0 = 0.912).
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The p-value for this second SNP in DecodeME is 0.98 in males, 0.83 in the full cohort.

Edit: And last one I checked, Dibble also found a near significant variant associated with the gene LPGAT1: rs116109664. The p-value for this variant in DecodeME is 0.28.
 
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forestglip said:
Dibble found another novel association in males with the gene PDE10A, with the SNP rs76346913, which has the ID 6:165736174:C:T, but that variant doesn't seem to be one of the variants they tested.
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It's puzzling why we can't find matches between the variants in the two sets of data. i wouldn't have expected to find multiple missing data in only a couple of variants we have spot checked for comparison..
 
wigglethemouse said:
It's puzzling why we can't find matches between the variants in the two sets of data. i wouldn't have expected to find multiple missing data in only a couple of variants we have spot checked for comparison..
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I'm not sure about the one in your previous post. I would expect it to be in the BioBank. But maybe that website GeneAtlas doesn't show every variant they tested for whatever reason.

For the one that Dibble tested in the BioBank that wasn't tested in DecodeME, maybe that's just a variant that didn't get a good read in the DecodeME sequencing.

Edit: For the variant that isn't in GeneAtlas, I see it on this other website that just shows the allele frequency in the BioBank: https://afb.ukbiobank.ac.uk/variant/chr13-53194927-GT-G Maybe it just wasn't compared to CFS in the BioBank for some reason. But the data is still there for a few hundred thousand people.
 
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voner said:
was anyone else besides me surprised that 86.1% of the cohort reported "muscle pain"? many years of following ME/CFS forums, webinars, conferences led me to believe the number would be much lower. I’m not saying this number is good or bad or inaccurate, just that it surprised me.
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I was surprised at the significance of pain too.
I do get a lot of pain but linked I thought mostly to musculoskeletal pain. Also pain from lipomas. Also spasmodic pain around shoulder blades. I have h(EDS). For the last 18 years I have been taking prescribed pain relief which might hide other types of pain but I was still surprised at this result.
 
Regarding long covid, there are a few mentions of long covid and COVID-19 itself in the "Candidate Gene" document Chris Ponting shared in post #15 upthread. I've copied the info on each candidate gene and bolded mentions of long covid and COVID itself.

SERPINC1 (Tier 1)
• Protein: Antithrombin-III. UniProt. GeneCards. The allele that increases the risk of ME/CFS is associated with decreasing SERPINC1 gene expression.
• Molecular function: Serine protease inhibitor in plasma that regulates the blood coagulation cascade: AT-III inhibits thrombin and matriptase-3/TMPRSS7, as well as factors IXa, Xa and XIa.
• Cellular function: Extracellular function.
• Link to disease: Mutations in SERPINC1 cause antithrombin-III deficiency, which is a strong risk factor for thrombosis. A reduction in the serum level of this protein is associated with severe cases of COVID-19. Mutated in cerebral venous sinus thrombosis (CVST).
• Potential relevance to ME/CFS: Previously proposed role of ischaemia–reperfusion injury in chronic, relapsing diseases such as rheumatoid arthritis, Long Covid, and ME/CFS (23). Reduction in SERPINC1 levels expected to increase risk of blood clots. However, the eQTL is only found in brain tissue, where it is only expressed at a low level.
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BTN2A2 (Tier 1)
• Protein: Butyrophilin subfamily 2 member A2. UniProt. GeneCards. The allele that increases the risk of ME/CFS is associated with decreasing BTN2A2 gene expression.
• Molecular function: Mouse Btn2a2 inhibits T-cell activation and promotes the induction of regulatory T cells (Tregs) (31). It also promotes central tolerance to prevent autoimmune disease (32).
• Cellular function: Innate immunity, microbe-sensing.
• Link to disease: Butyrophilins confer immunity against diverse pathogenic bacteria and parasites.
• Potential relevance to ME/CFS: Stoichiometric imbalance of BTN2A and BTN3A levels could alter the ability of Vγ9Vδ2 T cells to discriminate microbial- from self-antigens, and to kill infected cells. Vγ9Vδ2 T cells can be activated by TLR3 and TLR4 ligands. TLR4 variants have been associated with Long Covid in a combinatorial genetics analysis (33).
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BTN3A3 (Tier 1)
• Protein: Butyrophilin subfamily 3 member A3. UniProt. GeneCards. The allele that increases the risk of ME/CFS is associated with increased BTN3A3 expression in skin not exposed to the sun.
• Molecular function: Co-expression of BTN3A3 synergises with BTN3A1 to greatly boost the efficiency of pAg sensing (42). Confers a chaperone-like function in boosting cell surface expression of BTN3A1 (43).
• Cellular function: Innate immunity, microbe-sensing.
• Link to disease: Butyrophilins confer immunity against diverse pathogenic bacteria and parasites.
• Potential relevance to ME/CFS: Stoichiometric imbalance of BTN2A and BTN3A levels could alter the ability of Vγ9Vδ2 T cells to discriminate microbial- from self-antigens, and to kill infected cells. Vγ9Vδ2 T cells can be activated by TLR3 and TLR4 ligands. TLR4 variants have been associated with Long Covid in a combinatorial genetics analysis (33).
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This one is very long so I have not pasted everything. See the candidate gene document for more details:
ZNFX1 (Tier 1)
• Protein: Zinc finger NFX1-type containing 1. UniProt. GeneCards. The allele that increases the risk of ME/CFS is associated with increased ZNFX1 expression in blood and brain tissues.
• Molecular function: An interferon-stimulated dsRNA sensor that specifically restricts the replication of RNA viruses early after infection (82). Studies are unclear whether ZNFX1 is localised to the mitochondrion.
...
Among 3,044 COVID-19 cases, ZNFX1 expression level shows a strong negative correlation with SARS-CoV-2 viral load (85).
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Re: chronic pain, how is this defined? What does it mean in the context of genetics results? I see there have been multiple GWAS papers on chronic pain, but it's surprising to me that people with pain of various kinds might have a common signal genetically? There are so many conditions and situations that can cause chronic pain. Sorry if this is too basic a question.

I do have pain personally but I don't know if I would describe it as in my "muscles". Worryingly I can't remember what I answered in the questionnaire. I suppose I would answer yes, but most of the pain feels like it floats around independently of my muscles.
 
Ariel said:
Re: chronic pain, how is this defined? What does it mean in the context of genetics results? I see there have been multiple GWAS papers on chronic pain, but it's surprising to me that people with pain of various kinds might have a common signal genetically? There are so many conditions and situations that can cause chronic pain. Sorry if this is too basic a question.

I do have pain personally but I don't know if I would describe it as in my "muscles". Worryingly I can't remember what I answered in the questionnaire. I suppose I would answer yes, but most of the pain feels like it floats around independently of my muscles.
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Previously I wondered if the “Chronic pain gene“ (CA10 I think?), might actually be associated with ME not chronic pain. But since ME is commonly undiagnosed and has chronic pain for many, a lot of pwME may have ended up in a chronic pain GWAS and with large sample sizes it might show an effect.
 
Yann04 said:
Previously I wondered if the “Chronic pain gene“ (CA10 I think?), might actually be associated with ME not chronic pain. But since ME is commonly undiagnosed and has chronic pain for many, a lot of pwME may have ended up in a chronic pain GWAS and with large sample sizes it might show an effect.
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Yes, I was thinking the same thing. I was quite taken aback at all the genetic research for "chronic pain" compared to what we have been getting research-wise. I imagine this research looked at quite different cohorts but I am not well enough to read about it right now. Maybe someone who understands better how the analysis was done re: the chronic pain comparison will clarify the situation.
 
Yann04 said:
Previously I wondered if the “Chronic pain gene“ (CA10 I think?), might actually be associated with ME not chronic pain. But since ME is commonly undiagnosed and has chronic pain for many, a lot of pwME may have ended up in a chronic pain GWAS and with large sample sizes it might show an effect.
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That's an interesting thought.

Conversely, there seems to be a lot of overlap between ME and Fibro. Maybe the people who have this chronic pain gene
/have large amounts of pain with their ME symptoms - have fibro+ME.
 
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