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

Chris Ponting said:
To help, we wrote a document on candidate genes: https://www.pure.ed.ac.uk/ws/portalfiles/portal/533352484/Candidate_Genes.pdf
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Wow, that first gene RABGLP1 and its strep association. I’ve always struggled with strep throat after getting mono in my teens. Then my 20s my ME/CFS started after a strep throat infection did not fully clear from 1st round of antibiotics, sat with an infection for 2 weeks, before getting a second round. 1 month later ME/CFS started.

This feels on the money for me. I feel like there’s a guy on twitter chasing the strep angle, can’t remember his name off the top of my head.

Edit: Vijay Iyer on x was chasing a strep angle from what I remember
 
Andy said:
We found that people with ME/CFS are more likely to carry certain DNA differences in eight regions of their genome, and so these variants tell us about possible biological causes of ME/CFS. However, as these differences are also often found in people without ME/CFS they cannot cleanly separate who is at risk and who is not, and therefore do not provide a definitive test.
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Can someone clarify this for me, as it sounds contradictory - I know it won't be but I don't properly understand.

How is it that ME/CFS sufferers have significant DNA differences from the general population in the 8 regions of their genome, whilst at the same time this cannot differentiate ME/CFS sufferers because the general population also has them? What am I missing please?
 
Barry said:
Can someone clarify this for me, as it sounds contradictory - I know it won't be but I don't properly understand.

How is it that ME/CFS sufferers have significant DNA differences from the general population in the 8 regions of their genome, whilst at the same time this cannot differentiate ME/CFS sufferers because the general population also has them? What am I missing please?
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An oversimplified explanation I sent to someone else asking the same question on another group:
Basically they took 15k with Me/cfs and looked at what genes were more common/uncommon in pwME.

So those genes still exist in healthy people, just that theyre more common/uncommon in pwME. And that might give us clues, like do those genes contribute to factors that makes developing ME more likely
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Even though it was tough to get significance with the lower numbers in the male cohort, it's really nice to see that the effect direction is identical for all 8 of the main loci in females and male. And two of the three that were genome-wide significant in females were p<.017 (Bonferroni adjusted threshold for 3 tests) in males. More confidence that these aren't chance findings.
image.psd(5).png
 
I have 3 of the 8 SNPs, in RABGAP1L, CCPG1, CA10.

I'm not sure what this means. I can't find information on how common these SNPs are to get an idea of whether I have more of these SNPs than expected by chance or not. Presumably these are fairly common ones.

I'm going to try and look the candidate genes more in detail. If I found some variant in the vicinity that was flagged as likely pathogenic, would that be interesting?

Do people with a disease also tend to have more rare pathogenic variants in the vicinity of the common SNPs that GWAS can find to be associated with that disease?

I'm also struggling to find a free, working, easy to use program that allows me to copy the variants in the vicinity of these candidate genes from a VCF files into the Ensemble VEP or something similar.
 
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Jonathan Edwards said:
it is rather unlikely that men get there one way and women another - like one lot T cells and the other lot B cells for instance. If so that is a very major finding that makes things easier.
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And the questionnaire data looking at comorbidities (not coal visitors!), symptoms and severity differences, and onset types, but nothing that suggested two different categories
 
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Hoopoe said:
I can't find information on how common these SNPs are to get an idea of whether I have more of these SNPs than expected by chance or not. Presumably these are fairly common ones.
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If you look at the table I posted a few posts up, it shows the frequency of the effect allele under A1FREQ. So for RABGAP1L, it says 0.325, which means 32.5% of the combined cases and controls had the effect/risk allele.
 
Thank you so much @Chris Ponting @Andy and the decode team. There's no words really to properly express the gratitude.

FBXL4 can cause mitochondrial DNA depletion syndrome caused by elevated mitophagy.
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Loss of function causes excess culling of mitochondria leading to mitochondrial DNA depletion syndrome or mitochondrial encephalopathy. This reminded me of something from Josh Dibble's 2020 review about mitochondrial genetics:

Independent studies confirm that clinically proven mitochondrial DNA (mtDNA) variants do not commonly explain ME/CFS (26–28). People with ME/CFS, however, appear more likely to carry mtDNA that lacks even mildly deleterious variants (28), a finding whose implications require further investigation.
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I wonder if an FBXL4 mediated oversensitivity to removing slightly mutated mitochondria could explain that. It appears that FBXL4 loss is deleterious to mitochondrial function - from FBXL4's OMIM page:

Patient muscle homogenates or isolated mitochondria showed variably decreased activities of the mitochondrial respiratory chain complexes as well as decreased mtDNA content. Cultured skin fibroblasts had reduced maximal oxygen consumption rate and increased fragmentation of the mitochondrial network. At least 1 patient cell line studied showed a significant reduction of the mitochondrial membrane potential. These defects could be rescued by expression of wildtype FBXL4 in patient cells. The findings indicated that FBXL4 is necessary for the homeostasis of mitochondrial bioenergetics.
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ChronicallyOverIt said:
Wow, that first gene RABGLP1 and its strep association. I’ve always struggled with strep throat after getting mono in my teens. Then my 20s my ME/CFS started after a strep throat infection did not fully clear from 1st round of antibiotics, sat with an infection for 2 weeks, before getting a second round. 1 month later ME/CFS started.

This feels on the money for me. I feel like there’s a guy on twitter chasing the strep angle, can’t remember his name off the top of my head.

Edit: Vijay Iyer on x was chasing a strep angle from what I remember
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Strep triggered me and my partner's illnesses too.
 
I’ve done a quick pass at audio of the two blog posts and the abstract from the paper to help people access the results. They’re available at the below link. I’ve assumed this is okay with the authors, if not let me know and I’ll remove them.

https://u.pcloud.link/publink/show?code=kZqX2W5Z4yR8YkHhWUzzghs07AaMamsl6mW7

I’ll look at cleaning up any problems and get to the rest of the paper later as that’s a bigger job. If anyone has the straight text or even a latex file of the paper please message me, pdftotext conversion always seems to introduce extra text formatting problems to account for.
 
HFE (Tier 1)

• Protein: Homeostatic iron regulator protein. UniProt. GeneCards. The allele that increases the risk of ME/CFS is associated with increasing HFE gene expression in the cortex and prostate. 6• Molecular function: HFE protein regulates the interaction of the transferrin receptor with transferrin.

• Cellular function: HFE protein influences iron absorption by modulating the expression of hepcidin, the main controller of iron metabolism.

• Link to disease: Mutations in HFE can lead to hereditary haemochromatosis, an excessive absorption and accumulation of iron (41).

• Potential relevance to ME/CFS: Unclear.
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I think we are going to find a lot of interest as we dig into the detail. For example, this is from the Supplement on Candidate Genes (which covers more than the 8 highlighted in the paper). Haemochromatosis and issues with transferrin have a number of mentions on the forum. I know some of our members have diagnosed issues with iron, and infections can change iron homeostasis.

There is probably a paper waiting to be written on that issue alone.
 
forestglip said:
If you look at the table I posted a few posts up, it shows the frequency of the effect allele under A1FREQ. So for RABGAP1L, it says 0.325, which means 32.5% of the combined cases and controls had the effect/risk allele.
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To get a feel of the effect size, I've made an overview of the prevalence of these SNPs in patients versus controls. I couldn't find this in the paper or supplementary material so I've tried to calculate them using R (trying out different guesses until the combined prevalence and odds ratio match - hopefully someone will check if they get the same result!).

It shows that the effect size comes down to a 1-2% difference in prevalence of SNPs between ME/CFS patients and controls.

SNPid​
Combined prevalence​
Odds ratio​
Prevalence ME/CFS​
Prevalence controls​
chr1q25.1​
0.325​
0.927​
0.3095​
0.3259​
chr6p22.2​
0.261​
1.086​
0.2763​
0.2601​
chr6q16.1​
0.546​
0.934​
0.5300​
0.5470​
chr12q24.23​
0.139​
1.100​
0.1501​
0.1383​
chr13q14.3​
0.287​
1.077​
0.3015​
0.2861​
chr15q21.3​
0.312​
1.082​
0.3282​
0.3110​
chr17q22​
0.330​
1.084​
0.3470​
0.3290​
chr20q13.13​
0.634​
1.095​
0.6536​
0.6328​
 
ME/CFS Science Blog said:
To get a feel of the effect size, I've made an overview of the prevalence of these SNPs in patients versus controls. I couldn't find this in the paper or supplementary material so I've tried to calculate them using R (trying out different guesses until the combined prevalence and odds ratio match - hopefully someone will check if they get the same result!).

It shows that the effect size comes down to a 1-2% difference in prevalence of SNPs between ME/CFS patients and controls.

SNPid​
Combined prevalence​
Odds ratio​
Prevalence ME/CFS​
Prevalence controls​
chr1q25.1​
0.325​
0.927​
0.3095​
0.3259​
chr6p22.2​
0.261​
1.086​
0.2763​
0.2601​
chr6q16.1​
0.546​
0.934​
0.5300​
0.5470​
chr12q24.23​
0.139​
1.100​
0.1501​
0.1383​
chr13q14.3​
0.287​
1.077​
0.3015​
0.2861​
chr15q21.3​
0.312​
1.082​
0.3282​
0.3110​
chr17q22​
0.330​
1.084​
0.3470​
0.3290​
chr20q13.13​
0.634​
1.095​
0.6536​
0.6328​
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That’s very useful!

Would it indicate that whatever we’re looking for, it’s something that doesn’t need these genes to go wrong, they just make it more likely that it goes wrong?
 
I’m struggling to keep up so apologies if this question has already been asked but I’m wondering if the published data can tell us whether ME/CFS is likely to be one disease which involves the immune system and nervous system, or whether it is possible/likely that there may be two diseases – one which is predominantly associated with the immune system and another which is predominately associated with the nervous system. Or even if there may be more than two diseases.
 
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