Hoopoe
Senior Member (Voting Rights)
Can mildly excessive mitophagy promote metabolic inflexibility by removing mitochondria that might perform a little worse under optimal conditions but better in certain specific situations?
Preprint Initial findings from the DecodeME genome-wide association study of myalgic encephalomyelitis/chronic fatigue syndrome, 2025, DecodeMe Collaboration
Jonathan Edwards
Senior Member (Voting Rights)
I think we are on fairly safe ground there - with caveats. At least one gene is pretty specific for a subgroup of T cells - not even any old T cells. T cells will be upstream in this because T cells don't feel ill, brains do. So it looks like it is going to have something to do with immune cells making brains feel ill. That could still be via screwing up metabolism in other places.
There doesn't need to be an infection but the clinical evidence is already there for that.
Following up on this: in Norway there has been a huge increase in consultations for «fatigue» and various diagnostic codes that have traditionally been used for ME here following the start of the covid pandemic. So many seem to be susceptible of «something» following infection, although it might not be full blown ME/CFS.
Tilly
Senior Member (Voting Rights)
Just had a look at the SMC post about this and it was a well yes but from
I know you are busy but I need to ask
Where do we go with the unknowns because they look like keys to me.
In 2004 White with others carried out a study, their findings found the delay between start of activity and then 4 -5 days after TNF-a and TGF beta. They looked at this as deconditioning but with your findings of TRIM38 and known link to TGF beta would all these be elevated when in a PEM state and is that something we could ask researchers to do?
Not a scientist just a mother asking
Your work and findings plot and map the many problems that those with ME have been explaining and living through so a huge thank you.
I know you are busy but I need to ask
Where do we go with the unknowns because they look like keys to me.
In 2004 White with others carried out a study, their findings found the delay between start of activity and then 4 -5 days after TNF-a and TGF beta. They looked at this as deconditioning but with your findings of TRIM38 and known link to TGF beta would all these be elevated when in a PEM state and is that something we could ask researchers to do?
Not a scientist just a mother asking
Hoopoe
Senior Member (Voting Rights)
I have mixed feelings about the results. I'm happy that a big step forward has occurred, but the results are merely a hint where to look more in detail. We're still far away from a diagnostic test, understanding the disease and treatment. At least we can call it disease now, and the results seem to confirm that it's most likely an immune-mediated neurological disease.
There's a lot more to discover about the genetics of ME/CFS. DecodeME was just a successful attempt to find signals of the disease and some leads.
The lack of strong or even any association between the SNPs and depression also tells us that it's the people who made these claims of association that were biased. I think they're stuck in a certain way of thinking and interpreting information.
Also, I think we need better PEM questionnaires. I'm sorry to say but I'm not a fan of Jason's work on PEM questionnaires. PEM should be strictly defined as atypical and delayed aggravation of symptoms after relatively mild exertion, and not in ways that allow confusion of PEM with more ordinary responses to exercise which can include fatigue, muscle pain, or vague concepts like feeling dead or heavy after exercise. The aggravation must include atypical features not expected in people unaccustomed to exertion, like increased nerve sensitivity, inability to relax, difficulty thinking or organizing daily activities, disturbed sleep, feeling awful but ONLY beginning at least several hours AFTER exertion.
There's a lot more to discover about the genetics of ME/CFS. DecodeME was just a successful attempt to find signals of the disease and some leads.
The lack of strong or even any association between the SNPs and depression also tells us that it's the people who made these claims of association that were biased. I think they're stuck in a certain way of thinking and interpreting information.
Also, I think we need better PEM questionnaires. I'm sorry to say but I'm not a fan of Jason's work on PEM questionnaires. PEM should be strictly defined as atypical and delayed aggravation of symptoms after relatively mild exertion, and not in ways that allow confusion of PEM with more ordinary responses to exercise which can include fatigue, muscle pain, or vague concepts like feeling dead or heavy after exercise. The aggravation must include atypical features not expected in people unaccustomed to exertion, like increased nerve sensitivity, inability to relax, difficulty thinking or organizing daily activities, disturbed sleep, feeling awful but ONLY beginning at least several hours AFTER exertion.
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ME/CFS Science Blog
Senior Member (Voting Rights)
Made a brief summary of the results here (EDIT: added full text and Bluesky link)
Link to Bluesky:
1) The DecodeME study compared DNA of ca. 15,000 ME/CFS patients and 250,000 controls and found significant differences in 8 regions of our genome. The Manhattan plot below shows the genes and chromosomes involved.
Let’s unpack the results
2) A first major finding is that the results for females and males were very similar. This was quite a surprise, as some had expected the biological pathways behind ME/CFS to differ between males and females. Not so!
3) ME/CFS is much more common in women (84% of ME/CFS participants were female), but the millions of DNA variants analyzed didn’t provide an answer of why this is the case.
The sex chromosomes weren’t analyzed yet, so this is likely where the answer for the sex difference lies.
4) A second major finding: the genetic information could be used to estimate the heritability of ME/CFS: how much the illness is due to genetic differences in common DNA variants. The result was modest: 9.5%. This aligns with a previous estimate (8%) from the UK biobank.
5) Let’s now move on to the key results.
Big genetic studies apply a strict significance threshold of 5*10^-8 (less than one in a million) to avoid differences between patients and controls being due to chance. In DecodeME there were 8 findings or hits above this threshold.
6) Six hits showed up in the main analysis (GWAS1), while another was found using only the ME/CFS patients who reported an infectious onset. The last one came up in GWAS2 which used a different subset of controls.
7) So, what are the 8 results? Table 3 in the paper shows the main results: the location on the genome, the DNA letters that were different, how common these variants are and if the variant was increased or decreased in ME/CFS.
8) The effect sizes are quite small (odds ratios below 1.1), but this is expected for genetic studies like this (it’s the same in other diseases).
To get a feel of how subtle this is, we recalculated the prevalence in ME/CFS and controls, which only differ by 1-2% (see screenshot below).
9) The 8 hits or DNA variants occur in 13%-60% of the general population. So it’s not that these determine if you have ME/CFS or not. Instead, they should be seen as clues or pointers to what's really going wrong.
10) The 8 hits point to a specific region on our genome but a lot of DNA fragments (SNPs) are inherited together in what’s called linkage disequilibrium (LD). So, we’re not entirely sure which gene in the region is causally related to ME/CFS.
11) The first region (chr1q25.1) for example is associated with 11 genes. Luckily there are databases with info about how SNPs affect the expression of nearby genes. This lets the researchers zoom in on the most likely suspects.
12) Now it gets interesting because these suspect genes were often linked to the immune and nervous systems.
RABGAP1L for example promotes expulsion of the bacterium Streptococcus pyogenes and limits replication of multiple viruses.
13) Another gene, Olfactomedin-4 (OLFM4), suppresses antibacterial and inflammatory responses by binding to neutrophil proteins and neutralizing their ability to kill.
14) A third gene CA10 is involved in synaptic transmission and has previously been found in people experiencing chronic pain. It might explain why pain is such a common symptom in ME/CFS.
15) The HLA-region also got a significant result (HLA-DQA1*05:01). This region is important in differentiating your own body's cells from invaders like viruses or bacteria.
Many autoimmune diseases have abnormalities in the HLA region.
16) A caveat is that these genes have other functions as well. Future research will need to figure out which ones are relevant to ME/CFS. We suspect that a lot of scientists will use these leads to start new research and get closer to the pathology of ME/CFS.
17) DecodeME delivered, but we also have to highlight what is perhaps the main limitation of the DecodeME results: the authors tried to replicate their results in different cohorts, and this did not go very well.
18) A likely explanation was differences in case definitions. The other databases often did not select patients using modern case definitions that require the key symptom of post-exertional malaise (PEM).
19) One possible exception is the Dutch Lifelines cohort, where cases were clinically diagnosed with ME/CFS and had PEM (although there are some doubts if the study did so reliably). Here, some associations were repeated but did not reach full significance.
20) DecodeME also did not diagnose ME/CFS using clinical examinations (which would not be possible for such a large sample size). It required a self-reported diagnosis and checked this with questionnaires based on the IOM and CCC criteria.
21) Lastly, these were the initial findings from DecodeME, which only looked at common DNA variants (where the least common version still occurs in more than 1% of the population).
22) The researchers hope to look at rare genetic variants in a follow-up study called SequenceME. This will get an even more detailed picture of the DNA differences associated with ME/CFS.
Rare variants might also have bigger effect sizes. More info about this follow-up here
https://www.actionforme.org.uk/sequenceme-first-of-a.../
23) There’s much more to say about this study, but we’ll wrap it up here and save the rest for an in-depth blog post on our website. A warmhearted thanks to the researchers and patients who made this landmark study possible!
Link to Bluesky:
1) The DecodeME study compared DNA of ca. 15,000 ME/CFS patients and 250,000 controls and found significant differences in 8 regions of our genome. The Manhattan plot below shows the genes and chromosomes involved.
Let’s unpack the results
2) A first major finding is that the results for females and males were very similar. This was quite a surprise, as some had expected the biological pathways behind ME/CFS to differ between males and females. Not so!
3) ME/CFS is much more common in women (84% of ME/CFS participants were female), but the millions of DNA variants analyzed didn’t provide an answer of why this is the case.
The sex chromosomes weren’t analyzed yet, so this is likely where the answer for the sex difference lies.
4) A second major finding: the genetic information could be used to estimate the heritability of ME/CFS: how much the illness is due to genetic differences in common DNA variants. The result was modest: 9.5%. This aligns with a previous estimate (8%) from the UK biobank.
5) Let’s now move on to the key results.
Big genetic studies apply a strict significance threshold of 5*10^-8 (less than one in a million) to avoid differences between patients and controls being due to chance. In DecodeME there were 8 findings or hits above this threshold.
6) Six hits showed up in the main analysis (GWAS1), while another was found using only the ME/CFS patients who reported an infectious onset. The last one came up in GWAS2 which used a different subset of controls.
7) So, what are the 8 results? Table 3 in the paper shows the main results: the location on the genome, the DNA letters that were different, how common these variants are and if the variant was increased or decreased in ME/CFS.
8) The effect sizes are quite small (odds ratios below 1.1), but this is expected for genetic studies like this (it’s the same in other diseases).
To get a feel of how subtle this is, we recalculated the prevalence in ME/CFS and controls, which only differ by 1-2% (see screenshot below).
9) The 8 hits or DNA variants occur in 13%-60% of the general population. So it’s not that these determine if you have ME/CFS or not. Instead, they should be seen as clues or pointers to what's really going wrong.
10) The 8 hits point to a specific region on our genome but a lot of DNA fragments (SNPs) are inherited together in what’s called linkage disequilibrium (LD). So, we’re not entirely sure which gene in the region is causally related to ME/CFS.
11) The first region (chr1q25.1) for example is associated with 11 genes. Luckily there are databases with info about how SNPs affect the expression of nearby genes. This lets the researchers zoom in on the most likely suspects.
12) Now it gets interesting because these suspect genes were often linked to the immune and nervous systems.
RABGAP1L for example promotes expulsion of the bacterium Streptococcus pyogenes and limits replication of multiple viruses.
13) Another gene, Olfactomedin-4 (OLFM4), suppresses antibacterial and inflammatory responses by binding to neutrophil proteins and neutralizing their ability to kill.
14) A third gene CA10 is involved in synaptic transmission and has previously been found in people experiencing chronic pain. It might explain why pain is such a common symptom in ME/CFS.
15) The HLA-region also got a significant result (HLA-DQA1*05:01). This region is important in differentiating your own body's cells from invaders like viruses or bacteria.
Many autoimmune diseases have abnormalities in the HLA region.
16) A caveat is that these genes have other functions as well. Future research will need to figure out which ones are relevant to ME/CFS. We suspect that a lot of scientists will use these leads to start new research and get closer to the pathology of ME/CFS.
17) DecodeME delivered, but we also have to highlight what is perhaps the main limitation of the DecodeME results: the authors tried to replicate their results in different cohorts, and this did not go very well.
18) A likely explanation was differences in case definitions. The other databases often did not select patients using modern case definitions that require the key symptom of post-exertional malaise (PEM).
19) One possible exception is the Dutch Lifelines cohort, where cases were clinically diagnosed with ME/CFS and had PEM (although there are some doubts if the study did so reliably). Here, some associations were repeated but did not reach full significance.
20) DecodeME also did not diagnose ME/CFS using clinical examinations (which would not be possible for such a large sample size). It required a self-reported diagnosis and checked this with questionnaires based on the IOM and CCC criteria.
21) Lastly, these were the initial findings from DecodeME, which only looked at common DNA variants (where the least common version still occurs in more than 1% of the population).
22) The researchers hope to look at rare genetic variants in a follow-up study called SequenceME. This will get an even more detailed picture of the DNA differences associated with ME/CFS.
Rare variants might also have bigger effect sizes. More info about this follow-up here
https://www.actionforme.org.uk/sequenceme-first-of-a.../
23) There’s much more to say about this study, but we’ll wrap it up here and save the rest for an in-depth blog post on our website. A warmhearted thanks to the researchers and patients who made this landmark study possible!
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DMissa
Senior Member (Voting Rights)
Not on my best form today but seems fine to me!
This is a very ambitious question that I’m not sure we have the answers to, but I am not a mitophagy expert. Starting points might be 1) Can heteroplasmy and mitochondrial contiguity interact to produce localised “mitochondria” of different functional profiles? 2) If this is possible can they be differentially turned over versus the rest of the mitochondrial pool? 3) Proportionate to whole-cell metabolism are such variations in function sufficient to elicit feedback?
This is very abstract from my POV but I may be lacking knowledge.
Kronos
Established Member (Voting Rights)
Interesting, since the GPCR autoimmunity theory with BC 007 originally came from glaucoma people. So these auto antibodies are related to glaucoma.I have come across rabgap genes in this glaucoma paper
FOXC1 modulates MYOC secretion through regulation of the exocytic proteins RAB3GAP1, RAB3GAP2 and SNAP25 - PMC
The neurodegenerative disease glaucoma is one of the leading causes of blindness in the world. Glaucoma is characterized by progressive visual field loss caused by retinal ganglion cell (RGC) death. Both surgical glaucoma treatments and medications ...pmc.ncbi.nlm.nih.gov
Some of the transcription factors are interesting in decode ME genes
Eg foxo3 pax2/3 sox5
Ariel
Senior Member (Voting Rights)
Did they test the remaining 10, 000 (known) virally-triggered ME/CFS samples and still find the association in these samples without the other 5,000? I think you would have to know that?
Kronos
Established Member (Voting Rights)
That would significantly modify CCC though.
I get that this is what a subgroup feels, but from my impression there's also a significant other portion where there is already worse symptoms quite immediately after some exertion.
In your proposed case with many hours between worsening and exertion I would not make it anymore with the definition I think.
But this represents what I have been observing, maybe this is especially applicable for people who have a low number or even no symptoms doing absolutely nothing and then getting worse when doing anything. I have read from severe people who have zero symptoms at rest, but very bad symptoms when they do anything in the delayed way.
This is absolutely not how I feel, relatively spoken I'm always at a 7 out of 10 so the difference to 8.5 after too much exertion is not as large and not as significant.
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Ariel
Senior Member (Voting Rights)
Re: diagnostic criteria and the different cohorts they generate in studies: I am too unwell to look at the preprint in detail at the moment but was hoping someone would know.
I remember the samples were taken in two phases with separate ones taken at a later stage possibly on slightly different inclusion criteria as they did not know how many participants initially would be asked to give a sample and they perhaps wanted more people in the end. Some people were not invited to give a sample in the first round, and then were invited to give a sample later.
Do they mention the extra samples they took from people in their second round of collection and any differences in signal generated? Do they mention any difference or information from these separate groups?
I remember the samples were taken in two phases with separate ones taken at a later stage possibly on slightly different inclusion criteria as they did not know how many participants initially would be asked to give a sample and they perhaps wanted more people in the end. Some people were not invited to give a sample in the first round, and then were invited to give a sample later.
Do they mention the extra samples they took from people in their second round of collection and any differences in signal generated? Do they mention any difference or information from these separate groups?
I wondered if there was a way to use the UK Bio bank to see if common genetic variants being talked about had predictive power. I assume the Biobank data was recorded sometime ago and prior to the pandemic. So could people with these variants be contacted to see their current health and whether they have a higher than normal chance of developing ME (or LC meeting ME criteria)?
ME/CFS Science Blog
Senior Member (Voting Rights)
The failed replications are disappointing but I suspect that next too broad case definitions for ME/CFS in the other databases, the sample size might also have been too small.
In the supplementary material it says that the Lifelines cohort only had 3,440 cases and 17,080 controls (compared to 15.000 case and 250.000 controls for DecodeME).
I don't know more about this sample but there have been problems with the selection criteria of the Lifelines cohort in previous studies. Some Dutch patient organisations objected against this study getting ME/CFS funding because of this reason. And in a previous paper on heritability of ME/CFS, a lifelines paper used a prevalence of more than 4.7% for ME/CFS which is 10x larger than expected.
In the supplementary material it says that the Lifelines cohort only had 3,440 cases and 17,080 controls (compared to 15.000 case and 250.000 controls for DecodeME).
I don't know more about this sample but there have been problems with the selection criteria of the Lifelines cohort in previous studies. Some Dutch patient organisations objected against this study getting ME/CFS funding because of this reason. And in a previous paper on heritability of ME/CFS, a lifelines paper used a prevalence of more than 4.7% for ME/CFS which is 10x larger than expected.
ME/CFS Science Blog
Senior Member (Voting Rights)
I noticed that the HLA-region also got a significant finding (HLA-DQA1*05:01 at p = 1.4 x 10-10 but that it somehow reported separately form the other 8 hits. It seems to be a different SNP than what the Norwegians found but perhaps this is due to HLA being difficult to sequence?
Jonathan Edwards
Senior Member (Voting Rights)
DecodeME found evidence for DQA1 0501 being protective rather than high risk. DQ has come up repeatedly and I would like to see if these findings are actually complementary and consistent. The DQ link is nothing like that seen for MS or celiac. There is also an anomaly in the linkage. It will need its own thread.
Sasha
Senior Member (Voting Rights)
How well do the DecodeME findings fit with your model, @Jonathan Edwards? And do they help you refine it, or come up with additional testable aspects?
I can have days like these as a mild person. For example no symptoms when sitting down, but I will feel terrible if I try to move and might even need assistance such as supporting myself against furniture or a wall. Other days symptoms will be present also when being still.
It's certainly more significant in DecodeME than in the replication. It just didn't reach the strict threshold for genome-wide significance of p<5x10-8 so it wasn't reported as a candidate locus/gene.
In DecodeME, it got p=2.48x10-7. In the replication, it got p=.027 (before multiple test correction). The only reason it and the other SNPs were interesting in the replication was that far more than you'd expect were below p=.05 (9 out of 22, while you'd expect about 1). So we can be fairly confident that there's a real signal within these 9 SNPs, but it's not strong enough for any to pass multiple test correction for any specific SNP in the other cohort.
Edit: Also, while none of the 9 SNPs were significant in the replication after strict Bonferroni correction, I just did FDR correction, and these four remain significant:
| rsID | Nearest gene | Uncorrected replication cohort p-value | FDR |
|---|---|---|---|
| rs12071663 | DARS2 | .002 | 0.0385 |
| rs34626694 | CA10 | .005 | 0.0385 |
| rs35306732 | AL136359.1 | .007 | 0.0385 |
| rs291671 | CDK5RAP1 | .007 | 0.0385 |
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Bonferroni correction is also extremely stringent. Not everyone thinks it is useful to be that stringent. But that’s another discussion.