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

Andy

Andy

Senior Member (Voting rights)
[Additional line breaks added]

ABSTRACT

Myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS) is a common, poorly understood disease that has no effective treatments, and has long been underserved by scientific research and national health systems. It is a sex-biased disease towards females that is often triggered by an infection, and its hallmark symptom is post-exertional malaise. People with ME/CFS often report their symptoms being disbelieved. The biological mechanisms causing ME/CFS remain unclear.

We recruited 21,620 ME/CFS cases and performed genome wide association studies (GWAS) for up to 15,579 cases and 259,909 population controls with European genetic ancestry.

In these GWAS, we discovered eight loci that are significantly associated with ME/CFS, including three near BTN2A2, OLFM4, and RABGAP1L genes that act in the response to viral or bacterial infection. Four of the eight loci (RABGAP1L, FBXL4, OLFM4, CA10) were associated at p < 0.05 with cases ascertained using post-exertional malaise and fatigue in the UK Biobank and the Netherlands biobank Lifelines.

We found no evidence of sex-bias among discovered associations, and replicated in males two genetic signals (ARFGEF2, CA10) discovered in females. The ME/CFS association near CA10 colocalises with a known association to multisite chronic pain.

We found no evidence that the eight ME/CFS genetic signals share common causal genetic variants with depression or anxiety.

Our findings suggest that both immunological and neurological processes are involved in the genetic risk of ME/CFS.


LAY SUMMARY

Myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS) is a common, disabling illness. It affects more females than males, and in most cases, starts after an infection. Little is known about the biological mechanisms that cause ME/CFS, despite many attempts to uncover them, and it has no effective treatments.

To understand ME/CFS better, our study, DecodeME, compared the DNA of 15,579 people with ME/CFS with the DNA of 259,909 people without ME/CFS, all of European descent. DNA is a molecule that makes up our genes. Our genes make many different molecules called proteins, each of which does very specific things in the body. Finding variations in genes that differ between people with or without a disease can therefore point to what causes it.

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. Most of these regions contain several genes. Our methods did not allow us to conclusively locate the ones most relevant to ME/CFS in each region, but public data allowed us to pick out the most likely ones.

Three of the most likely genes produce proteins that respond to an infection. Another likely gene is related to chronic pain. None are related to depression or anxiety. We found nothing to explain why more females than males get ME/CFS.

Overall, DecodeME shows that ME/CFS is partly caused by genes related to the immune and nervous systems.

Preprint
________________

Moderator note:

For media coverage go to this thread:
DecodeME in the media

Simon McGrath has written an article for the DecodeME website explaining the research.
Thread here:
DecodeME blog: X marks the spot where ME/CFS biology can be discovered

Additional information about the candidate genes:
DecodeME candidate ME/CFS genes
 
Last edited by a moderator:
Well, this is exciting! Thank you to the team for this immense effort!

No explanation for the female bias is interesting. For selfish advocacy reasons, I’m happy there were no associations with known genes related to anxiety or depression.

Do we have any idea how the top hits relate to current hypotheses? Maybe we have to start from scratch?
 
Genecards:

RABGAP1L
GTP-hydrolysis activating protein (GAP) for small GTPase RAB22A, converting active RAB22A-GTP to the inactive form RAB22A-GDP (PubMed:16923123). Plays a role in endocytosis and intracellular protein transport. Recruited by ANK2 to phosphatidylinositol 3-phosphate (PI3P)-positive early endosomes, where it inactivates RAB22A, and promotes polarized trafficking to the leading edge of the migrating cells. Part of the ANK2/RABGAP1L complex which is required for the polarized recycling of fibronectin receptor ITGA5 ITGB1 to the plasma membrane that enables continuous directional cell migration (By similarity).

BTN2A2
Butyrophilin is the major protein associated with fat droplets in the milk. This gene is a member of the BTN2 subfamily of genes, which encode proteins belonging to the butyrophilin protein family. The gene is located in a cluster on chromosome 6, consisting of seven genes belonging to the expanding B7/butyrophilin-like group, a subset of the immunoglobulin gene superfamily. The encoded protein is a type I receptor glycoprotein involved in lipid, fatty-acid and sterol metabolism. Several alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2010]
Inhibits the proliferation of CD4 and CD8 T-cells activated by anti-CD3 antibodies, T-cell metabolism and IL2 and IFNG secretion.

FBXL4
This gene encodes a member of the F-box protein family, which are characterized by an approximately 40 amino acid motif, the F-box. F-box proteins constitute one subunit of modular E3 ubiquitin ligase complexes, called SCF complexes, which function in phosphorylation-dependent ubiquitination. The F-box domain mediates protein-protein interactions and binds directly to S-phase kinase-associated protein 1. In addition to an F-box domain, the encoded protein contains at least 9 tandem leucine-rich repeats. The ubiquitin ligase complex containing the encoded protein may function in cell-cycle control by regulating levels of lysine-specific demethylase 4A. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]
Substrate-recognition component of the mitochondria-localized SCF-FBXL4 ubiquitin E3 ligase complex that plays a role in the restriction of mitophagy by controlling the degradation of BNIP3 and NIX mitophagy receptors (PubMed:36896912, 38992176). Rescues also mitochondrial injury through reverting hyperactivation of DRP1-mediated mitochondrial fission

SUDS3
SDS3 is a subunit of the histone deacetylase (see HDAC1; MIM 601241)-dependent SIN3A (MIM 607776) corepressor complex. Regulatory protein which represses transcription and augments histone deacetylase activity of HDAC1. May have a potential role in tumor suppressor pathways through regulation of apoptosis. May function in the assembly and/or enzymatic activity of the mSin3A corepressor complex or in mediating interactions between the complex and other regulatory complexes.

OLFM4
This gene was originally cloned from human myeloblasts and found to be selectively expressed in inflammed colonic epithelium. This gene encodes a member of the olfactomedin family. The encoded protein is an antiapoptotic factor that promotes tumor growth and is an extracellular matrix glycoprotein that facilitates cell adhesion.
May promote proliferation of pancreatic cancer cells by favoring the transition from the S to G2/M phase. In myeloid leukemic cell lines, inhibits cell growth and induces cell differentiation and apoptosis. May play a role in the inhibition of EIF4EBP1 phosphorylation/deactivation. Facilitates cell adhesion, most probably through interaction with cell surface lectins and cadherin.

CCPG1
Involved in positive regulation of cell cycle and positive regulation of cell population proliferation. Predicted to be active in membrane.
Acts as an assembly platform for Rho protein signaling complexes. Limits guanine nucleotide exchange activity of MCF2L toward RHOA, which results in an inhibition of both its transcriptional activation ability and its transforming activity. Does not inhibit activity of MCF2L toward CDC42, or activity of MCF2 toward either RHOA or CDC42 (By similarity). May be involved in cell cycle regulation.

CA10
This gene encodes a protein that belongs to the carbonic anhydrase family of zinc metalloenzymes, which catalyze the reversible hydration of carbon dioxide in various biological processes. The protein encoded by this gene is an acatalytic member of the alpha-carbonic anhydrase subgroup, and it is thought to play a role in the central nervous system, especially in brain development. Multiple transcript variants encoding the same protein have been found for this gene.

ARFGEF2
ADP-ribosylation factors (ARFs) play an important role in intracellular vesicular trafficking. The protein encoded by this gene is involved in the activation of ARFs by accelerating replacement of bound GDP with GTP and is involved in Golgi transport. It contains a Sec7 domain, which may be responsible for its guanine-nucleotide exchange activity and also brefeldin A inhibition.
Promotes guanine-nucleotide exchange on ARF1 and ARF3 and to a lower extent on ARF5 and ARF6. Promotes the activation of ARF1/ARF5/ARF6 through replacement of GDP with GTP. Involved in the regulation of Golgi vesicular transport. Required for the integrity of the endosomal compartment. Involved in trafficking from the trans-Golgi network (TGN) to endosomes and is required for membrane association of the AP-1 complex and GGA1. Seems to be involved in recycling of the transferrin receptor from recycling endosomes to the plasma membrane. Probably is involved in the exit of GABA(A) receptors from the endoplasmic reticulum. Involved in constitutive release of tumor necrosis factor receptor 1 via exosome-like vesicles; the function seems to involve PKA and specifically PRKAR2B. Proposed to act as A kinase-anchoring protein (AKAP) and may mediate crosstalk between Arf and PKA pathways.
 
V.R.T. said:
So if the gene inhibits the proliferation of CD4+CD8 t cells activated by IFNG does that provide evidence for or againsts JE et als hypothesis?

Inhibition would suggest against to me but I know little about these things.
Click to expand...
It completely depends on what the variants with the strongest associations do functionally. When I have more time later I'll see if any have been predicted to be loss-of-function or gain-of-function mutations. Most likely, though, they just slightly change the functionality of the gene in a way that would have to be assessed in a series of experiments.
 
From p. 20:
Our results were not replicated in an analysis of data from 15,251 cases and 1,878,066​
controls assembled across seven national biobanks (R-2). This could be due to chance, or​
differences in case definition or ascertainment bias. DecodeME’s ME/CFS case-selection was​
based on international criteria, and evidence for a clinical diagnosis and post-exertional​
malaise, ME/CFS’s hallmark symptom. Many cases for R-2 may have been given a clinical​
diagnosis of ME/CFS yet did not meet international case criteria (70), or had postviral fatigue​
syndrome without post-exertional malaise, or had chronic fatigue but not ME/CFS.​
​
In another replication analysis (R-1), we compared 13,767 cases that were more narrowly​
defined and 212,183 controls, from two biobanks. This provided evidence of replication for 8​
out of 21 of GWAS-1’s less significant associations, but only after applying a p-value threshold​
of 0.05 without correcting for multiple tests. Variation in how post-exertional malaise and​
ME/CFS diagnoses are recorded in clinical practice and biobanks could explain why replication​
was not stronger.​
 
One thing I'll state right off the bat is that this finding does not have a [edit: smoking gun] top hit like in other diseases. For example, this is what the MHC locus looks like in a GWAS meta-analysis for rheumatoid arthritis (pasted from here):
1754505572499.png
So compared to that, the findings here are unfortunately relatively weak in association strength. That does not mean they are uninformative hits, it just means they don't provide the kind of undeniable evidence of involvement of a certain cell type or biological process that other GWA studies have been able to provide. [Edit: finding a smoking gun like that would have been the best case scenario]

Just based on the association, it is impossible to tell if the gene is involved in maintaining the disease process, or whether it is involved (perhaps a few degrees removed) in the set of events that ultimately trigger the disease process. But I do think there's useful jumping-off points here for forming hypotheses. [Edit: I’m happy to have these results]

Thanks again to @Andy , Chris, and the rest of the DecodeME team.
 
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I am not going to be contributing for a couple of days. Basically Sonya is right . The study shows that MECFS picks out a real biological problem (or a cluster). The results are pretty much what we saw in the last advisory board. There are immune genes and nerve genes but there are also some unexpected things which is good. There should be some mention of MHC but this turned out to be complicated and puzzling. I think it will prove relevant.

My understanding is that the main mitochondria linked gene wouldn't explain "feeble mitochondria". If anything maybe the reverse, but I wonder if it may show that the metabolic clues we have had make sense in an unexpected way.

No doubt when I am on dry land you will have sorted it all out.
 
Andy said:
[Additional line breaks added]

ABSTRACT

Myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS) is a common, poorly understood disease that has no effective treatments, and has long been underserved by scientific research and national health systems. It is a sex-biased disease towards females that is often triggered by an infection, and its hallmark symptom is post-exertional malaise. People with ME/CFS often report their symptoms being disbelieved. The biological mechanisms causing ME/CFS remain unclear.

We recruited 21,620 ME/CFS cases and performed genome wide association studies (GWAS) for up to 15,579 cases and 259,909 population controls with European genetic ancestry.

In these GWAS, we discovered eight loci that are significantly associated with ME/CFS, including three near BTN2A2, OLFM4, and RABGAP1L genes that act in the response to viral or bacterial infection. Four of the eight loci (RABGAP1L, FBXL4, OLFM4, CA10) were associated at p < 0.05 with cases ascertained using post-exertional malaise and fatigue in the UK Biobank and the Netherlands biobank Lifelines.

We found no evidence of sex-bias among discovered associations, and replicated in males two genetic signals (ARFGEF2, CA10) discovered in females. The ME/CFS association near CA10 colocalises with a known association to multisite chronic pain.

We found no evidence that the eight ME/CFS genetic signals share common causal genetic variants with depression or anxiety.

Our findings suggest that both immunological and neurological processes are involved in the genetic risk of ME/CFS.


LAY SUMMARY

Myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS) is a common, disabling illness. It affects more females than males, and in most cases, starts after an infection. Little is known about the biological mechanisms that cause ME/CFS, despite many attempts to uncover them, and it has no effective treatments.

To understand ME/CFS better, our study, DecodeME, compared the DNA of 15,579 people with ME/CFS with the DNA of 259,909 people without ME/CFS, all of European descent. DNA is a molecule that makes up our genes. Our genes make many different molecules called proteins, each of which does very specific things in the body. Finding variations in genes that differ between people with or without a disease can therefore point to what causes it.

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. Most of these regions contain several genes. Our methods did not allow us to conclusively locate the ones most relevant to ME/CFS in each region, but public data allowed us to pick out the most likely ones.

Three of the most likely genes produce proteins that respond to an infection. Another likely gene is related to chronic pain. None are related to depression or anxiety. We found nothing to explain why more females than males get ME/CFS.

Overall, DecodeME shows that ME/CFS is partly caused by genes related to the immune and nervous systems.

Preprint
Click to expand...
Thank you so much for all your work on this. It’s so validating.
 
jnmaciuch said:
Genecards:

RABGAP1L
GTP-hydrolysis activating protein (GAP) for small GTPase RAB22A, converting active RAB22A-GTP to the inactive form RAB22A-GDP (PubMed:16923123). Plays a role in endocytosis and intracellular protein transport. Recruited by ANK2 to phosphatidylinositol 3-phosphate (PI3P)-positive early endosomes, where it inactivates RAB22A, and promotes polarized trafficking to the leading edge of the migrating cells. Part of the ANK2/RABGAP1L complex which is required for the polarized recycling of fibronectin receptor ITGA5 ITGB1 to the plasma membrane that enables continuous directional cell migration (By similarity).

BTN2A2
Butyrophilin is the major protein associated with fat droplets in the milk. This gene is a member of the BTN2 subfamily of genes, which encode proteins belonging to the butyrophilin protein family. The gene is located in a cluster on chromosome 6, consisting of seven genes belonging to the expanding B7/butyrophilin-like group, a subset of the immunoglobulin gene superfamily. The encoded protein is a type I receptor glycoprotein involved in lipid, fatty-acid and sterol metabolism. Several alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2010]
Inhibits the proliferation of CD4 and CD8 T-cells activated by anti-CD3 antibodies, T-cell metabolism and IL2 and IFNG secretion.

FBXL4
This gene encodes a member of the F-box protein family, which are characterized by an approximately 40 amino acid motif, the F-box. F-box proteins constitute one subunit of modular E3 ubiquitin ligase complexes, called SCF complexes, which function in phosphorylation-dependent ubiquitination. The F-box domain mediates protein-protein interactions and binds directly to S-phase kinase-associated protein 1. In addition to an F-box domain, the encoded protein contains at least 9 tandem leucine-rich repeats. The ubiquitin ligase complex containing the encoded protein may function in cell-cycle control by regulating levels of lysine-specific demethylase 4A. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]
Substrate-recognition component of the mitochondria-localized SCF-FBXL4 ubiquitin E3 ligase complex that plays a role in the restriction of mitophagy by controlling the degradation of BNIP3 and NIX mitophagy receptors (PubMed:36896912, 38992176). Rescues also mitochondrial injury through reverting hyperactivation of DRP1-mediated mitochondrial fission

SUDS3
SDS3 is a subunit of the histone deacetylase (see HDAC1; MIM 601241)-dependent SIN3A (MIM 607776) corepressor complex. Regulatory protein which represses transcription and augments histone deacetylase activity of HDAC1. May have a potential role in tumor suppressor pathways through regulation of apoptosis. May function in the assembly and/or enzymatic activity of the mSin3A corepressor complex or in mediating interactions between the complex and other regulatory complexes.

OLFM4
This gene was originally cloned from human myeloblasts and found to be selectively expressed in inflammed colonic epithelium. This gene encodes a member of the olfactomedin family. The encoded protein is an antiapoptotic factor that promotes tumor growth and is an extracellular matrix glycoprotein that facilitates cell adhesion.
May promote proliferation of pancreatic cancer cells by favoring the transition from the S to G2/M phase. In myeloid leukemic cell lines, inhibits cell growth and induces cell differentiation and apoptosis. May play a role in the inhibition of EIF4EBP1 phosphorylation/deactivation. Facilitates cell adhesion, most probably through interaction with cell surface lectins and cadherin.

CCPG1
Involved in positive regulation of cell cycle and positive regulation of cell population proliferation. Predicted to be active in membrane.
Acts as an assembly platform for Rho protein signaling complexes. Limits guanine nucleotide exchange activity of MCF2L toward RHOA, which results in an inhibition of both its transcriptional activation ability and its transforming activity. Does not inhibit activity of MCF2L toward CDC42, or activity of MCF2 toward either RHOA or CDC42 (By similarity). May be involved in cell cycle regulation.

CA10
This gene encodes a protein that belongs to the carbonic anhydrase family of zinc metalloenzymes, which catalyze the reversible hydration of carbon dioxide in various biological processes. The protein encoded by this gene is an acatalytic member of the alpha-carbonic anhydrase subgroup, and it is thought to play a role in the central nervous system, especially in brain development. Multiple transcript variants encoding the same protein have been found for this gene.

ARFGEF2
ADP-ribosylation factors (ARFs) play an important role in intracellular vesicular trafficking. The protein encoded by this gene is involved in the activation of ARFs by accelerating replacement of bound GDP with GTP and is involved in Golgi transport. It contains a Sec7 domain, which may be responsible for its guanine-nucleotide exchange activity and also brefeldin A inhibition.
Promotes guanine-nucleotide exchange on ARF1 and ARF3 and to a lower extent on ARF5 and ARF6. Promotes the activation of ARF1/ARF5/ARF6 through replacement of GDP with GTP. Involved in the regulation of Golgi vesicular transport. Required for the integrity of the endosomal compartment. Involved in trafficking from the trans-Golgi network (TGN) to endosomes and is required for membrane association of the AP-1 complex and GGA1. Seems to be involved in recycling of the transferrin receptor from recycling endosomes to the plasma membrane. Probably is involved in the exit of GABA(A) receptors from the endoplasmic reticulum. Involved in constitutive release of tumor necrosis factor receptor 1 via exosome-like vesicles; the function seems to involve PKA and specifically PRKAR2B. Proposed to act as A kinase-anchoring protein (AKAP) and may mediate crosstalk between Arf and PKA pathways.
Click to expand...
To help, we wrote a document on candidate genes: https://www.pure.ed.ac.uk/ws/portalfiles/portal/533352484/Candidate_Genes.pdf
 
jnmaciuch said:
One thing I'll state right off the bat is that this finding does not have a [edit: smoking gun] top hit like in other diseases. For example, this is what the MHC locus looks like in a GWAS meta-analysis for rheumatoid arthritis (pasted from here):
View attachment 27583
So compared to that, the findings here are unfortunately relatively weak in association strength. That does not mean they are uninformative hits, it just means they don't provide the kind of undeniable evidence of involvement of a certain cell type or biological process that other GWA studies have been able to provide. Just based on the association, it is impossible to tell if the gene is involved in maintaining the disease process, or whether it is involved (perhaps a few degrees removed) in the set of events that ultimately trigger the disease process. But I do think there's useful jumping-off points here for forming hypotheses.

Thanks again to @Andy , Chris, and the rest of the DecodeME team.
Click to expand...
Could that point to ME/CFS as defined by CCC/ICC being more than one «thing»?
 
Simon M said:
Yes, though they have yet to analyse data for the sex chromosomes, which might be a more likely place to find any differences.
Click to expand...
It must be the place to find the explanation. And we already know there are loads of genes that would do it. I think this is a non-problem.

What to me looks interesting is the suggestion that although women have more of it MECFS may have the same basis otherwise for men and women . In other words 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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