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

Jonathan Edwards said:
it may also be worth remembering that 'MHC' originally refers to gene products that determine histocompatibility of allograft cells - which is not to do with their antigen presenting function.
Click to expand...
Indeed. And the alleles that matter for compatibility are the ones in the actual HLA protein complexes.
 
A gene that hasn't been disucssed much is TAOK3 on chromosome 12 (it wasn't a Tier 1 gene). It has been previously been associated with Lupus at around the same region as in DecodeME. The vertical dotted line in the graph below shows the location for the Lupus hit (12:118244946) with the SNP summary data from DecodeME.


1758826778973.png

The Lupus GWAS said this about it:
We also identified a missense variant in TAOK3 (the gene for tau kinase 3) as the top association signal in this locus. The risk allele (rs428073-T) substitutes the 47th amino acid of TAOK3 fromserine to asparagine (S47N), whose functional role remains unknown. S47 is located at the loop region between strands β2and β3, and the substitution should not change the overall strucure of the protein, despite being well conserved among orthologous proteins during evolutionary courses (SupplementaryFigure 10, on the Arthritis & Rheumatology website at https://onlinelibrary.wiley.com/doi/10.1002/art.42021). Taok3 plays animportant role in DNA damage–induced activation of the p38/MAPK14 stress-activated MAPK cascade. It enhances T cell receptor signaling by regulating its negative feedback by SH2domain–containing phosphatase 1 (44), and Taok3 deficiency in mice was found to cause defects in the development of marginalzone B cells but not follicular B cells (45).
Click to expand...
pubmed.ncbi.nlm.nih.gov

Identification of Shared and Asian-Specific Loci for Systemic Lupus Erythematosus and Evidence for Roles of Type III Interferon Signaling and Lysosomal Function in the Disease: A Multi-Ancestral Genome-Wide Association Study - PubMed

In this study both shared and Asian-specific loci for SLE were identified, and functional annotation provided evidence of the involvement of increased type III IFN signaling and reduced lysosomal function in SLE.
pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov
 
"It enhances T cell receptor signaling by regulating its negative feedback by SH2domain–containing phosphatase 1 (44), and Taok3 deficiency in mice was found to cause defects in the development of marginalzone B cells but not follicular B cells (45)."

Intriguing. An influence on SHIP1 would make some sense. Marginal zone B cell behaviour is odd in lupus too.
 
ME/CFS Science Blog said:
A gene that hasn't been disucssed much is TAOK3 on chromosome 12 (it wasn't a Tier 1 gene). It has been previously been associated with Lupus at around the same region as in DecodeME. The vertical dotted line in the graph below shows the location for the Lupus hit (12:118244946) with the SNP summary data from DecodeME.


View attachment 28547

The Lupus GWAS said this about it:

pubmed.ncbi.nlm.nih.gov

Identification of Shared and Asian-Specific Loci for Systemic Lupus Erythematosus and Evidence for Roles of Type III Interferon Signaling and Lysosomal Function in the Disease: A Multi-Ancestral Genome-Wide Association Study - PubMed

In this study both shared and Asian-specific loci for SLE were identified, and functional annotation provided evidence of the involvement of increased type III IFN signaling and reduced lysosomal function in SLE.
pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov
Click to expand...
Is this for the same hit that was annotated to SUDS3 in DecodeME?
 
ME/CFS Science Blog said:
Yes
Click to expand...
Interesting, so it seems like this is another case where the final annotation for DecodeME was chosen based on high number of [edit: coloc] tissues. The top SNP is within an intronic region in DecodeME, and seems to be quite a long deletion. The mutation in the lupus paper you posted was in a protein-coding region which might explain stronger effect of the mutation.

Also, interesting that 3 proteins in that whole region that looks to be in LD have well-established links to MAPK signaling (SUDS3, TAOK3, and PEBP1)
 
Last edited:
I've copied @ME/CFS Science Blog's chart and some discussion about TAOK3 to the discussion thread we had on SUDS3, renaming it Chromosome 12 SUDS3, TAOK3. Probably those discussion threads should have been titled about the identified regions of interest rather than individual genes.

Genetics: Chromosome 12: SUDS3, TAOK3

Those charts with the DecodeME results and gene positions are really useful, ME/CFS Science Blog.
 
Hutan said:
Those charts with the DecodeME results and gene positions are really useful, ME/CFS Science Blog.
Click to expand...
Thanks I should probably mention that I zoom out a bit more (1Mb) than most tools like LocusZoom (around 250kb) to get an overview of the entire region around the hit. The implicated genes are probably closer to the top SNP then the region I show (so don't pay too much attention to the genes at the borders of my graphs).
 
Reading some GWAS in other illnesses made me appreciate DecodeME even more.

Other GWAS are usually based on (1) extracting data from big databases like the UK biobank, Finngen, AllofUS, 23andME etc. where the case definition was often poor or (2) on multiple cohorts that are combined into a single meta-analysis which likely has extra problems in terms of preventing confounding.

I haven't seen many GWAS where they collected the entire sample in one study like DecodeME did. This had the benefit that the case definition could be stricter defined using extra questionnaires and that the researchers could include various questions that might help their analysis. DecodeME was in contact with all its participants that donated DNA, which is often not the case for other GWAS.

I'm curious to see if some of the hits we see are due to a comorbidity such as depression or pain (if the signal is the same in ME/CFS patients without depression or without pain). Hoping that the questionnaire data will allow such an analysis.
 
That's a really useful article @ME/CFS Science Blog - thank you. Looking forward to the next in the series. I'll try and find some articles that tie identified genes to the new post-synaptic AMPA receptor findings (X looks like it marks the spot quite nicely).

I spotted one instance of "DecodeMe" instead of "DecodeME" (also a few "Decode" abbreviations that may be intentional). I'd also change "it’s what they are pointing to what matters!" to "it’s what they are pointing to that matters!"
 
SNT Gatchaman said:
That's a really useful article @ME/CFS Science Blog - thank you. Looking forward to the next in the series. I'll try and find some articles that tie identified genes to the new post-synaptic AMPA receptor findings (X looks like it marks the spot quite nicely).

I spotted one instance of "DecodeMe" instead of "DecodeME" (also a few "Decode" abbreviations that may be intentional). I'd also change "it’s what they are pointing to what matters!" to "it’s what they are pointing to that matters!"
Click to expand...
Updated, thanks!
 
Andy said:
Blog: DecodeME: the biggest ME/CFS study ever

mecfsscience.org

DecodeME: the biggest ME/CFS study ever - ME/CFS Science

The first results of DecodeME are in, the largest research project ever undertaken on myalgicContinue readingDecodeME: the biggest ME/CFS study ever
mecfsscience.org mecfsscience.org
Click to expand...
Really good blog, as always @ME/CFS Science Blog

Some minor issues, comments and suggestions:

“Human DNA has 3.2 billion of these ‘base pairs’, but most of them are not relevant or the same in everyone.”

Human DNA has 3.2 billion of these ‘base pairs’, but most of them are the same in everyone or not relevant.

[Avoids ambiguity]


“If your data doesn’t include the top SNP, you can check one of the SNPs nearby that is highly correlated with it.”

Not quite sure what this means. What is “your data”?


“Humans have around 20.000 to 25.000 genes.”

20,000 to 25,000 not 20.000 to 25.000


“In the graph, we use the -log10 of p-values, so the higher on the plot, the lower the p-value, and the more unusual the SNP.”

Long dash without space (–log10) or write negative. I was confused because on my screen there was a line space between the - and log10. The graph should also indicate this.

“Indeed, the difference in prevalence of SNPs hits is only about 1% to 2% between patients and controls.”

I think you mean percentage points. The difference between 34% and 32% is 2 percentage points but approximately 6%.


“A recent paper in Nature backs this up. It examined data on drug development and found that effect sizes from genetic studies did not influence the chance that a drug will be successful.”

Perhaps make it clearer that you mean the size of the effect doesn’t matter, providing there is an effect.


“With another tool called ‘LD Score Regression (LDSC)’, we can also look at the genetic correlation between ME/CFS and other diseases registered in the UK Biobank.”

You use capitals so the inverted commas are redundant.


“There were substantial correlations with many illness categories, especially those related to gut problems, fatigue, pain, and depression.”

I thought the pre-print suggested there was no overlap with genes associated with anxiety or depression. I’ve not managed to keep up with discussions. Is that now considered to be inaccurate?


“There were also significant correlations with schizophrenia (rg = 0.53)”

I didn’t know that. I wonder if ME/CFS could tell us something useful about the mechanisms of schizophrenia.


“Lastly, DecodeME also provided an estimate of the heritability of ME/CFS, which was 9.5%”

I wonder if you should have explained what heritability of 9.5% means.


“DecodeME also looked at the common SNPs only where the frequency of the minor allele was 1% or higher.”

Also, DecodeME only looked at the common SNPs where the frequency of the minor allele was 1% or higher.


Thanks again. I’m looking forward to reading your next blog.
 
Last edited:
If it's a brain problem, there's not much we can do, right? Could it be invisible lesions with our current technology?
 
You must log in or register to reply here.
Back
Top Bottom