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

[V.R.T.]

Blockade of OX40/OX40L signaling using anti-OX40L alleviates murine lupus nephritis (2024)
Genetic variants of the OX40 ligand (OX40L) locus are associated with the risk of systemic lupus erythematosus (SLE), it is unclear how the OX40L blockade delays the lupus phenotype. Therefore, we examined the effects of an anti-OX40L antibody in MRL/Lpr mice. Next, we investigated the effect of anti-OX40L on immunosuppression in keyhole limpet hemocyanin-immunized C57BL/6J mice. In vitro treatment of anti-OX40L in CD4+ T and B220+ B cells was used to explore the role of OX40L in the pathogenesis of SLE.

Anti-OX40L alleviated murine lupus nephritis, accompanied by decreased production of anti-dsDNA and proteinuria, as well as lower frequencies of splenic T helper (Th) 1 and T-follicular helper cells (Tfh).

In keyhole limpet hemocyanin-immunized mice, decreased levels of immunoglobulins and plasmablasts were observed in the anti-OX40L group. Anti-OX40L reduced the number and area of germinal centers. Compared with the control IgG group, anti-OX40L downregulated CD4+ T-cell differentiation into Th1 and Tfh cells and upregulated CD4+ T-cell differentiation into regulatory T cells in vitro.

Furthermore, anti-OX40L inhibited toll-like receptor 7-mediated differentiation of antibody-secreting cells and antibody production through the regulation of the SPIB-BLIMP1-XBP1 axis in B cells.

These results suggest that OX40L is a promising therapeutic target for SLE. Web | PDF | Eur J Immunol. | Open Access

Edit: Aha! It was mentioned in the DecodeME candidate genes document as a potential gene that this locus applies to (thanks Evergreen for posting about this):

In her recent talk Michelle James lists OX40 as a PET tracer that is being investigated in ME. In my email I asked if it was her or someone else studying it but I haven't heard back yet.

I know I've been a broken record about these tracers lately but it's an interesting connection!

 

[V.R.T.]

Would it be worthwhile in trying to get those researchers who are already looking at the genetics of lupus (or other similar conditions) interested in the results of DecodeME?

Yes if anyone knows of any other lupus researchers (than the kings people) who are any good, perhaps letting them know about the Nov. 6 event might be an idea.

 

[Turtle]

In her recent talk Michelle James lists OX40 as a PET tracer that is being investigated in ME. In my email I asked if it was her or someone else studying it but I haven't heard back yet.

I know I've been a broken record about these tracers lately but it's an interesting connection!

As long as there are interesting connections there is no broken record as far as I can see. Keep them coming! Others might make a connection, somehow, somewhere.

 

[wigglethemouse]

Impressive work @forestglip. Can you look to see if you can find any datasets for Sjogrens. It's a CNS disease with some overlap to ME/CFS such as small fiber neuropathy.

Here is that RABGAP1L region. SLE is in blue and ME/CFS is in red.

This Sjogrens GWAS meta-analysis abstract also mentions RABGAP1L.

Meta-Analysis of GWAS data from 10,003 Sjögren’s Disease Cases Identifies Thirteen Sjögren’s Risk Loci. - ACR Meeting Abstracts

Background/Purpose: Sjögren’s disease (SjD) is a systemic autoimmune condition with a complex genetic architecture. To date, 22 genome-wide significant (GWS) SjD risk loci have been identified, while >100 risk loci have been described in other related autoimmune diseases (Khatri et al. 2022)...

acrabstracts.org

 

[forestglip]

Can you look to see if you can find any datasets for Sjogrens.

This study looks promising and has downloadable data: https://www.ebi.ac.uk/gwas/studies/GCST012796

Though it's a relatively small sample (585 cases if using just European participants). But I'll try to test the correlation with ME/CFS using this.

 

[forestglip]

This study looks promising and has downloadable data: https://www.ebi.ac.uk/gwas/studies/GCST012796

Though it's a relatively small sample (585 cases if using just European participants). But I'll try to test the correlation with ME/CFS using this.

I'm running into an issue with the Sjogren's data because the dataset only has the effect allele for each variant and not the reference allele, but Bigagwas requires both. So I'm not sure I'll be able to test a genetic correlation with this dataset.

I did explore the plots, looking at the significant loci from each study to see if anything similar popped out. I used the data that included all ancestries combined (1405 cases and 4747 controls). I didn't really see anything very similar.

Unlike the plot for SLE, there's nothing going on in the TNFSF4/RABGAP1L area:


The chromosome 6 area is interesting because of how huge the locus is for Sjogren's compared to the little ME/CFS locus on the left. (I cut off a lot of gene names below the plot because there were too many to fit). This is with only 1405 Sjogren's cases. And the locus when looking at only the 585 European cases has nearly the same significance (p=~3e-34).




The closest I saw to a matching locus of the ones I looked at, but it's not genome-wide significant in either disease:


Link to paper.

 

[forestglip]

chr6p22.2:

From the blue dots, we get a clear picture of exactly where the strongest regulatory regions are upstream of the BTNs

Sorry, my plot was probably a bit misleading on this front since it was so zoomed in. It gives quite a different picture if I zoom out to include the full SLE locus (not all genes shown):

 

[ME/CFS Science Blog]

it'd probably be very nice for both SLE and ME/CFS research to find a common pathway/gene.

Could you also check the region above TAOK3 on chromosome 12? It was found to be associated with lupus according to the GWAS catalog.

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

Sep 25, 2025

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.




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...

• ME/CFS Science Blog

• 

 

[V.R.T.]

A few OX40L monoclonals are coming to market soon:

Press Release: Sanofi’s amlitelimab met all primary and key secondary endpoints in the COAST 1 phase 3 study in adults and adolescents with atopic dermatitis

Sanofi’s amlitelimab met all primary and key secondary endpoints in the COAST 1 phase 3 study in adults and adolescents with atopic dermatitis Amlitelimab, dosed every four weeks or every 12 weeks,...

www.sanofi.com

"normalize the overactive immune system, without depleting T cells"

Originally for dermatitis, but I believe they think they will be good general immune T-cell suppression, possibly off-label

This particular monoclonal is made by Sanofi, who recently agreed to let Scheibenbogen trial their CD38 inhibitor in ME/CFS. So if there is a rationale for trying their OX40 monoclonal in ME they might well be amenable.

 

[forestglip]

Could you also check the region above TAOK3 on chromosome 12? It was found to be associated with lupus according to the GWAS catalog.

It doesn't look like it was significant in this study. And the Bentham 2015 paper doesn't mention any locus in this region. It mentions two other loci on chromosome 12, which can be seen if I zoom out really far. The ME/CFS TAOK3 locus is the left red tower. (Not all gene names shown.)


Looking at the lupus paper you're referring to, Wang et al, here's the data for that TAOK3 SNP (right side of table cut off):


They got 1.81e-3 for the p value of that SNP when they only look at ~5000 European cases, which is close to the sample size in the Bentham study. This p value isn't very far off Bentham et al's result of p=1.6e-2 (from the summary statistics).

It's only when Wang et al combined the European cases with another ~5000 Asian cases that it passed the genome-wide significance threshold.

 

[forestglip]

Could you also check the region above TAOK3 on chromosome 12? It was found to be associated with lupus according to the GWAS catalog.

That paper refers to a study/dataset from the same author from a year earlier: GCST011096. It has slightly fewer Asian cases, but it looks like the same European sample. So it is based on 8798 cases and 16470 controls from mixed ancestry.

I was able to download this data and plot it. And it does look like basically the same area for the locus in SLE and ME/CFS:


Also, this dataset demonstrates the benefit of multi-ancestry GWAS. Here's the chr6p locus when looking at the European cases from Bentham et al:

Here is the same area, but looking at the data when European and Asian cases were combined in Wang 2021:


Linkage disequilibrium patterns are different between ancestries, so if both populations share a common causal SNP, but this SNP is in LD with different non-important SNPs in the two populations, far fewer non-important SNPs will be significant, helping to narrow down where the actually causal variant is.

(Though the difference in shape isn't necessarily completely due to different LD. The two populations might not have identical causal variants.)

Same thing said in a paper:

Second, single-ancestry GWAS are hampered by the specific linkage disequilibrium (LD) structure in that ancestry, which could obscure the ability to effectively fine-map an associated locus. Multi-ancestry GWAS can improve fine-mapping resolution by leveraging the distinct LD structures in each ancestry

 

[ME/CFS Science Blog]

Thanks @forestglip!