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

[arnoble]

Whether SNPs were imputed in DecodeME is in the summary statistics files, where 1 means the SNP was actually measured,

Brilliant - I never would have found that.

I wouldn't think it would cause issues for the reference panel to be healthy unlike the cases being imputed, but I'm not sure.

For example, if ALL pathological ME variants are absent on the UKB Axiom array, how sure can we be that imputation against the general population will cause them to be associated with pwME?

 

[forestglip]

For example, if ALL pathological ME variants are absent on the UKB Axiom array, how sure can we be that imputation against the general population will cause them to be associated with pwME?

I don't think I understand imputation well enough to answer. In any case, we know there is a lot of the genome data missing in DecodeME. Imputation can only get you so far, and some of the imputed variants might be wrong.

A whole genome sequencing study, AKA SequenceME, would be very valuable so that we could actually measure all the positions instead of making educated guesses about all the non-measured positions.

 

[Jonathan Edwards]

My impression is that 'imputation' is used to cover more than one inferential process, at least one involving individual SNP profiles (imputing intervening SNPs) and another making use of population weightings of SNP forms (imputing risk genes from minihaplotypes of SNPs).

 

[Hutan]

On the TNFSF4 (also known as OX40L):

a paper on lupus (SLE) quoted by Forestglip said that an up-regulation of TNFSF4/OX40L (the OX40 ligand) predisposes to lupus. I think TNFSF4 activates CD4+ t-cells:

We hypothesize that increased expression of TNFSF4 predisposes to SLE either by quantitatively augmenting T cell–APC interaction or by influencing the functional consequences of T cell activation via TNFRSF4.

Two tumor necrosis factor (TNF) superfamily members located within intervals showing genetic linkage with SLE are TNFSF4 (also known as OX40L; 1q25), which is expressed on activated antigen-presenting cells (APCs)7,8 and vascular endothelial cells9, and also its unique receptor, TNFRSF4 (also known as OX40; 1p36), which is primarily expressed on activated CD4+ T cells10.

TNFSF4 produces a potent co-stimulatory signal for activated CD4+ T cells after engagement of TNFRSF4 (ref. 11).

Using both a family-based and a case-control study design, we show that the upstream region of TNFSF4 contains a single risk haplotype for SLE, which is correlated with increased expression of both cell-surface TNFSF4 and the TNFSF4 transcript.

Another quoted paper suggests that blocking the ligand and receptor can improve lupus:

Blockade of OX40/OX40L signaling using anti-OX40L alleviates murine lupus nephritis (2024)

BUT DecodeME seems to be suggesting the opposite for ME/CFS - a decreased expression of TNFSF4, at least in some defined tissues

The DecodeME paper says that the ME/CFS variants here are associated with decreased expression of TNFSF4 in the lung, skin of sun exposed lower leg, and thyroid.

Members have noted that some drugs that reduce expression of TNFSF4 are coming to market and there was a suggestion that it could be tried in ME/CFS.

A few OX40L monoclonals are coming to market soon:

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.

If I have understood things correctly, (and I may well not have, in which case, let me know), knocking down expression of TNFSF4 in people with ME/CFS would be very unlikely to help. The genetic variant found by DecodeME that reduces TNFSF4 expression might only be relevant to increasing the risk of developing ME/CFS, so an OXO40L monoclonal that reduces TNFSF4 expression might not make symptoms worse, but there doesn't seem to be a good rationale to try it.
?

 

[forestglip]

The genetic variant found by DecodeME that reduces TNFSF4 expression might only be relevant to increasing the risk of developing ME/CFS, so it might not make symptoms worse, but there doesn't seem to be a good rationale to try it.

I think there are often situations where the same variant can be associated with increases or decreases of gene expression depending on the tissue, or maybe depending on other factors like age.

For example, a variant from a past study:

So the only significant finding in terms of genetic mutations was a SNP which affects the expression of CCK (aka cholecystokinin). The database they used seems to say that this SNP decreases expression of CCK in cultured fibroblasts but increases expression in colon cells.

Apart from that, the gene expression database isn't comprehensive of every tissue that might be affected, both because there might be too low of statistical power and because not every possible cell type/tissue type is included in the database.

So just noting that it's possible this variant might lead to increased expression where it matters for ME/CFS. Or of course you might be right and it could be a dead end.

 

[V.R.T.]

If I have understood things correctly, (and I may well not have, in which case, let me know), knocking down expression of TNFSF4 in people with ME/CFS would be very unlikely to help. The genetic variant found by DecodeME that reduces TNFSF4 expression might only be relevant to increasing the risk of developing ME/CFS, so it might not make symptoms worse, but there doesn't seem to be a good rationale to try it.
?

So I may be misremembering but the Sanofi OX40L monoclonal was claimed by the company to have a t cell calming/soothing effect, and JE and others have theorised T Cells may be central to the mechinism of MECFS. So I was going from that and the connections I saw iirc.

But i didnt realise it was down not up in DecodeME.

 

[Kitty]

@Kitty, here is that thread: https://www.s4me.info/threads/main-candidate-genes-from-decodeme-2025.46949/

Thank you! Bookmarked.