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):

 

[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]

Some discussion about variants near SUDS3/TAOK3 and their possible relationship to lupus have been moved to: Genetics: Chromosome 12: SUDS3, TAOK3

 

[mariovitali]

@forestglip I am not sure if you have seen this analysis by Paolo Maccallini :

https://github.com/paolomaccallini-hub/MetaME?tab=readme-ov-file

I am particularly interested in genes EP300 and UGP2. Can these two be significant targets?

 

[forestglip]

@forestglip I am not sure if you have seen this analysis by Paolo Maccallini :

https://github.com/paolomaccallini-hub/MetaME?tab=readme-ov-file

I am particularly interested in genes EP300 and UGP2. Can these two be significant targets?

Interesting that in this meta-analysis, there actually is a significant gene set enrichment in MAGMA: GOCC_GLUTAMATERGIC_SYNAPSE

Paolo commented this on ME/CFS Science Blog's blog about overlapping controls, so I'm not sure how much impact this may have had on the results:

There is a problem though: DecodeME and UK Biobank have overlapping controls. Now I am trying to solve this problem using a correction of the weights used in the meta analysis.

I don't know enough about the method used for the meta-analysis calculation to really comment on it. But assuming it's valid, there are still 27 resulting candidate genes at the chr22 locus which includes EP300. So that could be a gene of interest, or maybe it's another of those many gene options. And there are four candidate genes at the chr2 locus that includes UGP2.

 

[mariovitali]

Interesting that in this meta-analysis, there actually is a significant gene set enrichment in MAGMA: GOCC_GLUTAMATERGIC_SYNAPSE

Paolo commented this on ME/CFS Science Blog's blog about overlapping controls, so I'm not sure how much impact this may have had on the results:


I don't know enough about the method used for the meta-analysis calculation to really comment on it. But assuming it's valid, there are still 27 resulting candidate genes at the chr22 locus which includes EP300. So that could be a gene of interest, or maybe it's another of those many gene options. And there are four candidate genes at the chr2 locus that includes UGP2.

Thanks @forestglip , yes I wonder if a key mechanism here is excitotoxicity via glutamate (and perhaps quinolinic acid). Another interesting finding can potentially be the gene ACO2 (exists also in the list of genes) which could be linked to the itaconate shunt hypothesis. If we have indeed issues with glutamatergic synapses coupled with ER stress and impaired ER autophagy (=ER-phagy) in the Endoplasmic reticulum then we may have a perfect storm taking place.

 

[forestglip]

Here's an attempt to bring together all of the main candidate genes from different sources: Tier 1 genes, tier 2 genes, genes significant in MAGMA, and the gene (or two genes if it is not clear) closest to a locus for the top 25 loci.

Gene	Method	CHR	Lead variant position (GRCh38)	Reference allele	Effect allele	Lead variant ID	Lead variant p-value
LRRC7	MAGMA	1	69696474	A	G	1:69696474:A:G	2.06E-07
								xxxxx
NEGR1	Nearest (1 of 2)	1	73126414	C	CA	1:73126414:C:CA	1.19E-07
LRRIQ3	Nearest (1 of 2)	1	73126414	C	CA	1:73126414:C:CA	1.19E-07
								xxxxx
ZNF644	Nearest	1	91028158	C	T	1:91028158:C:T	1.89E-07
								xxxxx
RABGAP1L	Tier 1	1	173846152	T	C	1:173846152:T:C	2.56E-08
DARS2	Tier 1, MAGMA, Nearest	1	173846152	T	C	1:173846152:T:C	2.56E-08
RC3H1	Tier 1	1	173846152	T	C	1:173846152:T:C	2.56E-08
GPR52	Tier 1	1	173846152	T	C	1:173846152:T:C	2.56E-08
ZBTB37	Tier 1, MAGMA	1	173846152	T	C	1:173846152:T:C	2.56E-08
TNFSF4	Tier 1	1	173846152	T	C	1:173846152:T:C	2.56E-08
ANKRD45	Tier 1	1	173846152	T	C	1:173846152:T:C	2.56E-08
KLHL20	Tier 1	1	173846152	T	C	1:173846152:T:C	2.56E-08
PRDX6	Tier 1	1	173846152	T	C	1:173846152:T:C	2.56E-08
SERPINC1	Tier 1	1	173846152	T	C	1:173846152:T:C	2.56E-08
SLC9C2	Tier 1	1	173846152	T	C	1:173846152:T:C	2.56E-08
								xxxxx
CACNA1E	Nearest	1	181676091	G	A	1:181676091:G:A	8.85E-07
								xxxxx
VRK2	Nearest	2	57808420	G	A	2:57808420:G:A	9.49E-07
								xxxxx
PLCL1	Nearest	2	197882813	A	G	2:197882813:A:G	6.64E-07
								xxxxx
HTT	Nearest	4	3240118	C	T	4:3240118:C:T	8.03E-07
								xxxxx
ECI2	Nearest	6	4336259	T	C	6:4336259:T:C	2.90E-07
								xxxxx
BTN2A2	Tier 1	6	26239176	A	G	6:26239176:A:G	4.11E-09
TRIM38	Tier 1	6	26239176	A	G	6:26239176:A:G	4.11E-09
ZNF322	Tier 1	6	26239176	A	G	6:26239176:A:G	4.11E-09
ABT1	Tier 1	6	26239176	A	G	6:26239176:A:G	4.11E-09
HFE	Tier 1	6	26239176	A	G	6:26239176:A:G	4.11E-09
BTN3A3	Tier 1	6	26239176	A	G	6:26239176:A:G	4.11E-09
HMGN4	Tier 1	6	26239176	A	G	6:26239176:A:G	4.11E-09
H4C8	MAGMA, Nearest	6	26239176	A	G	6:26239176:A:G	4.11E-09
								xxxxx
ZNF311	MAGMA	6	29016371	G	A	6:29016371:G:A	2.25E-06
								xxxxx
FBXL4	Tier 2	6	97984426	C	CA	6:97984426:C:CA	4.85E-08
POU3F2	Nearest (1 of 2)	6	97984426	C	CA	6:97984426:C:CA	4.85E-08
MMS22L	Nearest (1 of 2)	6	97984426	C	CA	6:97984426:C:CA	4.85E-08
								xxxxx
MLLT10	Nearest (1 of 2)	10	21748880	A	G	10:21748880:A:G	6.34E-07
DNAJC1	Nearest (1 of 2)	10	21748880	A	G	10:21748880:A:G	6.34E-07
								xxxxx
SOX6	Nearest	11	16217844	C	G	11:16217844:C:G	1.08E-07
								xxxxx
SLC2A14	Nearest	12	7860921	T	A	12:7860921:T:A	5.79E-07
								xxxxx
SUDS3	Tier 1, MAGMA	12	118202773	CTTTTTTTTTTTTT	C	12:118202773:CTTTTTTTTTTTTT:C	1.64E-07
PEBP1	Tier 1	12	118202773	CTTTTTTTTTTTTT	C	12:118202773:CTTTTTTTTTTTTT:C	1.64E-07
VSIG10	Tier 1	12	118202773	CTTTTTTTTTTTTT	C	12:118202773:CTTTTTTTTTTTTT:C	1.64E-07
TAOK3	Nearest, MAGMA	12	118202773	CTTTTTTTTTTTTT	C	12:118202773:CTTTTTTTTTTTTT:C	1.64E-07
								xxxxx
DNAH10	MAGMA	12	123924955	G	A	12:123924955:G:A	2.43E-07
ZNF664	MAGMA	12	123924955	G	A	12:123924955:G:A	2.43E-07
CCDC92	MAGMA	12	123924955	G	A	12:123924955:G:A	2.43E-07
								xxxxx
OLFM4	Nearest, Tier 2	13	53194927	GT	G	13:53194927:GT:G	1.16E-07
								xxxxx
PCDH17	Nearest	13	58456743	T	C	13:58456743:T:C	9.42E-07
								xxxxx
CCPG1	Tier 2	15	54866724	A	G	15:54866724:A:G	7.62E-09
UNC13C	Nearest	15	54866724	A	G	15:54866724:A:G	7.62E-09
								xxxxx
SHISA6	Nearest	17	11325637	G	C	17:11325637:G:C	8.26E-08
								xxxxx
CA10	Tier 1, Nearest	17	52183006	C	T	17:52183006:C:T	2.11E-09
								xxxxx
DCC	Nearest	18	53232948	C	T	18:53232948:C:T	2.48E-07
								xxxxx
CDK5RAP1	Nearest	20	33363039	G	A	20:33363039:G:A	5.41E-07
								xxxxx
CSE1L	Tier 1, MAGMA	20	48914387	T	TA	20:48914387:T:TA	9.51E-12
ARFGEF2	Tier 1, MAGMA, Nearest	20	48914387	T	TA	20:48914387:T:TA	9.51E-12
DDX27	Tier 1	20	48914387	T	TA	20:48914387:T:TA	9.51E-12
STAU1	Tier 1, MAGMA	20	48914387	T	TA	20:48914387:T:TA	9.51E-12
ZNFX1	Tier 1	20	48914387	T	TA	20:48914387:T:TA	9.51E-12
B4GALT5	Tier 1	20	48914387	T	TA	20:48914387:T:TA	9.51E-12
PTGIS	Tier 1	20	48914387	T	TA	20:48914387:T:TA	9.51E-12
								xxxxx
MRPL39	Nearest	21	25487862	A	AG	21:25487862:A:AG	5.10E-07

Spoiler: List of only genes for easy copying

LRRC7
NEGR1
LRRIQ3
ZNF644
RABGAP1L
DARS2
RC3H1
GPR52
ZBTB37
TNFSF4
ANKRD45
KLHL20
PRDX6
SERPINC1
SLC9C2
CACNA1E
VRK2
PLCL1
HTT
ECI2
BTN2A2
TRIM38
ZNF322
ABT1
HFE
BTN3A3
HMGN4
H4C8
ZNF311
FBXL4
POU3F2
MMS22L
MLLT10
DNAJC1
SOX6
SLC2A14
SUDS3
PEBP1
VSIG10
TAOK3
DNAH10
ZNF664
CCDC92
OLFM4
PCDH17
CCPG1
UNC13C
SHISA6
CA10
DCC
CDK5RAP1
CSE1L
ARFGEF2
DDX27
STAU1
ZNFX1
B4GALT5
PTGIS
MRPL39

Sources:
Tier 1 and 2 genes: Candidate genes document
MAGMA genes: Supplementary table 4
Top 25 loci: Supplementary table 3, with nearest gene to each lead variant found with LocusZoom. (Can also be done on UCSC Genome Browser.)

Spoiler: Steps to find nearest genes to a variant on UCSC Genome Browser

1. Go to genome browser at https://genome.ucsc.edu/cgi-bin/hgTracks

2. Press the "Hide All" button to turn off the unneeded tracks:


3. In the dropdown for GENCODE, select "pack", then press "Refresh":


4. In the search box at the top, enter a chromosomal position in the format CHROMOSOME: POSITION, then press "Search". For example, 20:48914387 is the location of the most significant variant in DecodeME:


5. Press the buttons to the right of "Zoom out" at the top of the page until you see protein coding genes show up in the main field of view, which will be colored blue. For example, I had to press the 10x zoom out button five times to see that ARFGEF2 is the nearest gene to the most significant variant: