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

[ME/CFS Science Blog]

The liability heritability of Crohn's using LDSC is around 24%. That's higher than the 10% found by DecodeME. I find that disappointing as well.

I kind of picked examples with high heritability though. There are other diseases with similarly low heritability estimates such as rheumatoid arthritis so the estimate for ME/CFS is nothing weird. But perhaps a bit lower than some expected.

 

[Yann04]

I’m not sure that’s the right interpretation. If the genes show up, they are always causal, so they do play a role in the disease mechanism(s).

(assuming perfect methodology including selection which in practice is impossible, there will always be some caveats).

But yes, it is very likely casual.

 

[Jonathan Edwards]

Do we know the heritability and the explanatory power of genetics for other diseases that are believed to primarily have an infectious onset?

Reiter's is the obvious one. We knew that there was an arthritis syndrome that occurred after dysentery or non-specific urethritis. It was discovered that a high proportion of patients are B27+, like ank spond and various other things allowed us to build a model of disease around the whole lot. Reiter's has a slightly different risk profile though if I remember rightly - B7 also confers risk. We are still waiting for Matt Brown to work out why these HLA-B alleles are important but one day we will know.

I think rheumatic fever is predisposed to by some immune response genes too but I forget which.

 

[Hoopoe]

ME/CFS does have a problem with misdiagnosis, and my intuition tells me that heritability estimates will be more accurate for diseases where there's less diagnostic uncertainty.

In the Neale database, h2 for fibromyalgia is 0.0112 (or about 1%).

ME/CFS is doing pretty well in comparison.

 

[Hutan]

I've been wondering about the lack of sex chromosome results in the preprint. Chris said in the interview with David that they had results by last September, October. And surely, for a disease where more women are diagnosed than men, the X chromosome would be the first one you would look at closely, not the last?

It's probably been a year since the DecodeME team started stressing that ME/CFS is a female disease, and people started to look at the evidence for the "twin peaks" idea for females onset. DecodeME publications have referred to a sex ratio of 4 to 1, which I think is higher than the evidence really warrants, and doesn't take into account the considerable bias against men choosing and being given an ME/CFS label.

There's been the odd comment about 'if there's not a genetic difference between males and females, it must be hormones making the difference'. And we've had OMF pushing for a study on hormones, stretching the evidence in order to justify one.

So, it's a bit puzzling. I'm assuming the sex chromosome results weren't prioritised for inclusion in the initial preprint for a strategic reason. I'm not sure what the reason is. @Andy, @Simon?

 

[ME/CFS Science Blog]

DecodeME publications have referred to a sex ratio of 4 to 1, which I think is higher than the evidence really warrants

The DecodeME participants were 85% females themselves.

So, it's a bit puzzling. I'm assuming the sex chromosome results weren't prioritised for inclusion in the initial preprint for a strategic reason. I'm not sure what the reason is.

I think it's the default of GWAS because sex chromosomes have additional difficulties to analyze see:
eXclusionarY: 10 years later, where are the sex chromosomes in GWASs? - PMC

EDIT: added quote from the paper above

The X chromosome presents multiple analytical challenges,9,10,11,12,13,14 including (1) a male has one copy of the X chromosome while a female has two, in contrast to the autosomes; (2) the X chromosome in male germ cells only recombines with the Y chromosome in the pseudo-autosomal regions (PARs) but not in the NPR; (3) in contrast to males, the two copies in female germ cells recombine across the entire X chromosome; (4) the two female copies are also subject to X inactivation (i.e., X chromosome dosage compensation); (5) the X-inactivation status at the population level can be random, skewed, or absent (i.e., X-inactivation escape); and (6) the true X-inactivation status at the individual level cannot be derived from GWAS data alone.

 

[leokitten]

I’m not sure that’s the right interpretation. If the genes show up, they are always causal, so they do play a role in the disease mechanism(s).

From my understanding GWAS findings by themselves aren’t causal only correlative. You need to perform additional analyses to do casual inference. See for example an explanation here https://pmc.ncbi.nlm.nih.gov/articles/PMC7614231/

GWAS estimate the association of each SNP with the phenotype, not the causal effect of each SNP on the phenotype.

 

[Jonathan Edwards]

I've been wondering quite a bit about the lack of sex chromosome results in the preprint. Chris said in the interview with David that they had results by last September, October. And surely, for a disease where more women are diagnosed than men, the X chromosome would be the first one you would look at closely, not the last?

It's an interesting question but I am not sure it is obvious to look at the X and Y chromosomes. The reason why women are more likely to get ME/CFS than men is that they have two X chromosomes and men have one plus a Y. We know that already. We are not expecting women with ME/CFS to have any different gene variants from other women, or indeed X gene variants from men.

Maybe we can argue that if we find women with ME/CFS have a higher rate of a variant of one gene that partly controls the difference in immune response between men and women and not another that does in a different way then the first way is more relevant. But I am not sure we even know which genes individually control the differences, or how we could test for that other than by complicated gene editing experiments on the X chromosome (and it would have to be mice). And these genes may not be polymorphic anyway.

 

[Jonathan Edwards]

From my understanding GWAS findings by themselves aren’t causal only correlative. You need to perform additional analyses to do casual inference. See for example an explanation here

I think you need to do other things to establish the precise nature of the causation and maybe the strength but if you correctly identify a gene polymorphism as linked to risk and have excluded linkage disequilibrium (assuming you can) then you have established a causal relation. That is the beauty of genetic studies.

 

[Hoopoe]

It's an interesting question but I am not sure it is obvious to look at the X and Y chromosomes. The reason why women are more likely to get ME/CFS than men is that they have two X chromosomes and men have one plus a Y. We know that already. We are not expecting women with ME/CFS to have any different gene variants from other women, or indeed X gene variants from men.

If that is the case, why did I have the impression that the result of finding no explanation for the increased risk in women was surprising?

 

[Jonathan Edwards]

If that is the case, why did I have the impression that the result of finding no explanation for the increased risk in women was surprising?

No idea, did someone say it was surprising?

 

[Hoopoe]

No idea, did someone say it was surprising?

It was mentioned in the abstract. To me that makes it seem that it was not something a person with basic knowledge would expect.

 

[Hutan]

The DecodeME participants were 85% females themselves.

We have discussed elsewhere about that not telling us much about sex ratios in ME/CFS though. There are too many confounders e.g. who gets diagnosed, who identifies with the ME/CFS community, who participates in unpaid research studies. What it does mean though is that there is a big female sample, so findings relating to the X chromosome could be quite robust. It is possible that the male sample was too small to produce good Y chromosome results I guess.

Thanks for the link, very interesting. It looks as though DecodeME is not alone in not reporting sex chromosome results. Hopefully in the case of DecodeME, the results are still coming.

 

[Jonathan Edwards]

We found no evidence of sex-bias among discovered associations

Were you meaning this?
I took this to mean that the risk gene profile looked the same in men and women. That would suggest that men's ME/CFS and women's ME/CFS are not two different diseases but I don't think it relates to the female predominance.

 

[Hoopoe]

Were you meaning this?

Yes.

I interpreted it differently, along the lines of "To our surprise, we were unable to explain why women are more likely to have ME/CFS". I was thinking of total risk.

What is actually meant is that the portion of risk that comes from the variants examined is insignificantly small.

It seems that a lack of sex-bias is actually a common finding in GWAS.

A question that remains is what exactly is causing the increased risk in women. Is it genetic variants on the X chromosome, hormonal or immune differences?

 

[Jonathan Edwards]

It seems that a lack of sex-bias is actually a common finding in GWAS.

I would have thought that for the non-sex chromosomes it was standard and in a sense almost a quality control exercise for the diagnostic category.

 

[Jonathan Edwards]

I think there have been several studies suggesting that phenotypic features of ME/CFS differ in men and women. The Beentjes study showed some features shared but not others. That raised a significant possibility that ME/CFS is mediated by different processes in the two sexes, just as arthritis is mediated differently in the two sexes (to a degree). The genetics did not provide evidence for that.

 

[Chris Ponting]

Sorry, can someone explain the "European ancestry" thing? I am not even sure what this means. Thank-you.

Hi. First, I should say that we didn't complete in time for the preprint a second DecodeME analysis that uses all cases passing quality control. We're going to keep going on this. But in answer to your question about "European ancestry", this is genetics short-hand for people whose DNA variation is very similar to the variation seen among people from Europe. We needed to do this to very accurately match the genetics of ME/CFS cases with our UK Biobank controls. If we hadn't done this accurately, then we could easily have wrongly found "ME/CFS associations" that would actually only reflect differences in ancestries between cases and controls. You can see from the preprint's Supplementary Figure S1 (https://www.pure.ed.ac.uk/ws/portalfiles/portal/533352490/Preprint.pdf) that we matched cases and controls really well: in each of 20 different dimensions genetic data from the ME/CFS cases (in green) fall on top of data from the UK Biobank controls (in black/grey). If there were cases from a non-European ancestry then these would fall outside of these "blobs". Hope that's OK.

 

[Deanne NZ]

Do we know the heritability and the explanatory power of genetics for other diseases that are believed to primarily have an infectious onset?

Type 1 Diabetes is believed to have an infectious onset - with genetic predisposition. In terms of heritability, off-spring of males with T1D are more likely to develop the disease, than off-spring of mothers with T1D. There is a greater ratio of males than females with T1D but more females are likely to have additional autoimmune conditions.
This paper has a good table (1) on the heritability ratios.

Risk Factors for Type 1 Diabetes - Diabetes in America - NCBI Bookshelf

 

[sb4]

I'm still trying to understand how confident we should be with these finding. I understand the difference in gene variants is very small between patients and controls but that's okay since large numbers were used. I also understand they failed to replicate the results using other databases.

Could somebody who understands this better say in laymen's terms how confident we should be that these findings are legit?