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

Does anyone know what is the genetic vs environmental influence they’ve estimated for ME given these new GWAS results? I swear I read somewhere that it’s estimated to be only a ~10% genetic contribution? Can’t find the source again

And if it’s predominantly environment that influences ME wouldn’t a large scale EWAS study make more sense than further genetic studies?
 
leokitten said:
Does anyone know what is the genetic vs environmental influence they’ve estimated for ME given these new GWAS results? I swear I read somewhere that it’s estimated to be only a ~10% genetic contribution?
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Would that just mean that anyone can get ME/CFS, but certain genes make it less or more likely that it occurs to you throughout your life?
 
Something that hasn't been discussed much is the low heritability estimate
We estimated ME/CFS SNP-based heritability from GWAS-1, based on the LDSC method and reported on a liability scale. It was modest but significantly different from zero, with ℎ^2 = 0.095 (SD = 0.006).
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This was estimated using linkage disequilibrium score regression ( LDSC). If I understand correctly the method is relatively simple: it does a regression analysis of linkage disequilibrium (how much SNPs correlate with each other) and test-score statistics for GWAS (how much different the variant was in ME/CFS compared to controls). The heritability estimate is then the slope of this regression line. If there is high heritability, then SNPs with high LD would have higher test statistics and lower p-values.

It seems that there are some problems with this method
The accuracy of LD Score regression as an estimator of confounding and genetic correlations in genome-wide association studies - PMC

And it also doesn't take the sex chromosomes and rare variants into account.

But if we take it as a rough estimate, it still seems quite lower than what many expected?
 
Kiristar said:
Does that finally answer the long-standing debate about whether it's the same as fibromyalgia then?

Or did a fibro GWAS study also report finding the CA pain gene?

Eta sorry but I'm too severe to watch the video at the moment. @Andy Apologies I did actually try to look at the FAQs but on my mobile only a couple results ones show up and I couldn't see the answer.
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All I can tell you is this from the FAQs.

"Are these findings unique to ME or have they been found in other illnesses?

The signals we have found are different from those found in other illnesses to date, except for the one on chromosome 17 that was previously found in people experiencing chronic pain."

But I can't answer as to whether sufficiently powered GWAS has been done on fibromyalgia. The GWAS my very quick look found seemed to be on very small cohorts, so I doubt we would make the claim that we have finally answered that debate.
 
leokitten said:
Does anyone know what is the genetic vs environmental influence they’ve estimated for ME given these new GWAS results? I swear I read somewhere that it’s estimated to be only a ~10% genetic contribution? Can’t find the source again

And if it’s predominantly environment that influences ME wouldn’t a large scale EWAS study make more sense than further genetic studies?
Click to expand...
I suspect that viewing it purely as genetic vs environmental might be to simplistic when you have complex dynamical interactions to account for which have to include stochasticity which may be neither (not genetic nor environmental).
 
Hoopoe said:
GWAS tend to underestimate heritability.
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I got the impression that the ME/CFS estimate still seems quite low compared to other diseases using the same method

UKB SNP-Heritability Browser

nealelab.github.io nealelab.github.io

Comparison of Family History and SNPs for Predicting Risk of Complex Disease - PMC

The clinical utility of family history and genetic tests is generally well understood for simple Mendelian disorders and rare subforms of complex diseases that are directly attributable to highly penetrant genetic variants. However, little is ...
pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov
 
EndME said:
I suspect that viewing it purely as genetic vs environmental might be to simplistic when you have complex dynamical interactions to account for which have to include stochasticity which may be neither (not genetic nor environmental).
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Right and if true a very high predominance of non-genetic influence, whether stochastic or epigenetic, would further suggest that it’s potentially quite limited what mechanistic insights we might glean from additional genetic studies.
 
Utsikt said:
Would that just mean that anyone can get ME/CFS, but certain genes make it less or more likely that it occurs to you throughout your life?
Click to expand...

Right but the underlying goal of a genetic study like this is to gain some mechanistic insights as to what triggers or continues to drive the illness, and if the genetic component/influence is very low then these gene variants more likely than not do not play a major role in the pathomechanism and therefore their utility in further research and treatment development is rather limited
 
ME/CFS Science Blog said:
I got the impression that the ME/CFS estimate still seems quite low compared to other diseases using the same method

UKB SNP-Heritability Browser

nealelab.github.io nealelab.github.io

Comparison of Family History and SNPs for Predicting Risk of Complex Disease - PMC

The clinical utility of family history and genetic tests is generally well understood for simple Mendelian disorders and rare subforms of complex diseases that are directly attributable to highly penetrant genetic variants. However, little is ...
pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov
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If you read the Wikipedia article, it explains that the more SNPs are considered, the more accurate heritability estimates from GWAS become.

Things like body parameters have presumably heritability estimates that can draw on far more SNPs than diseases.

I'm not sure that the second article is relevant.
 
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Yann04 said:
Previously I wondered if the “Chronic pain gene“ (CA10 I think?), might actually be associated with ME not chronic pain. But since ME is commonly undiagnosed and has chronic pain for many, a lot of pwME may have ended up in a chronic pain GWAS and with large sample sizes it might show an effect.
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I'm going to try and now find the thread on this specific gene. As I'm thinking is it pain or chronic pain, and which things does it relate to etc

Wary of getting the terminology right on this because some of the chronic pain sector, and eg one of the specific guidelines for something called eg chronic pain was a problem / quite bps wasn't it?

it is a term that currently is a bit of a bucket/one of those that has a variety of layman's meanings but also covers quite specific diagnoses, where I don't know what the finding it in the GWAS specifically it is referring to
 
Hoopoe said:
If you read the Wikipedia article, it explains that the more SNPs are considered, the more accurate heritability estimates from GWAS become.

Things like body parameters have presumably heritability estimates that can draw on far more SNPs than diseases.
Click to expand...
To clarify: the link to the Neal lab data includes a search function where you can find the heritability estimate for other diseases using UKB methods similar to what DecodeME used. It seems that ME/CFS isn't like schizophrenia, Crohn's disease or diabetes type 1 for example, which have a significant higher heritability.

Unless the rare variants shows up very interesting things, I do think this points to relatively low heritability of ME/CFS?
 
leokitten said:
Does anyone know what is the genetic vs environmental influence they’ve estimated for ME given these new GWAS results? I swear I read somewhere that it’s estimated to be only a ~10% genetic contribution? Can’t find the source again
Click to expand...

My memory is that a US- based twin study suggested a much higher genetic component - maybe 40-50%. I think Chris was disappointed that the SNPs only provided evidence for a modest ~10%.

In view of the fact that the obvious suspects like MHC genes did not turn up any major risk effect over a period of twenty years, together with the elusive nature of the ME/CFS pathology, I don't think it is that surprising that the score so far is lower than a lot of other diseases.

But I don't think this is a major reason to draw back from genetics. In other diseases rare gene variants that provide high risk for disease in a tiny proportion of cases can be extremely useful. The rare cases of homozygous complement gene defects show that one sure fire way to get lupus is through defective complement. Which why a whole genome sequencing project makes sense to me. And I presume that you would be lucky to get much out of it with less than 5,000 cases, just because the search is for rare gene variants.
 
leokitten said:
Right but the underlying goal of a genetic study like this is to gain some mechanistic insights as to what triggers or continues to drive the illness, and if the genetic component/influence is very low then these gene variants more likely than not do not play a major role in the pathomechanism and therefore their utility in further research and treatment development is rather limited
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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).
 
ME/CFS Science Blog said:
Unless the rare variants shows up very interesting things, I do think this points to relatively low heritability of ME/CFS?
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I am not sure that you can conclude that even after chasing rare genes. If genetic risk comes from combinations of genes looking at genes one at a time is not enough. That may be a rare situation but it something that cropped up in the context of NK receptors for Class I. We are all born with six Class I alleles and a whole bunch of receptor alleles that are supposed to fit the Class I. A disease might be linked to certain pairs of alleles or even more complex combinations.
 
ME/CFS Science Blog said:
To clarify: the link to the Neal lab data includes a search function where you can find the heritability estimate for other diseases using UKB methods similar to what DecodeME used. It seems that ME/CFS isn't like schizophrenia, Crohn's disease or diabetes type 1 for example, which have a significant higher heritability.

Unless the rare variants shows up very interesting things, I do think this points to relatively low heritability of ME/CFS?
Click to expand...
Okay, I think I understand you better. You were comparing heritability of ME/CFS to other diseases. 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. Maybe the estimate can be revised substantially in the future.

I was comparing the 10% heritability estimated by DecodeME with other ME/CFS studies that used different approaches and found much higher heritability.
 
Jonathan Edwards said:
My memory is that a US- based twin study suggested a much higher genetic component - maybe 40-50%
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I think it was this study:
Repurposing large health insurance claims data to estimate genetic and environmental contributions in 560 phenotypes (2019) Lakhani et al. | Science for ME

Here's the overview from Dibble et al.
Of three studies that have estimated narrow-senseheritability (h2) using large cohorts, two reported non-zero h2-values that provide evidence for heritability of risk for CFS and,presumably, ME/CFS. An analysis of US health insurance claimeda high narrow-sense heritability (h2 = 0.48) of CFS (23), whereasan analysis of the UK Biobank individuals self-reporting a CFSdiagnosis reported a less striking heritability (single nucleotidepolymorphism- [SNP-] based approximate h2 = 0.08 with low confidence) (24) (http://www.nealelab.is/uk-biobank). The third, alarge twin-based study of CFS-like cases, produced an inconclusive result, with the 95% confidence interval of h2 including zero[0.03 (0.00–0.65)] (25)
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