Genetic studies of ME/CFS and other diseases including GWAS - discussion thread

This discussion has been moved from:
Unexplained post-acute infection syndromes, 2021, Iwasaki et al

If there is a common cause then presumably this would be identified by a large genetic study (GWAS - Chris Ponting).
*( the cause and development of a disease or abnormal condition.)

Testing various hypothesis doesn't appear to have turned up the answer. As per my comment above - GWAS seems a reasonable (ignostic) approach.

 

I think the large scale genetic studies of pwME need to come out first. Will be interesting to see the correlation between personal and family history of auto-immune diseases. So many triggering pathogens and EBV is common within the population

 

Only if the cause is a genetic anomaly. I fear anything else discovered, e.g. a predilection to develop long-term sequelae, could lead to some unwanted consequences. Best to hone in on cause(s), imo, from multiple vantages.

I think we can no longer afford to look under rugs sequentially. If any given endeavor proves a dead end, especially a large and very public one, starting from scratch will be very difficult emotionally and financially (and politically what with the vultures descending in what I imagine would be a very nasty feeding frenzy).

 

Diseases like Alzheimer's have had large GWAS studies and that helped to understand the basic (underlying) cause - inflammation--- one gene identified coded for 3 forms or a protein - 1 form provided protection (protein with 1 X tyrosine-tyrosine bond) 1 form was neutral (2 X tyrosine-tyrosine bond) 1 form increased risk (3 X tyrosine-tyrosine bond) - tyrosine-tyrosine bonds are cleaved by a protein produced by gingivitis*.

With respect, your comment seems to suggest that we shouldn't focus on the best chance of identifying the underlying the cause and hence potentially treatments. Rather, we should be mindful of the fact that, if GWAS doesn't turn up a clear answer(s) then we'll get hammered by "I told you so" from folks who reluctantly (post Sajid Javid) have discovered that unblinded studies require objective controls! The purveyors of flawed psychological studies should just be reminded that none of the (600?) people in the PACE study recovered to live a normal life --- indicates that some psychological coaching doesn't seem to get people back to a normal life.

Perhaps GWAS won't initially turn up definitive leads but rather require refinement ---- additional studies, refinement to remove incorrect diagnosis (Nath NIH study?), whole genome sequences ---


*just Googled - haven't read reference -https://www.nia.nih.gov/news/large-study-links-gum-disease-dementia

 

Inflammation is a downstream effect. It does not appear unprovoked; something generates the inflammation. It's not the "cause."

With respect, you seem to be assuming something here that perhaps you should not. Afterall, this may have no chance at all. Perhaps the best chance is an all out effort to test tissue samples for as many pathogenic agents as you can shake a stick at with the most sensitive and least political diagnostics. Perhaps not. I'd just not put all my eggs in one basket.

Refinement? I sense more assumptions embedded somehow in this word. As for the NIH, I've personally come to not place much hope in them or their sister institution, but I do have hopes they will help fund research that will implicate cause(s).

 

Where to start - maybe assume that I'm extremely reluctant to change my preconceived ideas and I should acknowledge that maybe others do!

I've seen a presentation where the GWAS results didn't show much of a pattern initially; however, more data produced a clearer picture --- and that was hypertension, which seems to be a lot clearer diagnosis than ME/CFS.

If they ever get around to doing a GWAS study on people with MS (developed as a result of EBV infection) then I'd expect to see immune related genes turning up. So GWAS may lead to a focus on pathogens--- it's not either or.

Much of what has been tuned up by hypothesis testing seems to be downstream effects/consequence ---- we need to understand cause rather than consequence.

I'm all for the great and the good but I'd like to see them having leads ---- GWAS is one way to do that.

I wouldn't knock Nath (NIH) until we see what they have found ---- As for the failures of Government's --- well, we seem to have had to wait a while in the UK for progress --- NICE (much better recently), PACE --- Savid Javid seems to have forced some of the the great and the good to stop talking as much crap!

 

Explain this to me, please.

Then, if you would, explain it to me where it doesn't potentially end in a dystopian fashion for people it identifies with genes that renders them susceptible to many diseases, more than most people who presumably don't have that gene iteration/mutation.

Nods. It is one way.

I remember the controls when they set this ME/CFS thing up. I recall, too, the second lead investigator here, so to speak.

I also know what they've done in Lyme (speaking of ME/CFS study control groups), another hotly contested disease with a marginalized patient community. I realize one shouldn't extrapolate like that, but that realization does not resolve my concerns.

 

The risk related immune genes are already known for MS. You more or less have to have a particular MHC type to get MS. I forget which but it points towards a particular way of handling antigens. It may not have taken things that much further forward though since we already knew that MS was related to oligoclonic antibody production in CSF.

if a particular EBV antigen can be shown to behave oddly in the context of the immunogenetics then the story does get pretty clear though.

 

See Jonathan's reply - I should have known that --- but I think it may illustrate that a GWAS study might provide leads in ME/CFS.

The current position is pretty dystopian; OK it may turn out to be something with no off the shelf (repurposed) remedy. However, it may start a path to a remedy and perhaps progress in other diseases will assist (how to downregulate genes or whatever). I think everyone here will agree that, for many people with ME/CFS/their families, we don't have normal lives/the prospect of returning to normal functioning - that's the goal.

 

I am confused. Aren't oligoclonic bands just signs of brain or CNS inflammation, and though unusual, they're not specific to MS anymore than CD-57 is specific to Lyme? In fact, you can sometimes see those bands in spirochetal diseases that can impact the brain such as syphilis and Borrelia. Other diseases, too, like lupus. So how do such bands tie back to immune genes?

I apologize if this is bio-101 stuff...

Big if. But ok. But the GWAS endeavor isn't capturing that kind of data for ME/CFS patients, is it? It cannot since those connections have yet to be established. This is really just an effort to see if there is a unifying umbrella set of genetic abnormalities that are more or less unique to the ME/CFS patient community - ones that might help explain the disease, and yes, possibly explain it in terms of a cause, but also provide a really good, unequivocable diagnostic? Regardless, it's primarily intent on searching for genetic commonalities first?

Which I applaud (with the obvious possible social caveats) . I just wouldn't assume it will find anything. In fact, I think it safer to assume we will not. That way we keep exploring other possibililties.

 

No, most brain inflammation will produce a diffuse polyclonal rise in IgG.
Yes, oligoclonal bands occur in other diseases with antigen specific responses but that is the point - they are a sign of an antigen specific response. Finding a genetic link to MHC in MS was therefore not very surprising although it might tell us something very interesting if we could be sure what peptides T cells are recognising on EBV.

No, it is looking for a genetic link that might suggest what general category of process to look for and maybe point to a specific fault. A link to a micro tubular construction protein would catapult us into having a very specific clue for instance.

There have already been several studies in ME of the sort done in MS that picked up the MHC response genes and the final analysis is negative. With only a relatively small number of genes to trawl getting reliable data is much easier on smaller numbers. So a specific response to a specific antigen is much less likely.

The GWAS study is highly unlikely to provide a basis for a diagnostic marker in itself.

But if it finds nothing that will be hugely useful because it will exclude to all intents and purposes a simple Mendelian basis for the known familial clustering of ME. Negatives are hugely important in this game. It was negatives as much as anything that got me answers in RA.

If the GWAs comes out negative primary metabolic problems become even less plausible. Links to genetic hypermobile or mast cell activation states will be even less plausible.
And so on.

 

Does anyone know if DecodeME is collecting data from participants on family members with ME? Seems like it would be useful to rule in/out genetic factors in the subgroup of people with ME who also have family members with ME, just in case we're dealing with more than one illness. I guess if a rare variant would turn up in that subgroup, it would also turn up in the full group, but it would be a weaker signal and possibly not significant for more common variants.

 

Aren't the findings in MS weak risk marker associations (weak sensitivity/specificity as a biomarker), similar to what has been found in several ME studies?

https://www.sciencedirect.com/science/article/pii/S0889159121005092
https://www.nature.com/articles/s41598-020-62157-x
https://pubmed.ncbi.nlm.nih.gov/16049290/
etc

 

My understanding was that the genetic risk in MS was largely known and located on MHC and explained the 1 in 4 concordance in monozygotic twins (as compared to a roughly 1/750 concordance for randomly selected controls). I think the first association was with traditional DR2 nomenclature but that has changed I think. A Frontiers in Immunology article says:

The risk of developing MS increases from typically 1 in 1,000 in the normal population to 1 in 4 or so for identical twins where one twin is affected. Much of this heritability is now explained and is due almost entirely to genes affecting the immune response. The largest and first identified genetic risk factor is an allele from the MHC class II HLA-DRB1 gene, HLA-DRB1*15:01, which increases risk about threefold. The HLA-DRB1 gene is expressed in antigen-presenting cells, and its protein functions in presenting particular types of antigen to CD4 T cells.

I do not know the details but a recent review I remember suggested that without a haplotype that involved a certain MHC profile, plus maybe some other genes the risk of MS was essentially zero - i.e. the haplotype had near 100% sensitivity. It was still of little use as a diagnostic marker though.

 

No, we aren't, at least in the primary cohort selection questionnaire. We are still determining what optional secondary questionnaires we will invite people to complete, and our cohort is intended to be recontactable (or at least those of our cohort who opt in to that possibility).

@Simon M did run a consultation about additional questions, *Ends Mon 7 Feb* DecodeME - which research questions should we address in our 2nd questionnaire?, where "a family history of ME" was suggested as a potential question to ask about.

 

The actual magnitude of heritability versus environmental factors is disputed and still debated.

Example:
https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1468-1331.2008.02262.x
https://journals.sagepub.com/doi/abs/10.1177/1352458509104592
https://www.nature.com/articles/s41586-022-04419-4 (Notes that about 20% of the risk for a monozygotic twin is familial but only about 20% of that risk (in turn) can be reduced to known genetics)

Twin studies of Chronic Fatigue (yes I know, criteria matters...) also produce notable heritability numbers (and also suffer from the same potential methodological problems).

https://www.cambridge.org/core/jour...-twin-sample/0CF89D2D93C13569FDBBFF744C9DBCD4

Though we are talking about tetrachoric correlations of 0.4 compared to 0.7 for MS.

 

Darn, too bad about the timing. I think this is slightly different (or narrower) question, i.e. do you have any blood relatives who have or have had ME? Glad to hear there is a potential for follow up at least.

I've often thought that there could be a lot of potential in looking at families that have multiple members with ME (partly because in my own family there are 3 out of 4 in one generation and 3 out of 6 in another). It does seem like one could potentially get some clues by looking at a group of such families, since they are very likely to have high genetic susceptibility and are highly unlikely to have misdiagnosed patients. You would think that if there were any environmental or infectious factors, they'd be likely to show up in unrelated family members (which I don't think is common in ME). I suppose some kind of childhood exposure could be possible as well, but genetics seems much more likely.

 

The GWAS is limited to common genes. By omitting the less common it cannot be said to be definitive.

 

Is that true? I am not up on the technology but I thought it worked on the basis of markers all along the genome that may not include every gene but are likely to pick up haplotypes with weighted genes through linkage disequilibrium.


I am not sure there is such a thing as a 'common gene' is there?

 

I am not overly familiar with the large scale DNA database collection for ME overseas.

I think known, but yet undiagnosed genetic disorders, may be able to be identified and this would be useful for some patients.

Are they planning to do precision work on people in the DecodeME sample?

Eg. Based on severity or co-morbid groupings?