SequenceME genetic study - from Oxford Nanopore Technologies, the University of Edinburgh and Action for ME

[Jonathan Edwards]

How confident we are that ME/CFS has a strictly infectious origin ?

We aren't. Moreover the crucial importance of genetics in diseases of infectious origin is known by every medical student. Reiter's syndrome is the paradigm - very strongly predisposed to by HLA-B27. Then there is mannose binding protein deficiency and staph problems, HLA-DQ and post-influenza narcolepsy, lysosomal gene defects and chronic granulomatous disease and no doubt rheumatic fever and post-streptococal glomerulonephritis have genetic predispositions...

 

[V.R.T.]

HLA-DQ and post-influenza narcolepsy,

This would perhaps be an interesting connection to some of the things we've discussed recently but I assume the HLA DQ link didn't stand up in the separate analysis from what Chris apparently said at the Berlin conference.

 

[Jonathan Edwards]

I assume the HLA DQ link didn't stand up in the separate analysis from what Chris apparently said at the Berlin conference.

The HLA-DQ link was very weak compared to narcolepsy anyway. I was a bit surprised that Chris said that nothing came up on HLA at all. I thought that even with correction there was a weak DQ signal, but DQ is notorious for being misleading at this sort of level so that story probably doesn't not take us anywhere, sadly.

 

[Andy]

Can meaningful analysis be done on 6,000 samples? If for some stupid reason we can’t get the additional 3,000 funded

Yes, absolutely, and is why our hope is for analysis of those samples to be the next step forward.

In terms of costs for future phases, I'm afraid we don't currently have figures that we would want to release for each individual phase. I understand the interest though, and will see if we can come up with our best estimate for each phase.

 

[Andy]

Do you know if the MEA has been approached to ask if it would be willing to contribute to Sequence?

All I will say is that we are exploring many potential funding sources.

Is there any particular or new criteria for which samples will be used?

If you mean the ME/CFS samples, then they are samples from DecodeME, which used CCC and/or IOM selection criteria. If you mean the LC samples, then the inclusion criteria is yet to be decided. Pasting in an earlier answer I gave to the question of the LC selection critieria,

The definition is yet to be decided upon and forms part of the work already funded by previous supporters. I can't guarantee at this stage what the definition will be but we are well aware that it will need to be better than anything as vague as "3 months of any symptom at all after a Covid infection". Given that eventually we will be comparing them with DecodeME particpants I personally would like to see all LC participants evaluated with the DecodeME questionnaire for likely ME/CFS status.

 

[PeterW]

But I cannot suppress my contrarian streak: There is part of me that is skeptical of genetics being especially important in infectious-origin diseases.

It's a bit like trying to understand the plot of Midsomer Murders by looking at the blueprint of the Samsung TV.

Tonsillitis is infectious in origin, but recurrent tonsillitis has a significant genetic predisposition: link to paper here

 

[Robert 1973]

But I cannot suppress my contrarian streak: There is part of me that is skeptical of genetics being especially important in infectious-origin diseases.

Tonsillitis is infectious in origin, but recurrent tonsillitis has a significant genetic predisposition: link to paper here

Also, in a DecodeME webinar Chris Ponting explained how GWAS was used to develop effective treatments for acute COVID-19 (@41m):



More here: https://www.nature.com/articles/s41586-020-03065-y

I cant believe there is a disease – particularly one about which so little is known – for which a well-designed genetics studies would not reveal something useful about the causes and mechanisms, which would lead to novel targets for pharmaceutical interventions.

 

[ScoutB]

Do we have a thread on this? I can’t seem to find anything.

Looks like we have a thread for it, but no comments yet:
The Role of Prevention in Reducing the Economic Impact of ME/CFS in Europe

It cites some other papers that sound interesting (including on organophosphates) so might be worth a closer look.

 

[Murph]

Also, in a DecodeME webinar Chris Ponting explained how GWAS was used to develop effective treatments for acute COVID-19 (@41m):



More here: https://www.nature.com/articles/s41586-020-03065-y

I cant believe there is a disease – particularly one about which so little is known – for which a well-designed genetics studies would not reveal something useful about the causes and mechanisms, which would lead to novel targets for pharmaceutical interventions.

My philosophy is that doing the genetic work is vital. we must do it. I vote for funding it, and then funding it more to get it done even sooner. But that is not the same as believing it will fix everything. Or even lead anywhere.

I try to always remember the uncertainty.

This is how a contrarian streak develops, I guess. When I see everyone get a head of steam and rush off in the direction of being sure of something, whether they're sure it's nothing or sure it's something, I like to hedge my bets.

There's a basis for skepticism. Plenty of GWAS studies have been done in diseases that are not, apparently, materially closer to a cure than they were.

Genome-wide association studies (GWASs) have identified thousands of variants associated with neuropsychiatric disorders (NPDs), including autism spectrum disorder (ASD), schizophrenia (SCZ), and Alzheimer's disease (AD). However, deciphering the "causal" biological mechanisms and pathways through which these variants act remains a major obstacle that hinders translational understanding of NPD pathogenesis.

If a GWAS comes up with a few dozen SNP in neural, vascualr and immune systems, and says, well, me/cfs seems to have neural vascular and immune components, idk how far we get from that.

The individual SNPs don't look decisive. In DecodeME there are findings with statistical significance, but they don't separate the groups.

It shows that the effect size comes down to a 1-2% difference in prevalence of SNPs between ME/CFS patients and controls.

Which is why I'm pleased this is whole genome sequencing. Perhaps copy number variations or some other kind of issue will be revelatory.

I do feel like DNA is so complex, so new, that people are like, There! in all that! the answer must be in there! But just because a tunnel is deep and dark doesn't mean it's where the treasure is. I hope it is. But it's not guaranteed.

To conclude, just because I express the contrarian position doesn't mean i'm not also hopeful. I am actually the most optimistic person on this forum,usually. It just means in this case I think the gloomy position deserves more air time!

 

[Sean]

It would be a very rare medical condition that did not have a significant genetic influence somewhere in the process.

And by very rare I mean none.

Which doesn't mean that genes have a dominant or equal role in all conditions, just that genes play some part, at some stage.

My view is that basically all diseases should be sequenced. It is now easy and relatively cheap to do (and getting cheaper), it only has to be done once, and will be one of the richest sources of information for medical research we could get.

 

[Jonathan Edwards]

To conclude, just because I express the contrarian position doesn't mean i'm not also hopeful.

I think there is no harm in airing these doubts. However, I can assure you that each and everyone of your arguments is completely wrong for specific reasons that I could enumerate but don't want to be a bore about because we have covered them before. It is nothing to do with saying 'the answer must be in there'. There are very specific reasons why GWAS was an inspired direction to take for ME/CFS despite reservations about psychiatric disease or diabetes. The problem we faced was very specific and the hits obtained are precisely what were needed.

I also think we get a very long way by picking out a few pointers to neurons, immune cells and maybe vessels (that didn't come up I think) or maybe pointers that say 'hey guys this is maybe in the same ballpark as narcolepsy or Reiter's or whatever. At some point the penny has to drop with the medical world that this is a real disease of a particular sort. When that happens I see the lives of people with ME/CFS being transformed even if specific treatments are still to be found. And huge research teams will clamour to be part of the race to find solutions. I think that is already beginning, in a small way.

You don't have to know the detail of mechanism for sure to turn therapeutics on its head. With RA we had very little direct evidence of the process but the genetics and various other bits of circumstantial evidence allowed us to completely rethink which box the disease was in. Once that was done it just turned out to be a matter of reaching up to the pharmacy shelf.