Uncovering the genetic architecture of ME/CFS: a precision approach reveals impact of rare monogenic variation, 2025, Birch, Younger et al

Jonathan Edwards said:
I am not sure that anyone is disputing the logic here.
My thought is that if a rare gene variant has very strong evidence for pathogenicity - as in a multicase family with a Mendelian disease expression - or points very strongly to a very specific testable model, then it may take us a step forward on its own. The difficulty with ME/CFS of course is that we do not have pathology to slot a model in to, so we need to find evidence of a pathological pathway too. Otherwise rare genes of the sort picked out here are going to be candidates for reasonably large statistical replication studies as you say, with the plus of a smaller correction for multiple analyses.
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I think you mentioned before that it would be really interesting to look at the DNA of a family with three children under 13 with ME/CFS and here is one such poor family.
 
Jonathan Edwards said:
That is up to Chris to decide. He is well aware of the options I think. Paying for one family set of WGS might not be that hard but someone has to plan how the data are to be analysed in the most efficient way.
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If there's a possibility that Chris, or anyone else, is interested in doing this, would it be useful for the forum to try to identify such families from among its members and from public information, so that there's a bunch of known cases whom the researchers could approach?

I wouldn't feel comfortable doing that on a public or even a members-only thread because it would seem wrong to set up a public expectation that named individuals should take part in a particular piece of research. But a working party could be set up to tackle this on a private thread or convo.
 
This subject, of whole genome sequencing individual families, occured in the most recent PRIME meeting. The impression that I got was that this was not considered a priority activity for anybody involved in PRIME, which obviously includes Chris.
 
Andy said:
This subject, of whole genome sequencing individual families, occured in the most recent PRIME meeting. The impression that I got was that this was not considered a priority activity for anybody involved in PRIME, which obviously includes Chris.
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Thanks, Andy, I haven't watched the whole thing. Did someone actually say that? What was the rationale?
 
Sasha said:
If there's a possibility that Chris, or anyone else, is interested in doing this, would it be useful for the forum to try to identify such families from among its members and from public information, so that there's a bunch of known cases whom the researchers could approach?
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I'd find that very distasteful, to be honest—maybe even exploitative. People would need to volunteer themselves, assuming they want to do it. (Some may not, as it can be difficult to enable young children to give properly informed consent to genetic sequencing.) It would require a properly set up family study, and our role would be in publicising it.
 
Sasha said:
Thanks, Andy, I haven't watched the whole thing. Did someone actually say that? What was the rationale?
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It was in our weekly PRIME meeting, not the recent webinar. And yes, I have accurately reported my impression of the conversation, you can get in touch with Chris himself if you would like to ask him the question directly.
 
Kitty said:
I'd find that very distasteful, to be honest—maybe even exploitative. People would need to volunteer themselves, assuming they want to do it. (Some may not, as it can be difficult to enable young children to give properly informed consent to genetic sequencing.) It would require a properly set up family study, and our role would be in publicising it.
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Thanks, Kitty, that's a fair point - I hadn't thought it through properly from all angles. Let's bin that idea!
 
Jonathan Edwards said:
I would be interested to know what everyone's thoughts on that might be.
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I think it would be great, provided they wanted to do it for themselves rather than being put under pressure to be lab rats for the whole community.

But maybe the big sequencing project needs to happen first, to reveal where to look? First degree relatives will have vast numbers of genetic commonalities, and that could make it much more difficult than looking at unrelated people.
 
It could be interesting to do a genetic study on families with some parents, siblings and first cousins with ME/CFS and some without.

A confounding factor might be that the healthy ones can only be classified as not yet having ME/CFS, not that they will never get it.

The genome is so huge, we'd need multiple families, not just a few, and there may be many different patterns of genes that can predispose to ME/CFS. DecodeME clearly indicates there's no outright genetic cause, just slight indicators.

Maybe a starting point would be to use the same GWAS as was used for DecodeME as a cheaper starting point to analyse data from, say 100 whole families with more than one pwME and clear known family trees.
 
Kitty said:
I think it would be great, provided they wanted to do it for themselves rather than being put under pressure to be lab rats for the whole community.
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I think running recruitment campaigns on social media and through word of mouth would be fine. «We are looking for families with a least two cases of ME/CFS».

But I was approached about a study for a completely unrelated medical reason and felt no pressure to participate even though there are were few that could have done it due to the rarity of the event they were studying.

If all it takes is a spit sample and a family and medical history, I suspect most would be fine being asked directly by someone like Chris Ponting.
 
Utsikt said:
If all it takes is a spit sample and a family and medical history, I suspect most would be fine being asked directly by someone like Chris Ponting.
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If there are any sets of at least two siblings with ME/CFS in the DecodeME cohort, then they could potentially just request the DNA samples of healthy family of those people, since they already have the ME/CFS DNA.
 
Andy said:
Except that the data has been anonymised, so siblings can be identified as such but not their contact details.
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But the team could request sibling participants to get in touch to give their consent - surely there is some way of figuring out who's sample is who's retrospectively?
 
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