Significant association of DNA variants with self-reported ME/CFS (Chris Ponting blog)

Does this male/female split also occur in other diseases? (As well as different underlying causes producing the same pattern of symptoms?)

 

This is what I've thought, too, although it's not just Crawley who says this. Though she's certainly the first person I saw who says this.

 

It can actually be difficult to get a paediatrics appointment within 3 months from onset- GPs tend to suggest PVFS first and refer on afterwards if nothing is improving.
It is paediatricians who generally diagnose, not GPs

 

I think that the approach of diagnosing PVFS early, and then ME later, is the right one and strikes the balance between immediate care and waiting to see how the illness develops. This is what Charles Shepherd advocates, for instance.

But what that means is that the way you 'treat' PVFS shouldn't be contradictory if the illness later turns out to be ME. I.e., no GET/CBT.

 

At the risk of putting the cat amongst the pigeons, is this tentative finding a good case for resurrecting MEGA or an MEGA-like programme? I know MEGA has been controversial (I think I'm one of the few who was tentatively for it) but a large-scale patient repository to allow better-powered GWAS would seem to be a positive thing.

Side semi-related question: my other half took part in the 100,000 Genomes Project due to her rare(ish) type of epilepsy* - is/was there any kind of attempt to have ME/CFS included as a covered condition in this project or were they focussed on rarer diseases only?



*also misdiagnosed and treated, unsurprisingly to a total lack of effect, by CBT for a couple of years

 

With the likes of Crawley off of the scene and Chris Ponting more directly involved with the CMRC then I would have thought there would be far less opposition to the general concept. The challenge, as always, would be to collect enough well-defined samples.

The list of conditions can be found here, https://www.genomicsengland.co.uk/?wpdmdl=5207 (PDF document) - ME isn't one of them.

They do say though

https://www.genomicsengland.co.uk/taking-part/intro/

 

Thanks for that! As I was typing it I was thinking 'was it OMEGA?' but was too bone-idle (can't blame my fatigue this time) to check... now fixed.

 

Cheers. I think this would be the sticking point:

 

I think for me I’m a bit more optimistic. What I find interesting is that mitochondrial dysfunction and the urea cycle seems to keep cropping up from various angles. Genetic predisposition is interesting but not really the issue here as you point out.

The genetic testing would be good to screen a more precise sample of test subjects that would benefit from any treatment (which I presume would be based on “known science”) so not necessarily as far off as all that. I’m thinking 5-10 years rather than decades?

I may be wrong but I feel more optimistic about this than anything else I’ve seen since rituximab

 

I don’t know if this, from the blog, is relevant:
"Another of the Neale results is that women that have G at this position tend to have very slightly lower lymphocyte count (rs7337312; p = 4.6×10-7; other variants in LD have p < 5×10-8)."

they recruited people aged 40 to 69 to increase the chances of getting informative outcomes (such as developing a disease or having a heart attack).

I think it is a relatively unusual variant., But yes, currently there would be no point in getting tested.

my understanding is that one of the major benefits of GWAS is that they highlight particular biochemical processes (for instance) that might always also be affected by non-genetic triggers. So that even in diseases with a relatively low genetic component, the studies can still be very revealing about overall pathology.

see above.

agreed.

hopefully the CMRC will betaking a properly collaborative approach and bringing in the likes of the ME/CFS bio bank for such work. Louis Nacul was an observer at the last CMRC meeting, though the biobank has not yet joined the organisation.

 

This seems pessimistic to me. Repeating the result does not require GWAS, just a repeat analysis of this gene in another cohort. A tiny cohort should do if this gene variant is relevant to a substantial number of PWME.

When we got a piece of information of this sort in RA the whole story unravelled within months without doing any further experimental work. Thinking in a new direction can make you realise that lots of relevant data are already published. We already have quite a lot of data on mitochondria in lymphocyte subsets from Fane Mensah and Jo cambridge, for instance. An immediate question would be how many of the cases they have studied have this variant.

And if a plausible story emerges, backed up by some simple data, like all the B cells with small mitochondrial mass turn out to be in PWME with the gene variant, thenSimon Wessely has to eat his hat at last.

Leading to treatment might well take longer, but of course in the RA case I discovered that exactly the right drug was being licensed for another disease by Christmas.

We will have to see if this is replicable and maybe it isn't, but if it is I think things may change fast. Finding genetic risk is 100 times more powerful than most other evidence for causal pathways.

 

How quickly can a replication be attempted? Is there anything we can do to speed that up?

 

I just thought I would post this on the urea cycle for dummies (my level) and metabolic disorders therein ...seems ok and a bit of background

We can start a separate thread on this if appropriate?

http://adultmetabolicdiseasesclinic...-cycle-disorder-2013-with-changes-tracked.pdf

 

Network analysis generated in May 2017 suggests Urea Cycle involvement in ME/CFS :




http://algogenomics.blogspot.com/2017/05/machine-learning-nlp-and-network.html?m=1

 

dbSNP has the frequency for the minor allele at around 43%, so it is a common variant.

That doesn’t make it irrelevant though. In Celiac disease for example, 98% of people with the disease have the predisposing variants. Around 55% of the general population without Celiac Disease carry these variants too.