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

All good points. A single, non-replicated, GWAS finding is not sufficient - I agree. This is why my personal point of view is that a well-powered GWAS (with subsequent replications) is the first thing that is needed. Only then will causal hypotheses be generated, allowing findings to be "battle hardened" afterwards. The time-scale is long: probably 3-4 years. The cost is substantial: probably £3m. But in my view (and those of others) this is the quickest approach for generating causal hypotheses that can then be followed up.
With respect to this single observation from the Neale GWAS, I am more convinced than you are because the same DNA variants that predict ME/CFS risk are also associated with altered level of the ornithine transporter gene. On this, I am really pleased that two researchers - one already working in ME/CFS, one not - have been in touch. One indicates that there is much unpublished data that *might* be consistent with the ornithine transporter hypothesis. The other works on mitochondria and we will discuss soon.
I wish that all of this could have been done previously, by last Christmas, and the ones before that. I do not know how to go faster.
 
Jonathan Edwards said:
But to my mind the crucial step is confirming that there is a hard hit with one gene interval.
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Would it be possible to do a replication study on this gene interval using the samples in the UK ME/CFS biobank?

Chris Ponting said:
All good points. A single, non-replicated, GWAS finding is not sufficient - I agree. This is why my personal point of view is that a well-powered GWAS (with subsequent replications) is the first thing that is needed.
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Could they be done concurrently? Surely it's worth seeing if the single region found replicates as well as doing a GWAS.

Welcome to the forum, @Chris Ponting, and thank you for the work you are putting into trying to move this research forward.
 
Chris Ponting said:
All good points. A single, non-replicated, GWAS finding is not sufficient - I agree. This is why my personal point of view is that a well-powered GWAS (with subsequent replications) is the first thing that is needed. Only then will causal hypotheses be generated, allowing findings to be "battle hardened" afterwards. The time-scale is long: probably 3-4 years. The cost is substantial: probably £3m. But in my view (and those of others) this is the quickest approach for generating causal hypotheses that can then be followed up.
With respect to this single observation from the Neale GWAS, I am more convinced than you are because the same DNA variants that predict ME/CFS risk are also associated with altered level of the ornithine transporter gene. On this, I am really pleased that two researchers - one already working in ME/CFS, one not - have been in touch. One indicates that there is much unpublished data that *might* be consistent with the ornithine transporter hypothesis. The other works on mitochondria and we will discuss soon.
I wish that all of this could have been done previously, by last Christmas, and the ones before that. I do not know how to go faster.
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£3M - how I wish MRC was funding this kind of research instead of nonsense of PACE for £5M. It really was a crime they wasted all that money. I could weep forever. And thank you, Chris, for all you are doing.
 
Amw66 said:
I am speaking from a non science viewpoint, so apologize in advance if this is stupid, but would it not be better to run multiple gene association studies ( is it even possible to do this)? If things were down to a single gene, would tbat not have been found before now?
A sysyems condition would suggest a systems approach?.


Given the common expression of various genes, would it not be the combination of genes related to particular regulation/ feedback loops that may offer insights.

The very limited foray we did to try and look at tweaking nutrition highlighted gene combinations which if expressed would have significant issues for inflammation, detoxification and glucose and fat mechanisms. Many of these genes have different functions, so whereas nutritionally some genes are interesting for fat regulation, some are involved in calcium signalling too ( eg ADRB2Arg16Gly (rs1042713))does this happen concurrently, or does the primary fat unlocking function get to a critical level and then calcium signalling takes over?

If you were to downregulate what combinations would constitute the perfect storms and what are the rate limiting steps.

I am probably telling my granny how to suck eggs, and shiwing my woefull lack of biochemistry education . But i do wonder ( a lot)
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Thinking of knock on effects and expressions ( and apologies in advance for lack if acience background)
Both my aunt and daughter have genetic variants of genes regulating eNOS and glutathione. Being female, I' m guessing estrogen has an impact on modulation ?
Would these be knock on effects of the ornithine ?
I really need to seriously get into biochemistry - unfortunately going back to part time uni course may kick this into touch for a while.
 
Chris Ponting said:
Thank you for your generous comments and offer. Most science grants are for hundreds of thousands, if not millions, of pounds. For this, the nation's taxes need to be invested, in my opinion, via the MRC and the NIHR, to this cause. The CMRC is asking this question of the MRC/NIHR. It's taking longer than we expected. Still work to do.
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In the past the patient's community was able to crowdfund for OMF (Davis research), Lipkins research several millions. Maybe it's worth to try it also for your research. Also if you can show to MRC/NIHR a certain amount of money from patients maybe they will be more forced/motivated to give the rest
 
Andy said:
Random thought I had, several charities raised significant funds in anticipation of funding Rituximab studies I believe (MEA, IIME), does anybody know if they have been allocated to anything else?
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I may be wrong but I thought that the MEA didn't so much raise money specifically for a rtx study but ringfenced £60k of their existing funds if a study went ahead. I assume that money has been reabsorbed into the Ramsay Research Fund. IiME, of course, set up a separate fund and raised money for it. I think they ended up with over £400k. I thought they'd been spending it on B cell research at UCL with Jo Cambridge's team.

@Russell Fleming, @Jonathan Edwards - is that accurate?
 
Chris Ponting said:
Thank you for your generous comments and offer.
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Profound vested self-interest on my part!

Most science grants are for hundreds of thousands, if not millions, of pounds. For this, the nation's taxes need to be invested, in my opinion, via the MRC and the NIHR, to this cause. The CMRC is asking this question of the MRC/NIHR. It's taking longer than we expected. Still work to do.
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I think we all agree that governments need to invest but our experience as patients - many of us over decades - is that governments don't invest in this. I hope that things are approaching a turning point but if the CMRC's application fails, I hope you'll consider tapping the ME charities for grants and initiating a project-specific crowdfund.
 
SLC1A2 gets a mention at Stanford symposium
SLC13A3 (a target of PITX2) is one I’m looking into linked to Axenfeld Rieger syndrome (hyperammonia mentioned) https://www.genecards.org/cgi-bin/carddisp.pl?gene=SLC13A3
Another patient reported SLC16A1
Another two reported SLC1A1(OCD/Autism/schizophrenia/glutamate)
SLC25A15 mentions high ammonia
Would that lead to high glutamine and high NMDA tired and wired presentation
SLC25A33 pituitary FOXO1
SLC1A1 https://www.omim.org/entry/133550
 
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