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

Sasha said:
I'm wondering if promoting her study more widely might be helpful in getting a faster replication attempt of this finding.

What do you think, @Jonathan Edwards?
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I don't think sending off individual samples is much use if the gene variant is present at around 40% in normals. What is needed are formal, if small, stuies of well documented ME cohorts and matched controls. I am not sure that cohorts derived from internet based enquiries are going to be helpful.

I do not understand the technical details here but if we want to know if a single gene variant association holds up then I assume that replicating that is largely a matter of filling in forms, transporting samples and scheduling experiment time. I presume DNA extracted in the usual way can be probed with a specific probe for the gene probably using a box where you just press a button. The sample size needed is going to depend on the strength of association found.
 
Jonathan Edwards said:
I don't think sending off individual samples is much use if the gene variant is present at around 40% in normals. What is needed are formal, if small, stuies of well documented ME cohorts and matched controls. I am not sure that cohorts derived from internet based enquiries are going to be helpful.

I do not understand the technical details here but if we want to know if a single gene variant association holds up then I assume that replicating that is largely a matter of filling in forms, transporting samples and scheduling experiment time. I presume DNA extracted in the usual way can be probed with a specific probe for the gene probably using a box where you just press a button. The sample size needed is going to depend on the strength of association found.
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Can you think of any way we can help this to happen?
 
Q1) For us non-sciencey types, does this information about potential issues with the urea cycle relate in any way to Karl Morten's finding of higher levels of phenylalanine in ME patients ( https://www.s4me.info/threads/a-new...an-micro-spectroscopy-2018-morten-et-al.5445/ ) or not really?

Q2) Do any of you guys who have 23andMe results have results for this SNP? I just looked up rs7337312 in my file but it says "not genotyped". Not sure if that means the chip I had the testing done on didn't test for that SNP or whether they never test for this SNP.
 
Very intriguing. No one in my family have any autoimmune or other diseases that tend to pop up in the families of PwME, however my maternal grandmother (direct female line) have developed urea cycle-related issues in her later years.

No idea if that is even relevant, but it’s the first bit of research that connects to anything in my genetic makeup. Otherwise my extended family members are all so annoyingly healthy.
 
JamBob said:
Q2) Do any of you guys who have 23andMe results have results for this SNP? I just looked up rs7337312 in my file but it says "not genotyped". Not sure if that means the chip I had the testing done on didn't test for that SNP or whether they never test for this SNP.
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I did the same for me and my son and got the same result, 'not genotyped'.

So, if this gene is having an effect, (or if other non-genetic causes are driving our bodies to the same result) would we possibly expect to see higher levels of ammonia in our blood (all the time or perhaps just when the body is stressed e.g. by exertion)? Is this a common test? I haven't had it done.

Simon M said:
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)."
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For what it's worth, my son's and my lymphocyte levels are low normal compared to the lab ranges.
 
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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)
 
That makes sense to me Amw66. If we think a particular cycle is broken, then there may be some non-genetic ways to break it. But there might also be more than one gene that, if not perfect, can make the cycle perform less well.

So, if we do a study on all the genes affecting say the Krebs cycle, maybe people with ME have less good genes and more poor genes impacting on it than healthy people. It might be the sum effect, rather than something we can pin on a single gene. That's getting pretty complicated though, especially by the time you throw in the, possibly considerable, noise of environmental factors and the possibility that we don't know all of the genes that might be affecting one system.

Focusing on finding the functional thing that is wrong (e.g. by working on the metabolites, on the chemistry) might be a quicker way to zero in on the problem to start with. I mean, I would have thought identifying the exact functional problem in order to identify the cause(s) would be easier than the other way around, given we don't seem to have a disease with one clear faulty gene.

But I'm happy with anyone poking around in any of that stuff, who knows what will work.
 
Jonathan Edwards said:
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.
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Thanks all, @Jonathan Edwards, for your comments. Yes, only a small and well-defined ME/CFS cohort (with a well-matched control cohort) would be required to replicate this observation. But this isn’t what is needed IMO: we need *many* such genes/genomic intervals. If, for example, we had 4 intervals, all potentially significant, and 3 of them contained genes encoding for mitochondrial transporters then we, scientists, could all go home and confidently say that we know what’s wrong. So we need a well-powered GWAS not *just* for replication but also to find more genes/intervals. In addition, from the experience of diabetes GWAS which have found lots of genes/intervals, some of these are relevant to some clinical outcomes, but others are relevant to other, different clinical outcomes. (There likely will be multiple causes to ME/CFS.)
 
Welcome to the forum, @Chris Ponting! Thanks so much for all the hard work you're doing for us patients.

Is there any we can do to help move your work forward? Should we be trying to fundraise for you? Can patients and supporters donate to your lab? Would it be of any use to have 23andme etc. data from those patients who have it, combined with some sort of screening process?
 
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.
 
Chris Ponting said:
Thanks all, @Jonathan Edwards, for your comments. Yes, only a small and well-defined ME/CFS cohort (with a well-matched control cohort) would be required to replicate this observation. But this isn’t what is needed IMO: we need *many* such genes/genomic intervals. If, for example, we had 4 intervals, all potentially significant, and 3 of them contained genes encoding for mitochondrial transporters then we, scientists, could all go home and confidently say that we know what’s wrong. So we need a well-powered GWAS not *just* for replication but also to find more genes/intervals. In addition, from the experience of diabetes GWAS which have found lots of genes/intervals, some of these are relevant to some clinical outcomes, but others are relevant to other, different clinical outcomes. (There likely will be multiple causes to ME/CFS.)
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Thanks @Chris Ponting. But let me argue, because that is how I have always done my science. I find it saves a huge amount of wasted effort in the lab.

The patients want a result by Christmas.

I agree that further GWAS should be planned. But to my mind the crucial step is confirming that there is a hard hit with one gene interval. So far the evidence for a genetic component in ME is suggestive but there are confounding issues and we want it to be hard. The study of rheumatoid disease became a science when Stastny showed unequivocally, and others rapidly confirmed, a link to HLA-DR4. Chairs of rheumatology followed by the dozen.

I have not had time to look at this in detail but it looks as if there is quite a big DNA segment with linkage disequilibrium, which, fortunately, in rheumatic disease was not as much of a problem as we feared. So the mitochondrial protein gene might well be the wrong one? I can see that if that is the case then finding other mitochondrial genes would firm things up. However, in rheumatic disease things have not really panned out like that. For each disease a very heterogeneous list of genes have turned up. They give us a story but not an immediately obvious one.

For twenty five years after Stastny's identification of the link between rheumatoid and HLA-DR4 most of my colleagues drew the illogical conclusion that DR4 indicated a T cell problem because DR4 presents antigen to T cells and everyone wanted grants on T cells. It was not until some clues turned up in stromal cells that it became obvious that the DR4 indicated B cells. People had forgotten that MHC Class II was initially identified as a cell marker thought to be specific for B cells - which do the antigen presenting.

The next finding was PTPN22. That made people think even more of T cells because it is involved in T cell activation. But later it turned out to be critically involved in B cell receptor editing - and RA is basically a problem of B cell receptor editing.

And of course the other gene segment that gives risk for RA is the X chromosome. That leads to all sorts of spurious conclusions but B cell autoimmune diseases are mostly female predominant and T cell immune disorders are not.

What we have not found by and large in rheumatic disease is several genes encoding closely related functions turning up in the same disease. In ankylosing spondylitis there is HLA-B27 and a cytokine receptor. That fits for T cell activation maybe through antigen-independent recognition systems but it is still not clear.

A mitochondrial gene is not for me a particularly expected hit. It would do, but I do not buy the simple idea that mitochondria ought to be involved because energy seems to be low. So the fact that this candidate is in mitochondria might be spurious.

And so on.

Basically I agree that much more effort is worth putting into systematic genetics. But working out how to fit the pieces together is unlikely to be a systematic thing. Something will suddenly make sense and then lead to prediction that will slot into place hand in glove. So one gene may be enough to get the ball rolling.

And they are in a hurry.
 
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