Analysis of data from 500k individuals in UK Biobank shows an inherited component to ME/CFS (Ponting blog)

Guest blog by Professor Chris Ponting and colleagues at ME/CFS Research Review

UK Biobank - a national biobank different from the ME/CFS biobank - has data from around 500,000 individuals, including both healthy people and those with one or more of the many different diseases in the UK population. About 2,000 people in the sample reported that they had been given a diagnosis of CFS.

Analysis of data from this biobank indicates an inherited biological component for ME/CFS. The results show only one statistically significant change in a particular section of DNA and even this is problematic. This analysis indicates that a much bigger study, with many more ME/CFS cases, will be needed to indicate which genes and biological pathways are altered in people with ME/CFS.

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Statistical significance for the association between each DNA position and ME/CFS across 22 chromosomes. The arrow highlights the one “significant hit”.​

Introduction
Myalgic encephalomyelitis (ME, also described as chronic fatigue syndrome, CFS) is a devastating long-term condition affecting 250,000 UK individuals. People with ME experience severe, disabling fatigue associated with post-exertional malaise. A few make good progress and may recover, while most others remain ill for years and may never recover. There is no known cause, or effective treatment for most. Consequently, it is vital to try new approaches to understand the reasons for the development of the condition.

This blog sets out what we can glean from the release, last summer, of data from about 500,000 individuals who make up the UK Biobank. (This biobank is not to be confused with the UK ME/CFS Biobank, UKMEB.) The data were acquired from individuals between 40 and 69 years of age in 2006-2010 who live across the UK. These people provided samples (e.g. blood, urine and saliva) and answered questionnaires. In addition, for some of these people their electronic health record data are being linked in. Importantly for this blog, the DNA variation (‘genotype’) of all the volunteer participants has been determined.

Genetic variation can provide insights into the causes of disease when these have a heritable component (i.e. are inherited down through the generations). DNA sequence is not altered by disease (except in cancer) and so variants can reveal the causes, rather than consequences, of disease.
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Read the full blog

 

Very interesting
It does need a lot more research and confirmation but i do wonder if it is correct.

 

(Dangerously under-informed speculative question alert) The SNP identified seems to relate to a gene involved in collagen production - could this be linked to EDS? Either showing a link between the nature of ME/CFS and EDS or, possibly more likely, people with a form of EDS being misdiagnosed with CFS?

 

That is genius. Peter Rowe from John Hopkins has been dealing with patients with EDS and fatigue.

 

Is there some knowledge about other mutations in other genes coding for collagen, like ELN? And could there be a connection to EDS? (Also, highly speculative.)

The finding is very interesting, and the article is well written (good to understand). But the limitations mentioned aren't "peanuts":

 

This is certainly very interesting.

My first question is whether the genetic risk estimate and the link to the prolyl hydroxylase gene are the same in men and women. They will quite likely either be pretty much exactly the same or obviously different. I think that would tell us something very important.

The biggest worry for me here is confounding factors in patient sampling. A self-report of being given a diagnosis of ME or CFS in a group from 40-69 raises all sorts of potential biases. Not that that is a reason to dismiss the result but simply to be cautious about interpretation. The study might end up telling us something useful about people who do not actually have ME but get in the way of studying it!

The link to hypermobility seems to me tenuous. It looks as if the mutation would only account for causation in one in forty of people with ME/CFS. One person in forty in the normal population is hypermobile enough to get given an 'EDS III' diagnosis. And a mutation in proline hydroxylase does not convert very easily to hypermobility.

 

I'm struggling with understanding the concept of what they found as being something that is inherited.

"ME/CFS has a biological component because the heritability of ME/CFS is not zero. Canela-Xandri et al. estimate that the genetic heritability (liability scale) is 0.080. This is slightly lower than the median heritability of heritable binary traits (0.11; see Figure 1). So among all such things measured, it’s in the lower half of the heritability, but not zero. Note that this doesn’t rule out non-heritable biological causes." seems to be the argument/explanation that supports this but, frankly, I don't get what it's saying. If anybody can dumb it down for me that would be great.

 

Yes, that was my thought too - but this was only a small study with many caveats so it would be dangerous to put too much weight on the one hit.

It's more the other way around - the fact that something was found on what is a very small study in terms of GWAS - suggests a bigger study is likely to pay off.
As the blog says:
"To obtain robust indications of which genes and which biological pathways are altered in which cells or tissues in people living with ME/CFS, then a much larger study is required. A GWAS with ten- or twenty-thousand cases, is likely to be necessary. Results will then need to be replicated in a separate cohort."

A key point is that there doesn't have to be a huge level of hereditability for GWAS studies to be very helpful. Just assume for one moment that the "Dubbo" hypothesis is right and that at least some post-infectious cases could be down to an overly-strong immune response - as well as to the type of infection. The overly-strong response could be down to both genes and the immune history of the patient. So you've got many things interacting here: genes, pathogens, environment/immune history.

A GWAS might find a number of immune genes are involved - each having a very small influence - but the fact that various genes will have a similar effect could point towards the problem.

And to find multiple small effects you need a big study.

 

Does it point to Osteoarthritis or anything else?

 

What was the prevalence of the P4HA1 SNP in the 1829 people who self-identified with ME/CFS?

 

While I'm admitting my ignorance, another question I have.

In terms of a larger GWAS study, the biggest query I have, at the moment, is in regard to the selection criteria. To get the numbers of samples wanted, it looks like it will have to be self-reported CFS diagnosis, which obviously has its many issues. Is the idea that the sheer number of samples gets around those issues?

 

The EDS thought did occur, could this be simpler and be indicative of a catabolic / inflammatory predisposition?

 

This is a repetition of what I’ve just written on the blog (awaiting moderation):

Many thanks for this blog, @Simon M n and @Chris Ponting. Very interesting and informative.

Some questions:

1) I’ve just had a quick look at the UK Biobank website but I couldn’t see how patients were recruited. As many severe ME patients are bedridden without access to medical services, is it likely that people with severe ME are underrepresented in the biobank samples?

2) I don’t understand the second of five reasons to be cautious (b). It’s not conserved across species but there is a nematode with it. Can someone try to explain this to me? [Apologies if I’m being stupid.]

3) Is the estimate that a GWAS with 10-20 thousand cases would be necessary to obtain robust indications based on the assumption that ME/CFS is a single disease? If ME/CFS included x number of different diseases, would it be necessary to include 10-20x cases in order to obtain robust indications?

 

Would this be the same nematode that tends to get itself into a Dauer state?

 

Can you elaborate?

Do some genetic variants occur more often in one gender?

If it turned out that this variant here occurs as often in men as it does in women, would this be an indicator that it is not central to ME/CFS, because we know that women are more at risk than men?

(I am not sure what exactly you're telling us)

 

I was looking at protein folding and if that could cause EDS maybe that's the key protein folding

 

I think if an amino acid is not conserved across species for a very basic protein like prolyl hydroxylase it suggests that the amino acid is not crucial to the protein's function - perhaps an optional link in a chain that just contributes to framework structure. That would allow a nematode to use a different amino acid there too.

But this assumes that a mutation will be silent (not cause disease) if it is not crucial to the primary function of the protein, which here is the adding of a hydroxyl group to proline to make hydroxyproline. I don't think that is a safe assumption here, however. If the mutation damaged the hydroxylation capacity itself it would be likely to be lethal or produce a severe growth problem. If it caused something more subtle like a tendency to get ME maybe in mid life then you would expect the mutation to be involved in some more subtle property of the protein. That might be a binding site on the non-business end of the protein for other regulatory molecules. And the use of back end binding sites for regulation might not be conserved throughout evolution.

All I think one can say is that the mutation identified does not lead us to immediately say 'oh of course that would be how it works'. It is not something that would obviously give a disease like the one we are interested in. However, I doubt we were really expecting that anyway.

 

I was talking to Chris Ponting about this last week.

Take inflammatory arthritis. It is three times as common in women as in men and has a genetic association with HLA-DR4. BUT hidden within that it runs out that there are two groups of diseases. One is rheumatoid arthritis, which links to DR4 and is more common in women. The other is seronegative spondarthritis, which links to HLA-B27 and some forms are more common in men. So the link to DR4 is stronger in women with inflammatory arthritis than in men.

I would not be surprised if there were two main types of ME. One may be six times more common in women. The other may be twice as common in men. T cell diseases tend if anything to link to men so maybe men get the T cell disease that explains Mark Davis's finding. (And of course that means we want to know how Mark Davis's data break down for men and women too.) That would explain why ME seems to be more common in women yet the Davis 'immune signature' seems to have something to do with T cells. It also gets us away from always saying that because ME is more common in women it must be this or that sort of disease. One sort maybe, but not another.