UK Biobank Genetic Study - Commentary from Decode ME

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Below is an announcement regarding the UK genetic study of ME patients.

https://www.decodeme.org.uk/what-we-learned-from-the-current-largest-genetic-study-into-m-e-cfs/

The study did not include sufficient participants. COVID excuse. Below are some excerpts.

"Quick summary: The study did not find a gene with rare DNA changes which make people with those changes more likely to develop ME/CFS. Why was a genetic signal not found? Likely reasons include: many more people need to be studied, or a narrower definition of ME/CFS is needed."

The summary of what they learned so far also states:

"The background: The UK Biobank undertook a genetic analysis of 1,232 people with self-reported CFS, alongside thousands of other medical conditions.

DecodeME uses a method called a genome-wide association study (GWAS) to focus on DNA letters that are often different among humans. This UK Biobank project focuses, instead, on very rare DNA letters. They wanted to see whether these rare changes often hit the same gene for a particular condition.

A similar approach, using much less data, had previously been used to support the IDO Metabolic Trap Hypothesis that rare changes in a gene called IDO2 predispose people to ME/CFS. Using the new data we can immediately see whether any gene is often damaged in ME or ME/CFS."

...
As you can see, there is no gene (not even IDO2) that has suffered many more rare damaging changes in people with CFS than in others. This is disappointing. If there was such a gene then scientists could immediately begin to experimentally investigate it.

So why was there no “genetic signal”, despite this large study of 1,232 people? A likely reason is that the DNA of many, many more people is needed to detect this signal – the study is “under-powered”. Another possible reason is that people in this study had self-reported being diagnosed with CFS, and a narrower definition of ME (or ME/CFS) would be needed to improve the signal...."

***
Under powered- Power is an important component of statistical analyses. This was supposed to be a study including 20,000 ME patients.

I'd be interested in what the better informed think about this IDO2 discussion.
 
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The comments below were posted on Twitter regarding the IDO2 assertions from DeCode ME above:

To:
@JanetDafoe
Have you/Ron seen this? It mentions that the mutations that Ron discussed do not have a high prevalence in ME/CFS population in this study.

Comment:

The IDO hypothesis came about off of the back of data from 70-100 patients I think, so it’s not surprising that it fails to replicate on many more patients. Time to move on I guess.

Response From Janet Dafoe:

Absolutely not! every single patient in the Stanford study had the IDO2 mutation. Patients were carefully selected to be sure that they actually have MECFS. That is not true of the bio bank study. They were self-reported. It’s very important to carefully select patients. Also, 1/

Ron has looked at the bio bank data. IDO2 mutations occur equally in patients and healthy. We’ll never figure this out if the ME/CFS GROUP IS NOT CAREFULLY IDENTIFIED!
 

SNT Gatchaman

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A similar approach, using much less data, had previously been used to support the IDO Metabolic Trap Hypothesis that rare changes in a gene called IDO2 predispose people to ME/CFS. Using the new data we can immediately see whether any gene is often damaged in ME or ME/CFS.
I thought the metabolic trap hypothesis was predicated on the fact that damaging IDO2 mutations were common (eg 40%). The disease required a line up of Swiss cheese holes: eg gene mutation + specific virus + autonomic imbalance.

In this way geographically related clusters might be explained.
 

Pyrrhus

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So why was there no “genetic signal”, despite this large study of 1,232 people? A likely reason is that the DNA of many, many more people is needed to detect this signal – the study is “under-powered”. Another possible reason is that people in this study had self-reported being diagnosed with CFS, and a narrower definition of ME (or ME/CFS) would be needed to improve the signal.
Really, DecodeME?

You can't think of any other likely reason why a genetic signal might not be found?

What about: Because ME may not be a genetic disease.

Twenty years ago I worked at a company that ran Genome-Wide Association Studies (GWAS) on a variety of diseases that were suspected to have a genetic component. At the time, our company had a proprietary database containing the largest collection of (non-public) Single Nucleotide Polymorphisms (SNP).

None of the diseases which we really suspected of having a genetic component actually turned out to have any obvious genetic component. Interestingly though, our GWAS on liver disease in alcoholism revealed a very strong genetic component to liver disease in alcoholism, which was relatively unexpected.

Of course, there are always rare familial dispositions to non-genetic diseases, but these familial dispositions don't tend to show up in a GWAS.
 
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Really, DecodeME?

You can't think of any other likely reason why a genetic signal might not be found?

What about: Because ME may not be a genetic disease.

Twenty years ago I worked at a company that ran Genome-Wide Association Studies (GWAS) on a variety of diseases that were suspected to have a genetic component. At the time, our company had a proprietary database containing the largest collection of (non-public) Single Nucleotide Polymorphisms (SNP).

None of the diseases which we really suspected of having a genetic component actually turned out to have any obvious genetic component. Interestingly though, our GWAS on liver disease in alcoholism revealed a very strong genetic component to liver disease in alcoholism, which was relatively unexpected.

Of course, there are always familial dispositions to non-genetic diseases, but these familial dispositions don't tend to show up in a GWAS.
I also think it's possible that EVERYONE can “fall” into the trap, having ME. That shows the high prevalence of ppl who get LC after the infection. Yesterday, Dr. Nath talked in wide length about LC and I think it was him mentioning that 10-30% of Americans fall into the LC category after six months. So it seems to rather be a normal genetic predisposition than an unusual one. That would also resonate with Naviaux who said that CDR is a relict that we still have in play or with Jarred Younger and VanElzakker who think of an immune priming not bc of a rare mutation but bc of a high amount of stressors.

The other possibility is also possible: I'm really active on social media advocating. I've talked to hundreds of chronically ill ppl, most of the reported to have “chronic fatigue syndrome”. But if you dive deeper you'll find out that MANY don't have PEM and are really not well informed about the criteria of ME. There are ppl who state that they recovered from exercise and mind/body techniques for example.

The third would be also a possble theory: we don't have a single pathomechanism at play. We are not a homogeneous group but ME/CFS is an umbrella term for many diseases. So that's why they didn’t find one mutation.

Another thing to keep in mind is that a disease is often not caused by a single mutation but a variety of mutations of many genes. So it's also possible that they overlooked sth.
 

bertiedog

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The third would be also a possble theory: we don't have a single pathomechanism at play. We are not a homogeneous group but ME/CFS is an umbrella term for many diseases
I have thought that for the 20 years I have had the illness. I think there are many subsets if we are using the term ME.

Pam
 
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The orginally ME is chronic Infection with one or multiple Viruses. Immune System Exhaustion and Mitochondrial Fragmentation.
I more and more think so too. I have immune exhaustion and persistent EV infection (which seemed to reactivate HSV I/II and EBV).

But there are so many possibilities and I think we should concentrate on the pathomechanism of PEM in science. Bc without, it would be manageable.

Ability blocked PEM completely for me. I know many others who report the same. I think that is worth investigating and not only do a study of the efficacy but also on the mechanism behind it.
 
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I've talked to hundreds of chronically ill ppl, most of the reported to have “chronic fatigue syndrome”. But if you dive deeper you'll find out that MANY don't have PEM and are really not well informed about the criteria of ME.
This is a significant problem in collecting any statistics on me/cfs. Do they have it?
 
The other possibility is also possible: I'm really active on social media advocating. I've talked to hundreds of chronically ill ppl, most of the reported to have “chronic fatigue syndrome”. But if you dive deeper you'll find out that MANY don't have PEM and are really not well informed about the criteria of ME. There are ppl who state that they recovered from exerc
Yes, exactly. I think we really need to as patients start referring to our subset of ME/CFS the "norm" or "fad."

For example, when I introduce myself or post, I try to say "I have ICC-ME triggered by a virus, COVID suspected."

If this became the norm, patients would then naturally talk about the disease as such around medical and research professionals too, hopefully dropping a clue on the need for segmenting/creating subsets of the disease to research.

Like starting a revolution in how we refer to our disease.

What would the breakdown/tree of ME/CFS look like? (theoretical)
 

BrightCandle

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I signed up to it ages ago and they never even contacted me. I kind of suspected that it would be done poorly though but it is one of those things I figured I may as well do. Surprised to find they have results already and they never bothered to even contact me for a collection of DNA. Not surprised really I don't expect anything useful from UK medicine at this point its all useless but still to not even be told they didn't need my sample is just a little rude.
 

keepswimming

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Having read the article and looked at the website, I think there may be some confusion. The Decode ME study hasn't been launched yet, their homepage says it will start Autumn 2021 and should involve 20,000 participants. This article is talking about a different study which has just been published, the current largest, which was done by the UK Biobank. It included people with many different medical conditions, including 1,232 with self reported CFS.
 

Pyrrhus

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Having read the article and looked at the website, I think there may be some confusion. The Decode ME study hasn't been launched yet, their homepage says it will start Autumn 2021 and should involve 20,000 participants. This article is talking about a different study which has just been published, the current largest, which was done by the UK Biobank. It included people with many different medical conditions, including 1,232 with self reported CFS.
Thank you for emphasizing the fact that the link mentioned in the original post was DecodeME commenting on a separate study conducted by the UK Biobank.

Specifically, the separate study being referred to is this one:

Rare variant contribution to human disease in 281,104 UK Biobank exomes (Wang et al., 2021)
https://www.nature.com/articles/s41586-021-03855-y

It is also important to emphasize that the UK Biobank is entirely separate from the UK ME/CFS Biobank.
The UK ME/CFS Biobank may have better screened patients for ME than the UK Biobank.
 
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I signed up to it ages ago and they never even contacted me. I kind of suspected that it would be done poorly though but it is one of those things I figured I may as well do. Surprised to find they have results already and they never bothered to even contact me for a collection of DNA. Not surprised really I don't expect anything useful from UK medicine at this point its all useless but still to not even be told they didn't need my sample is just a little rude.
Same here.
Edit: read the next post too late
 

J.G

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I initially misunderstood as well, and wondered how on earth does DecodeME have results already :rofl:

The blog author writes the following about the BioBank study, which to me seems like a premature and overblown conclusion based on a dataset of ~1200 people with self-reported MECFS.

"UK Biobank’s research announcement reveals the scale of the challenge to find genetic signals of ME/CFS. It is clear that there is no “ME/CFS gene”, or even a handful of such genes."

They go on to moderate this statement by saying that the study could be underpowered and more tightly defined cohorts could be needed to identity a genetic signal. Considering how MECFS is a wastebasket diagnosis with historically variable interpretations by clinicians and patients alike, this seems rather obvious. Which begs the question - why make that sweeping statement at all? It can only do harm and no good.
 

BrightCandle

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The difficulty with the self report of ME/CFS is how poorly in the UK its diagnosed. I technically don't have an ME/CFS diagnosis, I had a Fibromylgia one for about a year and then I asked for the vaccine and my doctor withdrew it. 7 years, 172 appointments and they still can't say what is wrong with me at all. Self reported is the only way in that environment where they can possibly find a patient. Since the UK's diagnostic criteria are also completely garbage unless they adopt the CDC or Canadian symptoms list and they do their own diagnostics on patients that have been treated as mentally ill there is zero way they can go from self reported to a reasonable cohort for a study. Fact is the UKs guidelines as they stand prevent DecodeME from being able to do a proper study because the patient group isn't recognised the country over.

So I wouldn't dismiss self reported as an issue on its own, they do however have to adopt some criteria that dig deeper or it wont turn into something useful, but self reported is the only way you can reach ME patients in the UK, because they don't officially exist since its just a mental illness.