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

Simon

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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.​


manhattan-plot-biobank-gwas.png

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.
....

Read the full blog
 

melihtas

Senior Member
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Istanbul Turkey
My bolding;
This proposed “significant hit” is on chromosome 10 (position 74828696; rs150954845). The calculated p-value is 2.5×10-12. This DNA change (A-to-T) is predicted to alter a protein called P4HA1, changing an aspartic acid (“D”; GAT) for a valine (“V”; GTT) at its 124th amino acid position.

(b) Second, this part of the protein is not conserved across evolution. There is even a nematode worm known that has a valine at exactly the position (124) that would be predicted to alter risk for ME in humans.

Dauer state??? Coincidence???
 

Murph

:)
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1,794
If the prevalence of the genetic abnormality is .01 per cent and the prevalance of mecfs is 0.45% then this can't be more than a subset, right?

If the genetic hit is for collagen, which is part of connective tissue, and the people self-report they have mecfs could these people be misdiagnosed EDS patients?

Still, I'd like to hear more.
 

Simon

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Location
Monmouth, UK
If the prevalence of the genetic abnormality is .01 per cent and the prevalance of mecfs is 0.45% then this can't be more than a subset, right?

If the genetic hit is for collagen, which is part of connective tissue, and the people self-report they have mecfs could these people be misdiagnosed EDS patients?

Still, I'd like to hear more.
It’s complicated!

Normally, it’s not as simple as one gene defect causes disease, particularly as people tend to get it later in life, rather than from birth.

What these types of studies tend to throw up, I understand, is genes that individually have a small effect. Things get interesting when the genes affect one or a few biological pathways: different genes in different people could end up affect the same pathway, and that could point to a pathway playing a role. The pathway would then be the clue to follow up, rather than the individual genes.

The problem is that this study is a small (compared with typical studies in this field) and it doesn’t have the statistical power to detect smaller differences , hence the point about a bigger study being much more useful. But these early results they suggest there is more to be found.

Yes, lots of people have noted the EDS connection. But it’s probably too early to get excited about one particular hit, the evidence for genes in general playing a role is probably a more important conclusion.
 

FMMM1

Senior Member
Messages
513
It’s complicated!

Normally, it’s not as simple as one gene defect causes disease, particularly as people tend to get it later in life, rather than from birth.

What these types of studies tend to throw up, I understand, is genes that individually have a small effect. Things get interesting when the genes affect one or a few biological pathways: different genes in different people could end up affect the same pathway, and that could point to a pathway playing a role. The pathway would then be the clue to follow up, rather than the individual genes.

The problem is that this study is a small (compared with typical studies in this field) and it doesn’t have the statistical power to detect smaller differences , hence the point about a bigger study being much more useful. But these early results they suggest there is more to be found.

Yes, lots of people have noted the EDS connection. But it’s probably too early to get excited about one particular hit, the evidence for genes in general playing a role is probably a more important conclusion.

Check out Neil McGregor's presentation at the OMF Community Symposium in September 2017. Neil presented data showing increased incidence of SNIPs in langerin and some other genes. This was a small study.

Ron Davis is due to publish a small genetics study.

Maybe these genetic studies will help to establish a mechanism/diagnostic markers etc.
 

FMMM1

Senior Member
Messages
513
My bolding;




Dauer state??? Coincidence???

Way out of my understanding but I assumed/guessed that if a gene is found in other species (such as a naematode) then it would be described as conserved rather than not conserved (sorry quotation marks not working).
 

alex3619

Senior Member
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13,810
Location
Logan, Queensland, Australia
Way out of my understanding but I assumed/guessed that if a gene is found in other species (such as a naematode) then it would be described as conserved rather than not conserved (sorry quotation marks not working).
My interpretation is not that that the gene is not conserved, its this region of the gene that is not conserved. That is it has high variation. What I am unsure of is why they say this part of the protein is not conserved. Proteins are several steps away from the gene and subject to their own variations due to post gene processing. If the gene is not conserved then it follows the protein may not be conserved ... may, not is. It depends on the variations.
 
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FMMM1

Senior Member
Messages
513
My interpretation is not that that the gene is not conserved, its this region of the gene that is not conserved. That is it has high variation. What I am unsure of is why they say this part of the protein is not conserved. Proteins are several steps away from the gene and subject to their own variations due to post gene processing. If the gene is not conserved then it follows the protein may not be conserved ... may, not is. It depends on the variations.


Thank you very much for your explanation.

So they've discovered a potential variation in the gene in people with ME/CFS [i.e.at the 124th amino acid position].

Weirdly the variation discovered in people with ME/CFS changes the gene to the form found in a nematode worm [i.e. at the 124th amino acid position]. See melihtas's comments above. Also, Naviaux proposed that ME/CFS is similar to the Dauer state found in nematode worms.

I wonder what the protein does; i.e. do we know its function in humans/is it related to the Dauer state found in nematode worms?
 

alex3619

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Logan, Queensland, Australia
Weirdly the variation discovered in people with ME/CFS changes the gene to the form found in a nematode worm [i.e. at the 124th amino acid position].
This is interesting, and probably should be investigated, but its most likely coincidence. I am sure that patients share many coincidental match-ups with nematodes.

Doh, I wish I had been well enough to continue my biochem degree into an offered PhD. It was on nematodes if I recall correctly, though more about pesticide resistance.
 

FMMM1

Senior Member
Messages
513
This is interesting, and probably should be investigated, but its most likely coincidence. I am sure that patients share many coincidental match-ups with nematodes.

Doh, I wish I had been well enough to continue my biochem degree into an offered PhD. It was on nematodes if I recall correctly, though more about pesticide resistance.

Thank you very much for your response. It's good to have your contributions since you have such a good understanding of biochemistry.

Degrees not finished --- it seems the way in this disease.
 

wigglethemouse

Senior Member
Messages
776
I came across an article in Nature about a GWAS study into ME/CFS. It was small "42 cases with a confirmed diagnosis of ME/CFS and 38 healthy controls"
https://www.nature.com/articles/tp2015208

Abstract
Myalgic encephalomyelitis, also known as chronic fatigue syndrome or ME/CFS, is a multifactorial and debilitating disease that has an impact on over 4 million people in the United States alone. The pathogenesis of ME/CFS remains largely unknown; however, a genetic predisposition has been suggested. In the present study, we used a DNA single-nucleotide polymorphism (SNP) chip representing over 906,600 known SNPs to analyze DNA from ME/CFS subjects and healthy controls. To the best of our knowledge, this study represents the most comprehensive genome-wide association study (GWAS) of an ME/CFS cohort conducted to date. Here 442 SNPs were identified as candidates for association with ME/CFS (adjusted P-value<0.05). Whereas the majority of these SNPs are represented in non-coding regions of the genome, 12 SNPs were identified in the coding region of their respective gene. Among these, two candidate SNPs resulted in missense substitutions, one in a pattern recognition receptor and the other in an uncharacterized coiled-coil domain-containing protein. We also identified five SNPs that cluster in the non-coding regions of T-cell receptor loci. Further examination of these polymorphisms may help identify contributing factors to the pathophysiology of ME/CFS, as well as categorize potential targets for medical intervention strategies.
 

FMMM1

Senior Member
Messages
513
I came across an article in Nature about a GWAS study into ME/CFS. It was small "42 cases with a confirmed diagnosis of ME/CFS and 38 healthy controls"
https://www.nature.com/articles/tp2015208

I know very little about genetics but having looked at the text you quote I recall that non-coding DNA apparently does not mean it does not have a biological function see below. Also, the fact that Mark Davis (OMF) has found activation (clonal expansion) of T-cells (and this study found SNIPs on T-cells) is possibly relevant. Check out Health Rising for an article on Ron/Mark Davis's successful grant application looking at HLA locus genes (genes identifying self/non-self). I assume this study didn't look at HLA locus genes locus genes since these are very difficult to sequence.

My emphasis - bold text.
Non-coding DNA
From Wikipedia, the free encyclopedia
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In genomics and related disciplines, noncoding DNA sequences are components of an organism's DNA that do not encode protein sequences. Some noncoding DNA is transcribed into functional non-coding RNA molecules (e.g. transfer RNA, ribosomal RNA, and regulatory RNAs). Other functions of noncoding DNA include the transcriptional and translational regulation of protein-coding sequences, scaffold attachment regions, origins of DNA replication, centromeres and telomeres.

The amount of noncoding DNA varies greatly among species. Often, only a small percentage of the genome is responsible for coding proteins, but a rising percentage is being shown to have regulatory functions. When there is much non-coding DNA, a large proportion appears to have no biological function, as predicted in the 1960s. Since that time, this non-functional portion has controversially been called "junk DNA".[1]

The international Encyclopedia of DNA Elements (ENCODE) project uncovered, by direct biochemical approaches, that at least 80% of human genomic DNA has biochemical activity.[2] Though this was not necessarily unexpected due to previous decades of research discovering many functional noncoding regions,[3][4] some scientists criticized the conclusion for conflating biochemical activity with biological function.[5][6][7][8][9] Estimates for the biologically functional fraction of our genome based on comparative genomics range between 8 and 15%.[10][11][12] However, others have argued against relying solely on estimates from comparative genomics due to its limited scope. Non-coding DNA has been found to be involved in epigenetic activity and complex networks of genetic interactions, and is being explored in evolutionary developmental biology.[4][11][13][14]
 

Simon

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I came across an article in Nature about a GWAS study into ME/CFS. It was small "42 cases with a confirmed diagnosis of ME/CFS and 38 healthy controls"
https://www.nature.com/articles/tp2015208
To get robust results for a GWAS takes around 10k patients, so I wouldn't read anything into this study. In the early days of GWAS, studies used samples in the hundreds or low thousands of people. The results turned out to be just a lot of noise, and the field moved on. Maybe a sample of 5k would do it.
 

FMMM1

Senior Member
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513
To get robust results for a GWAS takes around 10k patients, so I wouldn't read anything into this study. In the early days of GWAS, studies used samples in the hundreds or low thousands of people. The results turned out to be just a lot of noise, and the field moved on. Maybe a sample of 5k would do it.

This is really interesting but slightly concerning.

Ron Davis's has been awarded an NIH grant to look at HLA genes in ME/CFS. From what you're saying this would require the sequencing of HLA genes in 5K (preferably 10K) people with ME/CFS. Haven't checked the numbers in the grant award but that looks challenging.

Also, other studies have examined the link between mutations (SNIPs) in HLA and cytokine genes* and an autoimmune disease [https://onlinelibrary.wiley.com/doi/full/10.1111/ijd.12894]. Therefore you would need good quality HLA data and data on cytokine genes etc.
(* E.g. TGF-B has been shown to be elevated in cytokine studies in ME/CFS)

Thankfully Davis etc are world leaders; therefore, they know what they are doing.

I seem to have gone off-topic here.
 

Simon

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With GWAS, researchers are looking at the whole genome , with hundreds of thousands of possible genetic changes. That dramatically increases the chance of false positives, so very big samples are needed to generate robust results.

Davis is focusing on a handful of genes, so much smaller sample sizes will be adequate.
 

FMMM1

Senior Member
Messages
513
With GWAS, researchers are looking at the whole genome , with hundreds of thousands of possible genetic changes. That dramatically increases the chance of false positives, so very big samples are needed to generate robust results.

Davis is focusing on a handful of genes, so much smaller sample sizes will be adequate.

Thanks.

I think you raised this before i.e. (Bonferroni correction) in relation to Griffiths University TRIP receptor study.

So, since Davis's group are testing a much smaller number of (HLA) genes then the sample size required to avoid false positives/negatives is much smaller i.e. compared to total genome study.

Interesting to see which genes are included and whether any cytokine genes are included.