Evidence for a genetic component in ME/CFS - discussion thread

I'm looking for evidence for a genetic component in ME/CFS and a discussion of the quality of evidence for each the studies.

Here are some I found after a quick search (haven't read them all), are there important ones missing?

Hickie et al. 2001. A Twin Study of the Etiology of Prolonged Fatigue and Immune Activation. https://www.cambridge.org/core/jour...e-activation/23C27BC6F37EC4D87ED788A9C0EB624C

Buchwald et al. 2001. A twin study of chronic fatigue. https://journals.lww.com/psychosoma...11000/A_Twin_Study_of_Chronic_Fatigue.12.aspx

Walsh et al. 2001. A family history study of chronic fatigue syndrome. https://journals.lww.com/psychgenet...tory_study_of_chronic_fatigue_syndrome.3.aspx

Schur et al. 2007. Twin Analyses of Fatigue. https://www.cambridge.org/core/jour...s-of-fatigue/BEA61FF0469B1F6FA994D987478B68F2

Ponting et al. 2018. Analysis of data from 500,000 individuals in UK Biobank demonstrates an inherited component to ME/CFS. https://mecfsresearchreview.me/2018...emonstrates-an-inherited-component-to-me-cfs/​

 

Ponting threads

https://www.s4me.info/threads/signi...self-reported-me-cfs-chris-ponting-blog.5520/

https://www.s4me.info/threads/analy...erited-component-to-me-cfs-ponting-blog.4529/


Cyclophosphamide study that demonstrated genetic link to treatment outcome!!! Esp. For DQB1.


https://www.s4me.info/threads/intra...-study-2020-rekeland-mella-fluge-et-al.14925/

 

This should have a good list:
Review of the Quality Control Checks Performed by Current Genome-Wide and Targeted-Genome Association Studies on ME/CFS, 2020, Sepulveda et al
Thread : https://www.s4me.info/threads/revie...studies-on-me-cfs-2020-sepulveda-et-al.15033/
Paper : https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7304330/

Alan Light has a current R01 grant from NIH
NOVEL GENE VARIANTS IN ME/CFS AND FIBROMYALGIA
Grant : https://projectreporter.nih.gov/project_info_description.cfm?aid=9600713&icde=31258613
Thread : Livestream Alan Light, PhD today at 6pm MST "New findings suggest that multiple mitochondrial mutations create susceptibility for ME/CFS"
https://www.s4me.info/threads/lives...ations-create-susceptibility-for-me-cfs.7072/

There are some HERV-K HERV-W studies as well. And quite a few gene expression studies.

Please read the last two comments in that post from Paolo and Chris. It was ONE patient only that had the genetic variant that the blog talks about.

 

Poeschla et al (incl. Buchwald) 2013 is as well about the Syndrome, as they say:
Chronic Fatique and Personalitiy: A Twin Study of Causal Pathways and shared Liabilities
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3643988/

page 6:

---
Schlauch et al 2016: Genome wide analysis identifies genetic variations in [ME/CFS]
https://www.nature.com/articles/tp2015208

They found especially in non-coding regions some SNP´s being somehow common enough in ME/CFS, only 12 out of 442 in coding regions. This - the non-coding thing - may seem strange, but I have read something similar in respect of another diesease, sadly I have forgotten which one. In the introduction the highlight autism, schizophrenia and putative circadian clock. (I personally find the first two interesting as I think that the failure arises in the basal ganglia and non-specific thalamus, and at least schizophrenia should be located right there.)

There is also the Perez/Klimas paper from 2019, but the data are said to be wrong.

 

Simon and Chris Ponting refer to data by Canela-Xandri on BioRxiv. I could not track that down but Simon McGrath should know.

I thought there was some recent information from a big epidemiological study in California that happened to check for CFS linkage. Again, Simon would know.

 

Perhaps you are thinking of the Lily Chu paper
Onset Patterns and Course of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
https://www.frontiersin.org/articles/10.3389/fped.2019.00012/full

 

Paolo Maccallini referred to Canela-Xandri's paper where he looked at the supplementary data of that paper to locate that only ONE ME patient had the variant described in Simons blog about Chris Pontings analysis of interesting variants that @Michiel Tack lists in the first post. Oh boy, that was a mouthful.
https://twitter.com/user/status/1157174471054286848

 

I picked just one value from table 1 of that paper. rs41493945 has an allele frequency of ~0.3% with a variation of C->T. I double checked the coordinates given and it matches the rsID. They show the variant as G->A with a huge difference between patients and control which is not right. This must be a mistake.



By the way, this is a GWAS with 42 patients and 38 controls. 20,000 ME and up to 500K controls will be a huge improvement with the DecodeME study.

 

I’m not sure what you’re thinking is a mistake. Do you mean C>T being written as G>A? This most likely is not a mistake, but simply that one group is reporting using the forward strand (+) and the other using the reverse (-)
When comparing your results you always have to look at which way it is being reported.

 

I've no idea what you are talking about. The data in the table seems to be referenced to GRCh38 where the reference allele is T and the variant is C according to official databases. Take a look at the first three variants in table 1 - they all conform correctly and call out the right reference and alternate alleles so why doesn't rs41493945?

Also 33 out of 42 CFS or 79% have the variant when the allele frequency is 0.3%. That's not right. That cannot happen. There are other examples in the table where the frequency is all wrong.

Okay let me pick another one at random. rs16827966 has an allele frequency of ~3% but 30 out of 42 or 71% CFS have the variant but only 1 out of 38 or 2.6% controls. Controls are in the right range but CFS is not. The numbers are too far off. The reference allele is C and the alternate is T which they get correct this time.


And they are sloppy. They leave the chromosome empty for this one when it should be 2.

 

Here is more evidence that the Schlauch et al 2016 paper is wrong. I searched for all the hugely significant variants in table 1 of that paper in the UK Biobank GWAS tool and selected data for chronic fatigue syndrome that has data for 2017 cases and 450247 controls, slighty more than Schlauch 42 CFS and 38 controls.

http://geneatlas.roslin.ed.ac.uk/se...010471+rs6757577+rs8029503+rs7849492+rs948440


It can be seen that for variant ID's that have matches there are no significant datapoints - nothing approaching a pv or p value of 10-8 that is usually used as a decision gate in this UK biobank GWAS study.

Sorry @Michiel Tack for taking things of track.

EDIT : Just a little rant about researchers. They like to fill their papers with big words and sound important with this and that correlation used, but sometimes they just forget to use common sense when evaluating and reporting the data.

 

Look up forward and reverse orientation for a better explanation than I can come up with.

The snp database used to report snps in whatever orientation researchers reported them so it wasn’t consistent throughout. Some companies like 23andme reported all snps in forward orientation and the difference has been a source of confusion for many.

Some time ago dbSNP changed to reporting all snps in forward orientation so papers written before that change may have differences to what you find now when you look up snps.


The red arrow points to the forward orientation for this snp, C
The green arrow points to the reverse orientation, G



I haven’t looked at the other things you wrote about yet.

 

Thank you @sea . That's why I enjoy coming here as there is always something to learn from others

 

To be fair they don’t expect people to pull a single line from their chart. When you look at the entire chart the chromosome is listed for the first snp on each relevant chromosome. All subsequent snps on the same chromosome are listed on subsequent lines without repeating the chromosome number.

I haven’t looked in detail at the frequencies and p values. I don’t have the brain for that at the moment. I agree it does appear odd to have a rare snp appear at such a high frequency in patients. It seems at odds though with the way they described their methods where they said they only included snps with MAF of 5% or greater

 

No problem, thanks for probing into these studies. We need more people like you who focus on dissecting biomedical ME/CFS research.

More relevant studies:

Tores-Harding et al. 2004. Family Medical History of Persons with Chronic Fatigue Syndrome https://www.tandfonline.com/doi/abs/10.1300/J092v12n04_03

Underhill & O'Gorman 2006. Prevalence of Chronic Fatigue Syndrome and Chronic Fatigue Within Families of CFS Patients https://www.tandfonline.com/doi/abs/10.1300/J092v13n01_02

That sounds interesting but it sounds like it was a study based on self-report. Do you know more @Simon M ?

 

Responding to tag.



I am afraid I am not able to look at this at the moment. However, there is a review paper in press that looks at these issues and might be available quite soon.

 

And there it is:
https://www.s4me.info/threads/genet...e-simon-j-mcgrath-chris-p-ponting-2020.16173/

 

This is referred to in Underhill 2015 [ME/CFS]: An infectious disease, open access (an interesting article).

Apart from some genetic influence referred to, the article focuses, as the title says, on transmission (spouses are mentioned as well).