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

Discussion in 'BioMedical ME/CFS News' started by Simon M, Aug 28, 2018.

  1. Simon M

    Simon M Senior Member (Voting Rights)

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    New blog at ME/CFS Research Review

    Guest blog by Professor Chris Ponting and colleagues.


    Summary
    A new analysis using data from UK Biobank indicates that one version of a particular gene increases the risk of ME/CFS in women. The gene codes for a transporter protein in the mitochondrial membrane and plays a critical role in the urea cycle, which is important for removing ammonia from the body. Reduced levels of the transporter protein, which are expected for the gene variant associated with ME/CFS, are likely to impair mitochondrial function. If replicated later, this finding would provide the first evidence that a person’s risk for ME/CFS is caused by changes to mitochondrial function.

    Background
    On June 11 2018 we posted a blog describing an analysis of the UK Biobank’s data, drawn from half-a-million individuals from around the UK. The data implied that there is a genetic contribution to an individual’s risk of ME/CFS but it did not provide strong evidence that change in any one section of DNA explained this risk.

    ...
    We are blogging again because a new analysis has revealed a promising finding.

    This new analysis is again of the UK Biobank data and has been posted by Ben Neale’s lab. After discarding data that they considered lower quality, they were left with data from 194,174 females and 167,020 males and kindly made their results freely available to all.

    Female-only GWAS
    Considering males and females together they identified no specific region of the human genome whose DNA variants were significantly associated with self-reported CFS/ME. (One variant, rs148723539, is possibly indicated [p = 2.3x10-9] but this is not supported by adjacent variants.)

    However, the female-only analysis revealed a single region, on chromosome 13. Ten DNA variants (single nucleotide variants, SNVs) were significantly associated [SNVs with minor allele frequency <0.001 or that were "low confidence” were filtered out] using a probability threshold of p < 5x10-8.

    These 10 SNVs are inherited down the generations together (they are in “linkage disequilibrium” [LD]) and so this looks like just one association, rather than ten different ones. The 10 SNVs all lie in a 51,000 base region that surrounds the SLC25A15 gene (Figure 1 below).

    orntgwasres.png

    Their conclusion is that DNA variation in this part of the genome slightly changes a woman’s risk of having a ME/CFS diagnosis. This must mean that one or more DNA differences in this part of the genome cause this risk change. But because all 10 differences are inherited together, it is not clear which one or ones are causing the increase in disease risk. Pinning down the causal DNA changes will require detailed experimental research.
    ...

    Ornithine Transporter type 1
    Figure 1 shows that the GWAS genetic associations are for DNA differences that lie in-or-around a particular gene called SLC25A15

    ornt tp t1.png
    So what do we know about SLC25A15? Interestingly, it encodes a protein called Ornithine Transporter type 1 (ORNT1). This transports ornithine (as well as lysine and arginine) across the inner membrane of mitochondria to the mitochondrial matrix. Ornithine is an amino acid (but not incorporated into proteins) that plays a role in the urea cycle. This cycle plays an essential part in removing ammonia from the body (see point iv below).

    This analysis predicts that if you have a letter G at this position then (Figure 2):

    (i) if you are female, then you have a greater risk of ME/CFS;

    (ii) many of your cells (for example in the heart or hippocampus, but not in muscle or liver) would tend to produce less ORNT1 RNA and less ORNT1 protein; and,

    (iii) if so, then ornithine would build up in these cells and mitochondrial function overall would be impaired; and,

    (iv) ammonia would accumulate in the blood.


    ... read the full blog
     
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  2. wastwater

    wastwater Senior Member (Voting Rights)

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    SLC25A15 at 13q14.11
    I was interested in FOXO1A at that location as it's a suspected Axenfeld Rieger site
    FOXC1 acts on FOXO1A
    I noted proline as potentially being involved there are many diagrams involving ornithine/proline
     
    Last edited: Sep 6, 2018
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  3. Londinium

    Londinium Senior Member (Voting Rights)

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    This is fascinating. One question I have (and apologies if I’ve misunderstood the article): is the lack of an equivalent result in males/both sexes as a whole because there is no such association in males, or because there is but due to a lack of power it just doesn’t reach the threshold for statistical significance?
     
  4. Andy

    Andy Committee Member & Outreach

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    To quote the blog
    So I read this to mean that they don't say whether they found a possible association or not, and even if they had a result then they wouldn't be confident in it due to sample size. Just my interpretation.
     
  5. Jonathan Edwards

    Jonathan Edwards Senior Member (Voting Rights)

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    Well there you go. I told Chris he had to analyse men and women separately in June.

    That seems a very pertinent question though @Londinium.


    The idea that there are at least two underlying causes for ME, one mostly female and one equally or maybe even more male seems to every plausible.

    I haven't read the full blog but I wonder if this mitochondrial protein would fit with the idea that the problem is a signalling one rather than a simple energy-supply one.
     
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  6. Sasha

    Sasha Senior Member (Voting Rights)

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    Wouldn't it be weird for two different mechanisms to cause the same downstream outcome? Are there examples of this elsewhere?

    I know people talk about ME probably being at least twelve diseases but I always thought that that maybe referred to different constellations of symptoms. I'm suddenly realising I haven't thought this through.
     
  7. strategist

    strategist Senior Member (Voting Rights)

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    That idea is based on the two age peaks, right?

    12916_2014_Article_167_Fig1_HTML.jpg
     
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  8. Amw66

    Amw66 Senior Member (Voting Rights)

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    Given that there is a higher incidence of onset at adolescence / pregnancy/ menopause, does this finding reflect any potential impact to hormone synthesis ?
     
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  9. Jonathan Edwards

    Jonathan Edwards Senior Member (Voting Rights)

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    Heapsand heaps of examples. The obvious one for me is rheumatoid arthritis and seronegative arthritis - we have only realised they have completely unrelated causes since about 1980. Until about 1960 nobody thought they were different much. Diabetes is caused by two completely different mechanisms - insulin resistance and insulin lack. Ricketts is caused by several completely different mechanisms- lack of vitamin D, failure to respond to vitamin D, failure to process vitamin D ... Haemophilia is due to two different gene defects. And so on and so on.

    In all these case, as in ME, there is some final common pathway to symptoms, lack high blood sugar or inflamed joints or bleeding.

    People have been talking about ME being an autoimmune disease - which would be B cells. But post-infective illnesses tend be driven by T cells. So I suggested to Chris that maybe women have B cell ME, because B cell diseases are more common in women,and men have T cell ME, because at least some T cell diseases are more common in men. But if it turns out not to be much to do with lymphocytes then maybe brain mitochondria are susceptible to different problems men and women.
     
  10. Jonathan Edwards

    Jonathan Edwards Senior Member (Voting Rights)

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    Actually not, because the shape is similar for both sexes, even if exaggerated in females. That is another issue. Adolescent ME may have a different cause from adult ME. Chris's friend had better do another sub-analysis - though I wouldn't be surprised if the UK Biobank only had people over 18.
     
  11. Sasha

    Sasha Senior Member (Voting Rights)

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    It's interesting that two of those examples (diabetes and ricketts), the mechanisms are different but the substance at the heart of the issue is the same (insulin and Vit D).

    But if RA and seronegative arthritis look the same but are completely different...

    I wonder which kind ME is (perhaps, with all our variants, both types are present).
     
  12. arewenearlythereyet

    arewenearlythereyet Senior Member (Voting Rights)

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    At last something to get reasonably excited about. :)

    Well if anyone was wondering where to spend all that spare research money ....a study to replicate this would do ...and the further work to dive into it further.

    Perhaps the MRC can fund this since I know CFS research is a real priority for them?
     
  13. Adrian

    Adrian Administrator

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    Have Fluge and Meller done an analysis of the Rituximab trial by sex - would that back up your theory?
     
  14. Adrian

    Adrian Administrator

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    Would it follow from this that adults who get ME as children have something different from adults who get ME as adults? Also when is an adult an adult, I assume the biology doesn't have a strict legal age of adulthood?
     
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  15. hixxy

    hixxy Senior Member (Voting Rights)

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    Where's the menopause peak? The graph only shows two peaks.
     
  16. Amw66

    Amw66 Senior Member (Voting Rights)

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    written prior to viewing the graph.
    It's anecdotal from forums, but dosn't look as though its borne out in reality as being significant as graphs show.
     
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  17. Adrian

    Adrian Administrator

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    That is one graph from one country so other places could have different profiles or there could be some reporting issues in the data shown here.
     
  18. Hutan

    Hutan Moderator Staff Member

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    Assuming that what I and my children have is ME, I think not. I had ME for a year (only) as a 10 year old and then it returned when I was in my late 40s and, this time, stayed. The symptoms are the same.

    My two children got it (at exactly the same time as I got it as an adult) as adolescents. Their symptoms were/are the same as mine.

    I think there are a number of families with both adults and adolescents affected.
     
    Last edited: Aug 29, 2018
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  19. Amw66

    Amw66 Senior Member (Voting Rights)

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    Hormones ?
     
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  20. adambeyoncelowe

    adambeyoncelowe Senior Member (Voting Rights)

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    But at the same time, this could be an autoimmune or genetic disease manifesting at the same time due to a shared trigger.

    Or, likewise, it could be a fluke, with one or more genetic susceptibilities interacting with either the same or different but concurrent triggers and manifesting together.

    It's obviously hard to be sure either way because we don't have biomarkers. We would have to do much larger studies, I think, especially because a number of doctors do think adolescent ME is somewhat different.
     

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