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Genome-wide association study identifies RNF123 locus as associated with chronic widespread musculoskeletal pain, Md Shafiqur Rahman, et al, 2020

Discussion in 'Health News and Research unrelated to ME/CFS' started by voner, May 1, 2021.

  1. voner

    voner Established Member (Voting Rights)

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    Abstract
    Background and Objectives Chronic widespread musculoskeletal pain (CWP) is a symptom of fibromyalgia and a complex trait with poorly understood pathogenesis. CWP is heritable (48-54%), but its genetic architecture is unknown and candidate gene studies have produced inconsistent results. We conducted a genome-wide association study to get insight into the genetic background of CWP.

    Methods Northern Europeans from UK Biobank comprising 6,914 cases reporting pain all over the body lasting more than 3 months and 242,929 controls were studied. Replication of three lead genome-wide significant single nucleotide polymorphisms (SNPs) was attempted in 6 independent European cohorts (N=43,080; cases=14,177). Genetic correlations with risk factors, tissue specificity, and colocalization were examined.

    Results Three genome-wide significant loci were identified (rs1491985, rs10490825, rs165599) residing within the genes RNF123, ATP2C1, and COMT. The RNF123 locus was replicated (meta-analysis p=0.0002), the ATP2C1 locus showed suggestive association (p=0.0227), and the COMT locus was not replicated. Partial genetic correlation between CWP and depressive symptoms, body mass index, age of first birth, and years of schooling were identified. Tissue specificity and colocalization analysis highlight the relevance of skeletal muscle in CWP.

    Conclusions We report a novel association of RNF123 locus with CWP and suggest a role of ATP2C1, consistent with a role of calcium regulation in CWP. The association to COMT, one of the most studied genes in chronic pain field, was not confirmed in the replication analysis.

    https://www.medrxiv.org/content/10.1101/2020.11.30.20241000v2.full
     
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  2. cassava7

    cassava7 Senior Member (Voting Rights)

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  3. Jonathan Edwards

    Jonathan Edwards Senior Member (Voting Rights)

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    I think this is the study from Frances Williams that has been working its way towards publication since late 2019 at least. It is an important pointer to what might turn out in ME/CFS on GWAS.

    As far as I can see the methodology is similar to that already tried for ME/CFS using diagnosis or self-report in people already known to the uk Biobank in Leeds. The numbers look bigger (6,900 vs 2,000), but the inclusion criteria look a bit cobbled. Self-report of pain all over is pretty vague. Pain in hip, shoulder and knee is likely to be due to arthritis rather than muscle pain. A doctors diagnosis of fibromyalgia can mean anything, including just someone with too many symptoms.

    Nonetheless, they seem to have found something and it may have a significant impact on the issue of taking ME and FM seriously. CBT and exercise are not going to change your genes!

    What I have not been able to get at from the data is how many people had a gene linkage to the RNF123 gene. It might have been 5% in CWP and 15% in controls or 80% in CWP an d 40% in controls. I would like to have some idea what proportion of cases the link might be relevant to.
     
    Last edited: May 1, 2021
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  4. strategist

    strategist Senior Member (Voting Rights)

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    RNF123plays a role in Class I MHC mediated antigen processing (and other things).
     
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  5. voner

    voner Established Member (Voting Rights)

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    I found the “Discussion“ section to be quite interesting and intriguing. plenty of fodder for speculation. I would like to hear from people about what the authors have to say.
     
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  6. voner

    voner Established Member (Voting Rights)

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    here is their decision tree for Selection of case and controls. Note the exclusion criterea.

    upload_2021-5-1_13-9-49.jpeg
     
  7. FMMM1

    FMMM1 Senior Member (Voting Rights)

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    "Conclusions We report a novel association of RNF123 locus with CWP and suggest a role of ATP2C1, consistent with a role of calcium regulation in CWP. The association to COMT, one of the most studied genes in chronic pain field, was not confirmed in the replication analysis."

    Here's a paper I found on the internet re calcium regulation:
    https://www.nature.com/articles/s41380-019-0622-y

    So presumably two entirely unrelated things found at random.
     
  8. Wonko

    Wonko Senior Member (Voting Rights)

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    I 'like' the association of calcium regulation with pain.

    I noticed a long time ago that a type of calcium channel blocker that I was on seriously reduced my 'background' pain levels. This was even mentioned at a work capability assessment. In his report the doctor took the piss and basically phrased it in such a way as to imply he thought I was delusional.

    I am no longer on these, as apparently several years ago they were deemed unsuitable for diabetics.

    So now I use co codamol, which is not as effective (might be, I just won't take them 24/7 but only when things get bad, or I need to sleep)

    So an association between calcium and pain 'interests' me.
     
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  9. Amw66

    Amw66 Senior Member (Voting Rights)

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    Would this relate in any potential way to the calcium.ion channel dysregulation reported by the researchers at Griffeth ?
     
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  10. Hutan

    Hutan Moderator Staff Member

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    I was reading about calcium channels the other day.
    This reference about them is very readable and interesting. Don't be put off by the reference to breast cancer, there's a lot of general stuff.
    Calcium signaling: breast cancer’s approach to manipulation of cellular circuitry

    Given the wide varieties of processes calcium is involved with, it would almost be surprising for it not to be involved in chronic pain and in ME/CFS.

    The paper I linked has a nice diagram of a whole lot of different calcium pumps, including ATP driven ones (which is what the ATP2C1 one seems to be).

    What I thought was really interesting, aside from the number of different types of calcium channels, is that the signalling is a lot more complicated than just the concentration of calcium inside the cell. There are things like pulses of calcium inflow, with the speed of the pulse affecting the signalling. And then there is the gradient of calcium within the cell, and all sorts of other details that makes things work.

    It's amazing stuff.

     
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  11. Mithriel

    Mithriel Senior Member (Voting Rights)

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    This sounds as if it could be a way to differentiate fibromyalgia from ME
     
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  12. Ravn

    Ravn Senior Member (Voting Rights)

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    This recent hypothesis paper proposes a calcium problem in ME (not that I understand any of it).
    https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-021-02833-2

    Discussed here: https://www.s4me.info/threads/patho...ces-in-me-cfs-2021-wirth-scheibenbogen.20256/
     
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  13. Milo

    Milo Senior Member (Voting Rights)

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    Anything else that you know is in the works?
     
  14. Jonathan Edwards

    Jonathan Edwards Senior Member (Voting Rights)

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    No. I imagine they will have to do a study focusing on these markers with a better characterised cohort.
     
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  15. Milo

    Milo Senior Member (Voting Rights)

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    Thank you, and it was a broadly cast question :nerd: because it sounds like you are in the know
     

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