The 12th Invest in ME Conference, Part 1
OverTheHills presents the first article in a series of three about the recent 12th Invest In ME international Conference (IIMEC12) in London.
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Need help interpreting Genetic Genie results

Discussion in 'Genetic Testing and SNPs' started by ellecognito, Jan 11, 2017.

  1. ellecognito

    ellecognito

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    Hi all,

    I'm relatively new to this board, though I was here briefly, many years ago. I've been sick for ages (30 years or so) and had long ago given up finding out what was wrong. Luckily my case is mild compared to some, so I've always been functional at a somewhat low level, though it's been very hard to support myself.

    Anyway, I recently came out of my shell again to poke around and see if anything new is on the horizon and, lo and behold, came across information on methylation and mitochondrial dysfunction. I ended up running a Genetic Genie methylation analysis on 23andme data, and while I have been able to figure out that I probably need to supplement methylcobalamin and methylfolate, I'm not sure if there's something else I should do. I thought I'd see if there are any other indications and perhaps what you think I should expect with these supplements I am about to start taking. Here are my mutations:

    Homozygous (+/+)

    BDR Bsm
    MAO-A R297R
    CBS A360A

    Heterozygous (+/-)

    MTHFR A1298C
    COMT V158M
    COMT H62H
    MTR A2756G
    MTRR A66G
    BHMT-02
    BHMT-04
    BHMT-08

    TIA for any help, and feel free to inbox me privately if you prefer.
     
  2. Valentijn

    Valentijn WE ARE KINA

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    @ellecognito - MTHFR A1298C +/- by itself is very common and very mild. Having only that MTHFR mutation means you are processing folate better than the average person.

    MTRR mutations need to be homozygous or compound heterozygous with another serious MTRR missense mutation to have a substantial impact. So MTRR A66G +/- also shouldn't be causing any problems.
     
  3. ellecognito

    ellecognito

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    Thank you, Valentijn. Yes, it appears to be the other mutations that may be causing more of the problems but they are not as "famous" as the MTHFR so I've been able to find limited information on them. Having brain fog doesn't help, of course.
     
  4. Valentijn

    Valentijn WE ARE KINA

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    The other SNPs don't look like ones which have much impact either, and at least several of them have no impact at all.
     
  5. ellecognito

    ellecognito

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    That's pretty interesting. The Genetic Genie analysis suggests otherwise, so I guess I'll just take a stab at methylation and see if things get better. Frustrating that even science-based information isn't going to give me a straight-up answer.
     
  6. Sherpa

    Sherpa Ex-workaholic adrenaline junkie

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  7. Valentijn

    Valentijn WE ARE KINA

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    No, it's a synonymous variant in a coding region, which means it's incapable of doing anything at all. I wouldn't trust anything from a site which fails to understand the basics.
     
  8. alicec

    alicec Senior Member

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    I quite like Joseph Cohen and have read many useful things on his website but that article is not one of them.

    It is confused and confusing and doesn't even explain what the warrior gene is really about. And what are 2,3,4 and 5 R?

    The original research about the so-called warrior gene correlated a promoter polymorphism with antisocial behaviour under conditions of neglect. The polymorphism was a repeated sequence in the promoter of the gene (2, 3, 4, 5 and some intermediate numbers of repeats were found) which affected that rate at which the gene was transcribed.

    More or less enzyme with normal activity was produced; more repeats, more enzyme. People with a low activity promoter (2R) make less of the enzyme, hence are less able to breakdown various neurotransmitters. These are the people who developed aggressive behaviour if placed in conditions of childhood neglect/abuse. Just having this promoter variation was not enough to cause problems.

    Cohen doesn't explain any of this, instead focusing on proxies for the number of repeats (dubious approximations), then lapsing into a few underpowered and probably meaningless association studies.

    Nowhere does he explain that simply having the 2R promoter polymorphism is not enough to cause the problem.

    I suppose it's not as bad as all the internet chatter which claims that rs6323 IS the warrior gene and means that you have a slow form of the enzyme. Wrong on all counts.

    There are a few serious MAO A variants but R297R is not one of them.
     
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  9. Sherpa

    Sherpa Ex-workaholic adrenaline junkie

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    Can you suggest (or write) a better article on MAO A gene polymorphism and treatments???

    Last I checked there was extremely little useful web / blog info for the end user. People post and ask about this SNP literally every day.
     
    Last edited: Jan 13, 2017
  10. ellecognito

    ellecognito

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    Thank you for your replies. MAO-A R297R is at rs6323 and is TT. As for my personal level of aggressiveness, I have a pretty long fuse but there is a line that most people don't know exists until they cross it. Then they wish they hadn't. Not a physically violent person, but definitely not someone who suffers fools gladly, so perhaps there's a bit of warrior there after all.

    One thing that concerns me is this statement, again from the Genetic Genie site, which may or may not be credible. "When a (+/+) MAO-A mutation is combined with a +/+ or +/- COMT V158M mutation, imbalances in neurotransmitters may be more severe." And yes, I have suffered with not just CFS but deep depression my whole life, which only mildly responds to an SSRI. Anything else to be tried that anyone can suggest, based on this?
     
  11. alicec

    alicec Senior Member

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    Genetic Genie reports the SNPs that Yasko is interested in and is essentially repeating her rationale for focusing on these SNPs along with her interpretation of what they mean.

    Yasko is not a reliable source of information and should not be considered to give science-based information. Often there is no science behind her claims or the science contradicts them.

    The early association studies between various SNPs and various health conditions, including mental health, which are usually the basis for the claims about what SNPs mean, were almost entirely inadequate - too small with underpowered statistics. More recent extensive genome wide association studies have seen these associations disappear.

    In the case of depression, extensive GWAS saw all associations fall away - in other words, no particular genes were robustly associated with the condition. Possibly the sample sizes were still too small since the condition is so widespread, heterogeneous and the heritability component is small. See this discussion.

    I believe some very recent studies have found some robust candidates, but these are not the simplistic SNPs that Yasko and others make claims for.

    There might be a genetic component to your life long depression but the studies revealing what that might be are only just appearing.

    Here and here are two recent reports. I haven't looked in any detail but on the surface they don't appear to have identified the same things. A lot more work is needed. And remember the heritability component is small.
     
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  12. ellecognito

    ellecognito

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  13. alicec

    alicec Senior Member

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    I could write a better article but I don't have the energy nor the motivation to do the research about what recent robust GWAS have found about MAO A - ie what disease associations are likely to be real, nor about any recent robust studies of genetic linkage to MAO A protein activity and the consequence.

    Nor could I comment about treatment since, as far as I know, there are only two well established polymorphisms with consequences - viz the promoter repeat polymorphism which I mentioned above, and the one which leads to Brunner syndrome. The former appears to mediate a complex interaction between environment and gene to exert an effect, while the latter, in which a truncated non-functional protein is produced, results in aggressive behaviour and mental retardation in males.

    I am not qualified to comment about treatment for such complex conditions.

    I can make some general comments about MAO A SNPs and some of the inadequacies in the Cohen article.

    First I would draw peoples attention to the OMIM entry which explains that only the two MAO A variants I noted above have been robustly shown to be pathogenic.

    Then I would point out that R297R doesn't need treating.

    The people asking about treatment for this SNP have been mislead by the claims by Yasko, endlessly repeated on the internet with no basis whatsoever. They have fallen for the notion that because a variant is identified, something must be done about it. This may sell supplements but it has no basis in reality.

    I would explain that this variant doesn't do anything. The name gives it away. The arginine (abbreviated as R) at position 297 in the protein remains as arginine. This variant does NOT produce a slow form of the enzyme as is claimed, it produces a protein identical to the one produced by the ancestral gene.

    I would go into explanations about other possible reasons for such a synonymous variant exerting an effect. For example the nucleotide change could lead to an unstable mRNA which could result in less protein being produced (NOT a slower form of the protein). This has been described for some SNPs but not in isolation. Usually it is the presence of several such SNPs close together in the secondary structure which destabilised the mRNA.

    There is no evidence that this applies to this SNP so I can find no basis for Cohen's claim that this variant produces less enzyme, nor does he give any reference for the claim.

    Alternatively the SNP could be acting as a proxy for something else and the latter is really exerting the effect. I did once try to chase down this possibility but I came up with nothing.

    I would explain that R297R is not the warrior gene by first explaining about the repeat motif in the promoter that does define this gene, as in my earlier post. Cohen doesn't explain this at all and one is left wondering what 2R, 3R etc refer to. Furthermore I would emphasise that an environmental interaction was necessary for the low repeat variant to exert its effect. There appears to be an epigenetic component.

    Regarding Cohen's discussion of SNPs which are proxies for the promoter repeats, I have read the references he linked. Although he appears to give a lot of references actually most of them are for a single article - there are only two references.

    These don't say what he says they say. The one which he uses over and over again is actually just an association study between various SNPs and anger expression in suicide vs non-suicide attemptors and in succeeders. It has nothing to do with the promoter polymorphism. It is a very small study, much too small to be definitive.

    The other study is interesting, a bit complicated, trying to look at epigentic and genetic factors involved in mRNA expression. It does define some haplotypes which include the promoter repeat but it most definitely does not say the the three SNPs he lists define the 5R version.

    He gives no reference for his opening statement that rs909525 is the best proxy for the number of repeats in the promoter. I looked at the references linked by dsSNP to this SNP and can't find anything and I don't have the energy or the interest to follow this up further. Even if we take Cohen at face value it is only an association, something that is more likely. Association studies are notoriously poor so I would definitely need to see this study before I gave it any credence, but as I said I can't find it.

    At this point in the article I pretty much gave up. I thought his evidence was poor and his explanations were either wrong, dubious or incomprehensible.
     
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