The power and pitfalls of omics part 2: epigenomics, transcriptomics and ME/CFS
Simon McGrath concludes his blog about the remarkable Prof George Davey Smith's smart ideas for understanding diseases, which may soon be applied to ME/CFS.
Discuss the article on the Forums.

Genome-wide association analysis identifies genetic variations in subjects with ME/CFS

Discussion in 'Latest ME/CFS Research' started by voner, Feb 10, 2016.

  1. voner

    voner Senior Member

    Messages:
    540
    Likes:
    846
    This is an open acess paper. interesting collaboration of authors. 42 ME/CFS patients and 38 controls ... published in the journal, "Translational Psychiatry".

    http://www.nature.com/tp/journal/v6/n2/pdf/tp2015208a.pdf

    Genome-wide association analysis identifies genetic variations

    in subjects with myalgic encephalomyelitis/chronic fatigue

    syndrome


    authors:
    K A Schlauch1, S F Khaiboullina2,3, K L De Meirleir2, S Rawat2, J Petereit1, A A Rizvanov3, N Blatt3, T Mijatovic4, D Kulick5, A Palotás3,6 and V C Lombardi1,2

    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.
     
    serg1942, Ritto, sue la-la and 12 others like this.
  2. msf

    msf Senior Member

    Messages:
    3,188
    Likes:
    4,454
    I´ve been waiting for this one for a while, particularly as I am one of the patients in the study (well, I gave my blood for it anyway!).
     
    serg1942, AndyPandy, Ritto and 5 others like this.
  3. Asa

    Asa Senior Member

    Messages:
    175
    Likes:
    526
    Could someone, please, "dumb-down" this info for me? Thank you!
     
    TiredSam and John Mac like this.
  4. msf

    msf Senior Member

    Messages:
    3,188
    Likes:
    4,454
    They seem to have found some mutations in genes in some people with ME that are not present in controls. Some of these mutations are in the T-cell receptor genes, another is in another part of the immune system, and there are some with possible neurological implications too (one of these is similar to a previous finding by a different group).
     
    Asa, Ritto, jadam914 and 6 others like this.
  5. Helen

    Helen Senior Member

    Messages:
    2,066
    Likes:
    3,186
    As far as I can see only four of the significant twenty-three SNP´s listed on page 4 in the article were analyzed in the 23andme test ( the version used 2011) if you would like to check your own data.

    rs6757577 KRT18P33

    rs41378447 CASC14

    rs7849492 --

    rs2249954 FBLN5
     
    Last edited: Feb 10, 2016
    cigana, helen1, ahmo and 1 other person like this.
  6. Valentijn

    Valentijn Senior Member

    Messages:
    14,281
    Likes:
    45,811
    The rs479448 missense mutation on CLEC4M is the one that looks the most interesting. The mutation scores -2 on the BLOSUM62 scale, which means there's a pretty big difference in the substituted amino acid. And CLEC4M is a gene involved in the innate immune system.

    Data from the study shows 2.6% MAF for controls and 26.2% for the ME/CFS patients.
     
    MeSci, sue la-la, ukxmrv and 3 others like this.
  7. Helen

    Helen Senior Member

    Messages:
    2,066
    Likes:
    3,186
    Could it be that the studied patients were more carefully diagnosed than those you have data on, or are they all diagnosed by a ME/CFS specialist?
     
  8. Valentijn

    Valentijn Senior Member

    Messages:
    14,281
    Likes:
    45,811
    No, I made an error in searching my excel data sheet, and a very similar number (extra 8 on the end) led me astray. It's not actually tested on 23andMe, so I edited my post.
     
    Helen likes this.
  9. ahmo

    ahmo Senior Member

    Messages:
    4,340
    Likes:
    6,526
    Northcoast NSW, Australia
    I'm homozygous for 3 of these 4.
     
    MeSci likes this.
  10. merylg

    merylg Senior Member

    Messages:
    824
    Likes:
    637
    Sydney, NSW, Australia
    I have one copy of the minor allele C for rs2249954 FBLN5. I am CT.
    FBLN5 is interesting.

    http://ghr.nlm.nih.gov/gene/FBLN5

    I was actually considering taking part in a research study into Cutis Laxa but on enquiry I thought myself not well enough to complete all the required testing. Others may be interested.

    http://cutislaxa.pitt.edu/
     
  11. GreyOwl

    GreyOwl Dx: strong belief system, avoidance, hypervigilant

    Messages:
    258
    Likes:
    905
    None of those SNPs are in my results (tested in early 2015).
     
  12. roller

    roller wiggle jiggle

    Messages:
    451
    Likes:
    215
    not that some decimal point...
     
  13. Helen

    Helen Senior Member

    Messages:
    2,066
    Likes:
    3,186
    In my opinion this study deserves a lot more of attention from PWME. I think it mediates hope and future treatment possibilities.

    Surprisingly a study that indicates genetics as a cause of ME/CFS was published in a well-reputed journal of psychiatry. It´s time for the psychobabblers to change side; ME/CFS IS a disease or a syndrome of physical origin.
    From the Journal of Translational Psychiatry
    http://www.nature.com/tp/journal/v6/n2/full/tp2015208a.html
    http://www.nature.com/tp/journal/v6/n2/suppinfo/tp2015208s1.html

    From the abstract- to start with:

    "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."

    "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." (My bolding)

    I think we could learn a lot by looking thorough at the 23 significant SNP´s (page 4) and how they can affect us. We might find explanations to our disparate symptoms while waiting for more research and a possibility to get the actual genes, or SNP´s, tested.
     
    Sushi, sue la-la, ballard and 2 others like this.
  14. Helen

    Helen Senior Member

    Messages:
    2,066
    Likes:
    3,186
    @voner , I ask you as a TS, could we save this thread for discussions about the research and create another thread for sharing our own data as far as they are known? No blame on you who already have shared yours.
     
    Last edited: Feb 12, 2016
  15. Valentijn

    Valentijn Senior Member

    Messages:
    14,281
    Likes:
    45,811
    It's not quite that simple, unfortunately. The first problem is that there's probably been a dozen or more studies involving SNPs in ME/CFS, and there's no consistent results. It's likely that they are not including the same set of SNPs in different studies, but they need to be replicated before they'll be taken seriously.

    The other problem is that false positives are a pretty huge problem in genetic studies. For example, most of the "significant" results in this study involve SNPs which aren't even resulting in missense mutations. Even when correcting for multiple comparisons, there still seems to be a lot of positive results which don't hold up.

    Correlations found in those non-coding SNPs also tend to have a very small effect size, meaning they aren't very relevant. So many healthy people will have the "risk" genotype for those SNPs, and many (most) patients probably won't have those "risk" genotypes.

    The final problem is that similar SNP correlations are frequently found for supposed mental disorders. While it would possible suggest a genetic/biological underlying mechanism (if they results hold up consistently), it has done nothing at all to change the perception or treatment of those disorders. People don't just suddenly say "Oh, I guess it's not your fault for being (supposedly) weak-minded after all, here's a higher rate of disability payments which won't expire after two years." They're still expected to fix themselves with the prescribed counseling and psychotropic drugs.

    If a genetic finding is going to be an impressive breakthrough for any disease, it won't be due to someone finding dozens of non-coding SNPs which are weakly correlated with a tiny increase of risk in developing a disease. It'll be from missense mutations, nonsense mutations, splicing errors, or similar drastic mutations which fundamentally alter how a gene (or a group of genes) functions.

    To some extent, I think these typical SNP comparison studies are not suitable for finding such drastic changes. When pathological mutations are found in other diseases, it's not like 100% of those patients have the same mutation. Some mutations may be more common in causing that particular disease, but there also may be 20+ mutations on the gene which cause the disease (often presenting with different features and severity), with just a few patients having each mutation. And then there may be more genes, with more mutations, which also cause the same disease.

    In that case, significance may be artificially lost, because none of the actually relevant individual mutations are prevalent enough in the patients to be statistically significant, even if none of the controls have those same mutations.

    So I think genetic studies need to take a much more systematic approach, by focusing on the historically more relevant sections of DNA, such as exons and splice sites. It can also focus more specifically on genes likely to be relevant, such as those in the immune system, since genetic differences in the immune system could conceivable cause problems in a lot of other systems, whereas it's harder to imagine how genetic flaws with the nervous system or muscular system might cause problems with the immune system.
     
    Last edited: Feb 12, 2016
    Simon, sue la-la, Sea and 1 other person like this.
  16. msf

    msf Senior Member

    Messages:
    3,188
    Likes:
    4,454
    They found some missense mutations in the study, and one was in a gene related to the immune system.
     
  17. Valentijn

    Valentijn Senior Member

    Messages:
    14,281
    Likes:
    45,811
    12 coding mutations, and 430 non-coding :p It doesn't inspire a lot of faith.
     
  18. msf

    msf Senior Member

    Messages:
    3,188
    Likes:
    4,454
    From the study:

    Twelve of the 442 candidate SNPs associated with the ME/CFS
    cohort were identi*ed in the coding region (exon) of their
    respective gene: *ve of these were synonymous substitutions
    (rs16973831, rs2274515, rs3732196, rs7613828 and rs17722227),
    two were missense substitutions (rs2015035 and rs479448) and
    the remainder were within T-cell receptor or immunoglobulin loci.
    With respect to the missense substitutions, the observed SNP in
    the gene CCDC157 (rs2015035), which codes for the coiled-coil
    domain-containing 157 protein, results in a non-conservative
    substitution of the amino acid Serine (S) to Alanine (A). The SNP in
    the coding region of the CLEC4M gene, which codes for the C-type
    lectin domain family 4, member M, results in a non-conservative
    substitution of the amino acid tyrosine (Y) to cysteine (C). Whereas
    the function of CCDC157 has not been fully characterized, coiledcoil
    domains are common motifs and function as oligomerization
    domains for a wide range of proteins such as structural proteins,
    motor proteins and transcription factors.
    43
    CLEC4M, also know as
    L-SIGN or CD299, is a mannose-binding C-type lectin receptor, a
    component of the innate immune system that recognizes a broad
    range of pathogens.
     
  19. msf

    msf Senior Member

    Messages:
    3,188
    Likes:
    4,454
    Well, the way I see it is one is better than none. Did you want them to find all the genetic contributions to ME in a single study? They seem to have found more than the last group to attempt this, and also made a similar finding with a GRIK gene:

    Two SNPs were identi*ed in the GRIK2 gene, which codes
    for an excitatory neurotransmitter receptor that is primarily
    expressed in the brain. A number of neurological maladies,
    including autism and schizophrenia, are associated with GRIK2.
    The second identi*ed SNP lies in the NPAS2 gene, which is a
    putative circadian clock gene. Although the two SNPs identi*ed
    for GRIK2 in the Smith et al. study were not represented on the
    SNP Array 6.0, an ortholog of this gene (GRIK3) was observed to
    signi*cantly associate with our ME/CFS cohort. Both GRIK2 and
    GRIK3 code for transmembrane subunits of neuroexcitatory
    receptors, belonging to the kainate family of glutamate receptors.
    These receptors are composed of four subunits and function as
    ligand-activated ion channels on presynaptic and postsynaptic
    neurons.
     
  20. Helen

    Helen Senior Member

    Messages:
    2,066
    Likes:
    3,186
    @Valentijn , apparently I have more trust in our doctor, KDM. Do I get you right that you dismiss this study, or is there anything of value in it, in your opinion?
     

See more popular forum discussions.

Share This Page