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Genome - Epigenome Interactions Associated with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, 2017, McGowan et al

Discussion in 'BioMedical ME/CFS Research' started by Andy, Dec 23, 2017.

  1. Andy

    Andy Committee Member

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    Hampshire, UK
    Full text pre-print in PDF form - https://www.biorxiv.org/content/biorxiv/early/2017/12/22/237958.full.pdf
  2. Valentijn

    Valentijn Not a moderator

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    Not a convincing study, but perhaps a starting point. The number of subjects was very low (61 patients, 48 controls) for a genetic study, with millions of comparisons being made between SNPs and genetic expression. And then 10 were completely excluded for genetic reasons (too closely related, too different in ethnic background, technical issues with missing results, etc).

    They also then did a (post-hoc?) re-analysis which excluded an additional 18 patients and 12 controls who had some overlap in health scores, for a total of 39 patients and 30 controls. Emotional well-being scores tend to be fairly normal for ME/CFS patients, so they may have turned a small difference into a much larger one by including it as a criteria for excluding patients if their scores were too normal. It could have the effect of primarily selecting for mood disorder in the re-analysis, in preference over ME/CFS symptoms or diagnosis:
    Lymphocyte proportions were normal:
    In the original analysis, they did correct for making millions of comparisons and did not find any associations. But the study probably didn't have enough participants to find an association anyhow:
    They then repeated the analysis with only female patients and controls, and rs11712777 came up as barely being significant. This is likely a fluke, however, since even the minor allele is pretty common (up to 39% MAF in Europeans), and the SNP is not on a gene, and quite far from any genes (40,000-60,000 SNPs). One of the closer genes is CCK, a receptor for which is associated with sickness behavior, and there are SNPs which rs11712777 is in strong linkage disequilibrium with (people often inherit the two SNPs together) and can impact gene function somewhat. But there's no explanation for the apparent lack of significant difference between patients and controls on the linked SNPs.

    It sounds like there weren't any significant epigenetic results, after corrections for multiple comparisons were applied, though there were 100+ prior to corrections being made. It is a bit interesting that some of the uncorrected results were in line with previous results (assuming different patients were used):
    So it looks like this is a null result under the proper analysis, but it was too underpowered to find much that way. The uncorrected secondary analyses found some differences, but many or all of those results are likely to be false positives due to comparing so many variables. I don't think anything can be concluded from this study, but it could serve as a starting point for more focused analysis in small samples. Given the lack of power resulting from the low number of participants, I wish they'd used this study to verify their earlier work by focusing on a very small number of earlier identified SNPs and/or gene products, rather than going on another fishing expedition which also now needs replication.
    Last edited: Dec 23, 2017
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