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Gene Set Analysis

I aimed to run a MAGMA-based1 competitive gene set analysis of DecodeME, but suspected that DecodeME would have insufficient statistical power for a fully-unbiased hypothesis-free study. Therefore, I curated a list of about 50 gene sets from MSigDB selected according to current leading theories of the pathogenesis of ME/CFS. The list of curated gene sets can be found here.

The results of MAGMA analysis using these curated gene sets are plotted below:

Disappointingly, none of the gene sets meet the Bonferroni-corrected significance threshold. It is interesting to observe the T-cell receptor signalling gene set is the closest to being significant. This is consistent with T-cell-centric theories of ME/CFS pathogenesis2.

A reasonable next step might be to boost statistical power by pooling multiple studies. Methods like GenomicSEM3 could be used to combine DecodeME both with biobank GWAS of ME/CFS and with distinct but genetically correlated conditions (e.g. multisite pain4).

  1. Christiaan A De Leeuw, Joris M Mooij, Tom Heskes, and Danielle Posthuma. MAGMA: generalized gene-set analysis of GWAS data. PLoS Computational Biology, 11(4):e1004219, 2015. URL: https://journals.plos.org/ploscompbiol/article?id=10.1371/journal.pcbi.1004219. ↩

  2. Jonathan Edwards, Geraldine Cambridge, and Jacqueline M Cliff. A proposed mechanism for ME/CFS invoking macrophage FcγRI and interferon gamma. Qeios, 2025. URL: https://meassociation.org.uk/wp-content/uploads/2025/05/Proposed-Mechanism-for-MECFS-Invoking-Macrophage-Fc%CE%B3RI-and-Interferon-GammaEdwards-et-al-2025.pdf. ↩

  3. Andrew D Grotzinger, Mijke Rhemtulla, Ronald de Vlaming, Stuart J Ritchie, Travis T Mallard, W David Hill, Hill F Ip, Riccardo E Marioni, Andrew M McIntosh, Ian J Deary, and others. Genomic structural equation modelling provides insights into the multivariate genetic architecture of complex traits. Nature Human Behaviour, 3(5):513–525, 2019. URL: https://pmc.ncbi.nlm.nih.gov/articles/PMC6520146/. ↩

  4. Keira JA Johnston, Mark J Adams, Barbara I Nicholl, Joey Ward, Rona J Strawbridge, Amy Ferguson, Andrew M McIntosh, Mark ES Bailey, and Daniel J Smith. Genome-wide association study of multisite chronic pain in UK Biobank. PLoS Genetics, 15(6):e1008164, 2019. URL: https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1008164. ↩