Highlights:
- ME/CFS shows distinct genetic influences on metabolic regulation.
- Lipid and hormone-related pathways emerge as key areas of interest.
- Many small genetic effects may collectively disrupt metabolic resilience in ME/CFS.
Summary:
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a clinically heterogeneous disease lacking approved therapies. To assess genetic susceptibility towards a specific metabolic phenotype, we performed a genome-wide association study on plasma biomarker levels (mGWAS) in ME/CFS patients (n=875) and healthy controls (HCs) (n=36,033).
We identified 112 significant SNP–biomarker associations in ME/CFS, compared with 4,114 in HCs. Two SNPs specific to ME/CFS, mapping to HSD11B1 and SCGN, were associated to phospholipids in extra-large very low-density lipoproteins (VLDL) and total fatty acids respectively. Genetic effects of VLDL associations were among the least correlated between ME/CFS and HCs. Heterogeneity tests found differential effects for several lipid traits at ADAP1, NR1H3 and CD40, which are involved in immune regulation.
ME/CFS mGWAS summary statistics were decomposed to uncover shared genetic-metabolic patterns, where enrichment analysis highlighted pathways in lipid metabolism, neurotransmitter transport, and inflammation. These findings provide a genetic and molecular rationale for patient heterogeneity and suggest a polygenic predisposition in which many small-effect variants may jointly perturb metabolic mechanisms.
Source: Katherine Huang, Muhammad Muneeb, Natalie Thomas, Elena K. Schneider-Futschik, Paul R. Gooley, David B. Ascher, Christopher W. Armstrong. Exploring a genetic basis for the metabolic perturbations in ME/CFS using UK Biobank. iScience, 2025, 114316 ISSN 2589-0042, https://doi.org/10.1016/j.isci.2025.114316. https://www.sciencedirect.com/science/article/pii/S2589004225025775 (Full text available as PDF file)