Exploring a genetic basis for the metabolic perturbations in ME/CFS using UK biobank
Katherine Huang1, Muhammad Muneeb2, Natalie Thomas1
1Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, VIC 3052, Australia.
Iscience
|January 15, 2026
Summary
Genetic factors influence Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) by affecting metabolic processes. This study reveals specific genetic links to lipid metabolism, offering insights into disease heterogeneity and potential polygenic predisposition.
Area of Science:
- Genetics
- Metabolomics
- Immunology
Background:
- Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex, heterogeneous disease with no approved treatments.
- Understanding the genetic underpinnings of ME/CFS is crucial for identifying disease mechanisms and therapeutic targets.
Purpose of the Study:
- To investigate genetic susceptibility toward specific metabolic phenotypes in ME/CFS using a genome-wide association study (GWAS) of plasma biomarkers.
- To identify genetic variants associated with metabolic traits and explore their differential effects in ME/CFS patients compared to healthy controls.
Main Methods:
- Performed a genome-wide association study (GWAS) on plasma biomarker levels in 875 ME/CFS patients and 36,033 healthy controls (HCs).
- Analyzed single nucleotide polymorphism (SNP)-biomarker associations, focusing on lipid traits and immune-related genes.
- Utilized enrichment analysis on ME/CFS GWAS summary statistics to identify affected metabolic pathways.
Main Results:
- Identified 112 significant SNP-biomarker associations specific to ME/CFS.
- Discovered two ME/CFS-specific SNPs linked to phospholipids and total fatty acids, involving very low-density lipoproteins (VLDLs).
- Found differential genetic effects on lipid traits at immune-related genes (ADAP1, NR1H3, CD40) and highlighted pathways in lipid metabolism, neurotransmitter transport, and inflammation.
Conclusions:
- The findings suggest a polygenic predisposition for ME/CFS, where numerous small-effect genetic variants collectively impact metabolic mechanisms.
- These results provide a genetic and molecular basis for the observed patient heterogeneity in ME/CFS.
- The study underscores the role of metabolic dysregulation, particularly in lipid pathways, in the pathophysiology of ME/CFS.
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