Genetic variants associated with chronic fatigue syndrome predict population-level fatigue severity and actigraphic measurements.
Liu, Patrick Z, Raizen, David M, Skarke, Carsten et al. · Sleep · 2025 · DOI
Quick Summary
This study looked at whether the genetic factors that cause ME/CFS also influence fatigue levels in people without ME/CFS. Researchers compared movement patterns and body temperature rhythms in people with ME/CFS versus healthy controls, then checked if genetic variations linked to ME/CFS were also connected to fatigue in the general population. They found that people with ME/CFS showed significantly less movement and flatter daily temperature patterns, and some genetic variants associated with ME/CFS were also linked to fatigue symptoms in the broader population.
Why It Matters
Understanding whether ME/CFS shares biological mechanisms with fatigue in the general population could accelerate research into disease pathophysiology and potentially identify new therapeutic targets. This study provides evidence that some genetic factors contributing to ME/CFS also influence fatigue in otherwise healthy people, bridging basic fatigue biology with ME/CFS-specific pathology. For patients, this suggests that insights from fatigue research broadly may yield relevant treatments for ME/CFS.
Observed Findings
People with ME/CFS had significantly lower overall movement compared to controls (Cohen's d = -0.220, p = 2.42 × 10⁻¹⁵)
People with ME/CFS showed reduced activity amplitudes—i.e., less variation between active and inactive periods (Cohen's d = -0.377, p = 1.74 × 10⁻⁶)
People with ME/CFS had flattened wrist temperature rhythms, indicating dampened daily temperature cycles (Cohen's d = -0.173, p = 0.002)
Of 30 ME/CFS-associated genetic variants tested, only 1 was significantly associated with subjective fatigue in the general population
Of 30 ME/CFS-associated genetic variants tested, only 1 was significantly associated with actigraphic measurements in the general population
Inferred Conclusions
Some biological mechanisms that drive pathological fatigue in ME/CFS patients also contribute to fatigue variation in the general population
The genetic architecture of ME/CFS fatigue overlaps with but is not entirely explained by population-level fatigue biology
Understanding general fatigue mechanisms may provide insight into ME/CFS pathophysiology, though ME/CFS appears to involve additional disease-specific mechanisms
Remaining Questions
Why do most ME/CFS-associated genetic variants (27 of 30) show no association with fatigue or activity measures in the general population? What are the disease-specific mechanisms in ME/CFS beyond those shared with population fatigue?
What This Study Does Not Prove
This study does not establish that fatigue in people without ME/CFS is caused by the same mechanisms as ME/CFS, only that some genetic variants are associated with both. The limited replication of CFS-associated variants in the general population (only 1-2 of 30 variants) suggests that most CFS biology may be distinct from population fatigue. The cross-sectional design cannot determine causality or whether genetic variants directly cause activity reductions or other outcomes.
Tags
Symptom:FatigueTemperature Dysregulation
Biomarker:Gene Expression
Method Flag:PEM Not DefinedSmall SampleExploratory Only
Do the genetic variants associated with fatigue in both populations cause activity reduction directly, or do they influence intermediate factors such as mitochondrial function, immune activation, or circadian biology?
Would longitudinal or mechanistic studies of the identified overlapping variants reveal causal pathways relevant to ME/CFS treatment?
How do environmental and non-genetic factors interact with these genetic variants to produce ME/CFS versus subclinical fatigue?