Five major fatigue-causing illnesses share a common biological basis, new research suggests
For millions of people worldwide, chronic fatigue is not merely tiredness. It is a debilitating condition that can make everyday tasks feel impossible. New research from the University of East Anglia (UEA) and Oxford BioDynamics suggests that five major illnesses that cause persistent exhaustion, including chronic fatigue syndrome (CFS/ME), long COVID, PTSD, rheumatoid arthritis, and multiple sclerosis, may share a common biological foundation.
The study, published in the Journal of Translational Medicine, analyzed genetic data from thousands of patients across these five conditions. While each illness has distinct triggers and pathologies, the researchers found that they converge on the same underlying biological networks, offering what they describe as a 'unifying theory of fatigue'.
What links chronic fatigue syndrome, long COVID, PTSD, rheumatoid arthritis, and MS?
Chronic fatigue syndrome, also known as myalgic encephalomyelitis (CFS/ME), is a condition with no known cause or cure. Its hallmark symptoms include extreme exhaustion, cognitive difficulties, and 'brain fog'. Long COVID emerges from viral infection, PTSD is triggered by trauma and linked to chronic inflammation, while rheumatoid arthritis and multiple sclerosis are autoimmune disorders. Despite these differences, patients often report strikingly similar experiences.
“One thing that links them all is that patients frequently report remarkably similar symptoms: overwhelming fatigue, brain fog, poor concentration, disturbed sleep, autonomic dysfunction, and a dramatic reduction in everyday functioning,” said Dmitry Pshezhetskiy, a clinician-scientist at UEA and the study's lead researcher.
How did researchers uncover the shared biology?
The team used data from genome-wide association studies (GWAS) covering thousands of cases across the five illnesses. They then applied Oxford BioDynamics' EpiSwitch® platform, a machine learning tool that examines the genome's three-dimensional architecture rather than just linear DNA sequences. This approach allowed them to see how spatially distinct genes interact, revealing connections that standard genetic analysis might miss.
“What we discovered is something approaching a biological unifying theory of fatigue,” Pshezhetskiy said.
Although there was little direct overlap in the genes associated with each condition, the researchers identified several highly influential 'hub' genes at the convergence points of shared biological networks. These genes regulate critical functions such as immune and inflammatory responses, hormonal signaling, and mitochondrial energy production, processes previously linked to ME/CFS and long COVID.
Why have these conditions appeared unrelated for so long?
Many of the identified hub genes were not standout candidates in the original GWAS data. According to Pshezhetskiy, “This is not something you can see by reading the genetic sequence alone, which is why these conditions may have looked unrelated for so long.”
The study also highlighted immune cell exhaustion as a central mechanism potentially connecting the five conditions. The researchers describe a state of chronic immune activation followed by functional exhaustion, which may contribute to persistent symptoms.
What could this mean for diagnosis and treatment?
The findings, if validated, could lead to objective blood tests for conditions like CFS/ME and long COVID, reducing reliance on patient-reported symptoms. “We hope our work could pave the way for objective blood tests capable of identifying underlying biological signatures rather than relying solely on patient-reported symptoms,” Pshezhetskiy said.
Future therapies might aim to calm overactive immune cells or boost mitochondrial energy production to combat fatigue. The research also encourages a broader perspective on chronic exhaustion as a symptom of deeper systemic dysfunction.
“In that scenario, chronic exhaustion is not simply a symptom. It is the visible consequence of a deeper systems failure affecting immune function, metabolism, and stress-response pathways,” Pshezhetskiy concluded.
What are the limitations of this study?
The study relies on GWAS data, which captures only select populations and a small fraction of the functional genome. However, the EpiSwitch® platform's focus on 3D genome architecture and epigenetic modifications offers a promising avenue for understanding how environmental factors like stress and infection can have long-lasting effects on gene expression.
Further experimental and clinical validation is required to confirm the role of the identified hub genes in each illness. Nevertheless, this research provides a framework for understanding how different triggers can lead to the same profound clinical exhaustion.