Scientists uncover shared biology behind profound fatigue in five major illnesses

A shared biological mechanism that helps explain chronic exhaustion in conditions including long COVID and PTSD has been identified by researchers .
The paper, published in the Journal of Translational Medicine, reveals striking biological similarities among five major illnesses that until now have largely been viewed as separate disorders.
The findings suggest that chronic fatigue syndrome (also known as ME), long COVID, post-traumatic stress disorder (PTSD), rheumatoid arthritis and multiple sclerosis (MS) may be driven by common underlying mechanisms.

This is despite the conditions being triggered by different events—from viral infections to psychological trauma or autoimmune responses.

Until now, illnesses including long COVID, PTSD, ME/CFS, multiple sclerosis and rheumatoid arthritis were viewed as seemingly unrelated and triggered by completely different events.

ME/CFS often follows viral infection. Long COVID develops after SARS-CoV-2 infection. PTSD emerges after traumatic experiences. Rheumatoid arthritis is an autoimmune disease attacking the joints, while multiple sclerosis attacks the nervous system.

But 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.

What this new study discovered is something approaching a biological unifying theory of fatigue.

Rather than conventionally analyzing DNA sequences, researchers from UEA used Oxford BioDynamics' innovative EpiSwitch Orion platform, which examines the three-dimensional architecture of the genome, essentially studying how DNA folds and interacts inside living cells.

The analysis was computational. Published genomic data for long COVID, PTSD, rheumatoid arthritis and multiple sclerosis, drawn from existing genome-wide association studies, were combined with 3D genomic data from an earlier ME/CFS patient study, without needing to collect new patient samples.

DNA is folded in our cells, so regions far apart in the linear sequence can touch, and those contact points are where genes get controlled. Orion predicts where these contact points are likely to be.

Applied to the five conditions, Orion found that genetic changes that appeared to have little in common connected into the same regulatory circuitry.

At an individual gene level, there was surprisingly little direct overlap between long COVID, ME/CFS, PTSD, multiple sclerosis and rheumatoid arthritis.

But when the researchers analyzed how those genes interact in complex biological networks, a completely different picture emerged. Suddenly, the diseases appeared deeply connected.

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.

Although these conditions are triggered by completely different events, they may ultimately disrupt the same fundamental biological systems and produce the similarly devastating exhaustion experienced by millions worldwide.

The study found that genes linked to each illness fed into the same major biological systems—including immune and inflammatory signaling, mitochondrial energy production, metabolic regulation, stress-response mechanisms and neuroendocrine signaling.

Why trauma and viruses can produce the same symptoms
The team said the study could help explain why people who have experienced a viral infection or psychological trauma can go on to develop similar symptoms.

The scientists now think the answer may lie in shared regulatory networks embedded within the body's immune and metabolic systems.

A COVID infection may trigger prolonged immune activation. Traumatic stress may disrupt stress-hormone pathways and inflammatory responses.

But both disturbances appear capable of converging on common biological circuits controlling energy production, immune regulation and cellular resilience.

When those systems become persistently dysregulated, the result may be the profound and disabling fatigue seen across multiple disorders.

The study also highlighted several "hub genes" that sit at the busiest points within these shared networks.

Among them were genes involved in immune regulation, inflammatory signaling and mitochondrial energy production. The authors stress that these are candidates identified by the analysis, and more work is needed to confirm their role.

One part of the analysis, looking specifically at ME/CFS, flagged LAG3 as a gene to investigate. This is a molecule associated with 'T-cell exhaustion,' a state in which immune cells become worn out after prolonged activation.

The team said that if this can be confirmed in further studies, it could help explain why many patients appear to be stuck in a state of chronic illness long after the original trigger has disappeared.

This work adds to a growing body of evidence suggesting that persistent immune dysfunction may play a far larger role in chronic fatigue-related illnesses than previously recognized.

Now, the team hopes the newly identified shared biological pathways could eventually lead to broader diagnostic tools and even treatments that work across several chronic conditions.

Ewan Hunter et al, Beyond genes: EpiSwitch® and Orion platform-powered 3D genome architecture biomarkers reveal shared biology across ME/CFS, long COVID, PTSD, rheumatoid arthritis, and multiple sclerosis, Journal of Translational Medicine (2026). DOI: 10.1186/s12967-026-08874-9