Researchers at the University of East Anglia have identified shared biological mechanisms that may help explain chronic exhaustion in conditions including long Covid and PTSD. A new paper published in the Journal of Translational Medicine reveals biological similarities between five major illnesses long viewed as separate disorders: chronic fatigue syndrome (also known as ME), long Covid, post-traumatic stress disorder, rheumatoid arthritis, and multiple sclerosis. The findings suggest these conditions may share common underlying mechanisms, despite being triggered by different events ranging from viral infections to psychological trauma or autoimmune responses.
According to lead researcher Dmitry Pshezhetskiy, “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.” He noted that patients across all five conditions “frequently report remarkably similar symptoms—overwhelming fatigue, brain fog, poor concentration, disturbed sleep, autonomic dysfunction and a dramatic reduction in everyday functioning.” As he put it: “What we discovered is something approaching a biological unifying theory of fatigue.”
Rather than analyzing DNA sequences directly, researchers used a computational method that examines the three-dimensional architecture of the genome—how DNA folds inside living cells, bringing regions that sit far apart in the linear sequence into contact at points where gene activity is controlled. Published genomic data for long Covid, PTSD, rheumatoid arthritis, and multiple sclerosis, drawn from existing genome-wide association studies, were combined computationally with 3D genomic data from an earlier ME/CFS patient study, without collecting new patient samples. Applied to the five conditions, the analysis found that genetic changes with little in common connected into the same regulatory circuitry.
“We expected to find at least some overlap in genes across the conditions. But we actually found the opposite,” Pshezhetskiy said. “But when we 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.”
The study found 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. The team also identified “hub genes” sitting at the busiest points within these shared networks, including genes involved in immune regulation and mitochondrial energy production—candidates the authors say require further work to confirm. One part of the analysis focused on ME/CFS flagged LAG3, a gene associated with T-cell exhaustion.
“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,” Pshezhetskiy said. ME/CFS and long Covid are currently diagnosed largely through symptoms, with no universally accepted laboratory test available, leaving many patients facing years of uncertainty. Earlier work using this same genomic approach had already produced a blood-based ME/CFS test promising high diagnostic accuracy, though further validation is needed before clinical use; the new findings raise the prospect of shared biological signatures across several conditions, not only ME/CFS.
“Rather than viewing long Covid, ME/CFS, PTSD, rheumatoid arthritis, and multiple sclerosis as entirely separate disorders, we now think they may be different manifestations of disturbed biological networks operating throughout the body,” Pshezhetskiy said. “This study offers a framework for understanding how different triggers can converge to cause the exact same profound clinical exhaustion.”
According to lead researcher Dmitry Pshezhetskiy, “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.” He noted that patients across all five conditions “frequently report remarkably similar symptoms—overwhelming fatigue, brain fog, poor concentration, disturbed sleep, autonomic dysfunction and a dramatic reduction in everyday functioning.” As he put it: “What we discovered is something approaching a biological unifying theory of fatigue.”
Rather than analyzing DNA sequences directly, researchers used a computational method that examines the three-dimensional architecture of the genome—how DNA folds inside living cells, bringing regions that sit far apart in the linear sequence into contact at points where gene activity is controlled. Published genomic data for long Covid, PTSD, rheumatoid arthritis, and multiple sclerosis, drawn from existing genome-wide association studies, were combined computationally with 3D genomic data from an earlier ME/CFS patient study, without collecting new patient samples. Applied to the five conditions, the analysis found that genetic changes with little in common connected into the same regulatory circuitry.
“We expected to find at least some overlap in genes across the conditions. But we actually found the opposite,” Pshezhetskiy said. “But when we 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.”
The study found 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. The team also identified “hub genes” sitting at the busiest points within these shared networks, including genes involved in immune regulation and mitochondrial energy production—candidates the authors say require further work to confirm. One part of the analysis focused on ME/CFS flagged LAG3, a gene associated with T-cell exhaustion.
“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,” Pshezhetskiy said. ME/CFS and long Covid are currently diagnosed largely through symptoms, with no universally accepted laboratory test available, leaving many patients facing years of uncertainty. Earlier work using this same genomic approach had already produced a blood-based ME/CFS test promising high diagnostic accuracy, though further validation is needed before clinical use; the new findings raise the prospect of shared biological signatures across several conditions, not only ME/CFS.
“Rather than viewing long Covid, ME/CFS, PTSD, rheumatoid arthritis, and multiple sclerosis as entirely separate disorders, we now think they may be different manifestations of disturbed biological networks operating throughout the body,” Pshezhetskiy said. “This study offers a framework for understanding how different triggers can converge to cause the exact same profound clinical exhaustion.”
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