A new study by researchers at the University of East Anglia (UEA), Oxford BioDynamics, and other institutions suggests that the severe fatigue associated with several very different diseases may be attributable, in part, to common biological regulatory processes.
The study examined ME/CFS, Long COVID, post-traumatic stress disorder (PTSD), rheumatoid arthritis, and multiple sclerosis. Although these conditions have different causes and clinical presentations, they sometimes share similar symptoms—including severe fatigue, cognitive impairments, sleep problems, and disorders of the autonomic nervous system. The study was published inthe Journal of Translational Medicine.
Not the Same Genes – But the Same Networks
A distinctive feature of the study is that the scientists did not focus exclusively on identifying which individual genes are involved in the five conditions. Instead, they examined the three-dimensional organization of the genome. DNA in our cells does not simply exist as a straight chain but is spatially folded. As a result, regions of the genome that are far apart in the DNA sequence can come into contact with one another and jointly influence which genes are active.
For this analysis, the researchers used the EpiSwitch Orion platform from Oxford BioDynamics. They combined existing genome-wide association data on Long COVID, PTSD, rheumatoid arthritis, and MS with 3D genomic data from a previous ME/CFS study.
This revealed an interesting pattern: At the level of individual genes, there was only minimal direct overlap between the conditions. However, when the researchers examined the biological networks in which these genes interact, significantly more commonalities became apparent.
Focus on the Immune System, Energy Metabolism, and Metabolism
Among other things, the shared networks were linked to several fundamental processes.
These included:
- regulation of the immune system,
- inflammatory and cytokine signaling,
- mitochondrial function and, consequently, cellular energy production,
- metabolic processes,
- stress responses,
- neuroendocrine signaling pathways.
This suggests a possible biological model for how different triggers could lead to similar symptoms. An infection such as SARS-CoV-2, prolonged immune activation, or a traumatic experience are, at first glance, completely different events. However, if they affect certain regulatory systems, this could result in partially similar changes in the networks that link immune function, metabolism, stress response, and energy supply.
So far, however, this remains a biological hypothesis and does not constitute proof that the same mechanism is at work in all five diseases. The authors themselves consider further research to be necessary.
A Gene Called LAG3 is Coming into Focus in ME/CFS
Of particular interest is the part of the analysis that focused on ME/CFS. Among other findings, the researchers identified LAG3 as a potential candidate for further investigation. The gene plays an important role in regulating T cells, which are involved in controlling the immune response.
LAG3 is one of the so-called immune checkpoints. These regulate the activity of immune cells and prevent an immune response from spiraling out of control. If activation persists for a long time, T cells can reach a state known as T-cell exhaustion. This alters their function and their ability to respond to certain signals.
This connection is of interest in the context of ME/CFS because a persistent alteration in immune regulation is one of the possible mechanisms currently being investigated. However, the current study does not yet demonstrate that LAG3 is the cause of ME/CFS. Rather, the analysis suggests that this signaling pathway should be investigated more closely in relation to the disease.
Should future studies confirm this link, LAG3 could help us better understand why changes in the immune system persist over the long term in some people with the condition.
Why the Findings Could be Relevant for Diagnosis
Another area of interest concerns the development of objective biomarkers. For ME/CFS, there is currently no generally accepted laboratory test that can reliably diagnose the condition based solely on a blood sample. Similarly, for Long COVID, there is no single, universally accepted diagnostic laboratory marker. The diagnosis therefore relies primarily on medical history, symptoms, and clinical examination.
The researchers hope that characteristic biological patterns could help identify such diseases more objectively in the future. Previous studies using EpiSwitch technology have already investigated a potential blood-based biomarker for ME/CFS. However, this biomarker must undergo further validation before it can become a clinically established test.
From a shared biology to a shared treatment?
The question of new treatment options lies even further in the future. Should future studies confirm that certain regulatory networks do indeed play a central role in multiple diseases, these networks could potentially provide new targets for drugs or other therapies.
This would be particularly interesting because the existing disease categories have very different causes. A common biological mechanism could explain why some symptoms look so similar despite having different triggers.
However, researchers are still a long way from developing such a common therapy. The current study primarily identifies connections within biological networks. It does not show that the signaling pathways identified are the cause of the diseases or that specifically targeting these processes would alleviate the symptoms.
A New Perspective on Chronic Fatigue
The study offers a new perspective on why chronic fatigue can manifest in such similar ways across different diseases. The key factor here does not necessarily appear to be that the same individual genes are altered. Rather, different genetic alterations could affect shared biological networks.
The focus is on several closely interconnected systems: immune system regulation, inflammatory processes, cellular metabolism, mitochondrial energy production, and stress and neuroendocrine signaling pathways. If such networks are disrupted by various triggers, this could result in symptoms that are, in part, similar—such as severe fatigue, difficulty concentrating, and reduced resilience.
This approach is particularly interesting for ME/CFS and Long COVID. It could explain why different triggers—such as an infection or other physical stresses—can lead to similar biological changes over the long term. At the same time, the study makes it clear that chronic fatigue likely cannot be reduced to a single mechanism.
However, the results should initially be understood as an indication of possible common biological connections. The researchers analyzed existing genomic data and data on the spatial organization of DNA. This does not yet prove that the identified networks are the cause of the diseases or directly responsible for the symptoms. Further studies must therefore determine whether the biological patterns found can be directly confirmed in affected patients and whether they are associated with specific disease courses or symptoms. Only then will it become clear whether these findings could lead to new diagnostic markers or, in the long term, therapeutic approaches.