Scientists at the University of East Anglia and British biotech firm Oxford BioDynamics compared genetic data from five seemingly different illnesses: long Covid, ME/CFS (also known as chronic fatigue syndrome), post-traumatic stress disorder, rheumatoid arthritis and multiple sclerosis. They found almost no genes in common between them. But the genes linked to each of the five conditions feed into the same wider network, one that controls the immune system and how cells produce energy. The study, published in the Journal of Translational Medicine, does not prove the five diseases share a single cause. It points to a possible direction for future blood tests, one that still needs checking in larger groups of patients.
DNA folding and the key genes LAG3 and mTOR
Instead of reading DNA as a straight line of letters, the scientists used a platform made by Oxford BioDynamics called EpiSwitch Orion, which tracks how DNA folds inside a cell. When the strand folds, sections that sit far apart in the straight sequence end up touching each other, and at these contact points genes switch on and off. The team took already published data from large genetic studies on long Covid, PTSD, rheumatoid arthritis and multiple sclerosis, and compared it with earlier 3D genetic data on ME/CFS. No new patients were examined; the whole analysis ran on a computer, using data already collected.
The gene lists varied widely in length: from 885 for rheumatoid arthritis to just 324 for PTSD, while ME/CFS and long Covid each had around 570. On their own, these genes barely overlapped. But mapped as a network of connections, the picture changes, says the study's lead author, Professor Dmitry Pshezhetskiy from the university's medical school: "Suddenly the diseases turned out to be deeply connected. That's not something you can see just by reading the genetic sequence." He says chronic exhaustion looks like the visible result of a deeper breakdown in the body's immune, metabolic and stress-response systems, rather than a stand-alone symptom.
The most connected "hub" genes in the network include LAG3, which immunologists link to T-cell exhaustion, when immune cells stop responding normally after being overworked for too long, as well as parts of the mTOR pathway, which controls cell growth and energy use. Other well-connected genes include RUNX1; PPARGC1A, which drives energy production in mitochondria, the cell's "power plants"; CDH2, which helps nerve cells connect to each other; NRP1; and PLCG2. A coronavirus infection can trigger a long-running state of immune alert, while severe stress can throw the body's hormonal and inflammatory pathways out of balance, Pshezhetskiy says. But both routes lead to the same circuits that control energy, immunity and how resilient cells are.
Clinically, the five conditions have more in common than their names suggest. Patients with long Covid, ME/CFS, PTSD, rheumatoid arthritis and multiple sclerosis often describe the same complaints: severe fatigue, brain fog, poor concentration, disrupted sleep, and problems with the autonomic nervous system, which controls heart rate, blood pressure and digestion without a person thinking about it. It was this overlap in symptoms that pushed the team to look for a shared biological basis behind the separate diagnoses.
A study funded by Oxford BioDynamics
The authors and outside experts warn against jumping to conclusions. The UK's ME Association says the analysis is "largely computational, based on statistical overlaps," and does not prove these biological pathways cause the diseases, only that they appear to be linked. The patient groups behind each diagnosis are very different sizes: the multiple sclerosis data comes from about 21,500 people, while the PTSD data draws on more than 1.2 million, from different sources, which makes a direct comparison risky. None of the data sets were chosen based on how severe the fatigue was or how long it had lasted, and the researchers did not run a separate statistical test to check whether the overlap between the networks could simply be down to chance.
Oxford BioDynamics itself funded the study, and also owns the EpiSwitch Orion platform. Eleven of the fourteen authors work full-time at the company. The firm already sells a blood test for ME/CFS which it says identifies the disease with 96% accuracy, and the new study raises the question of whether a similar test could cover the other four conditions too. As for whether the most connected genes actually do something in a patient's body, or just look well-connected on paper, the authors admit they cannot yet say.
The researchers also point to what should come next: measuring the levels of these genes in blood taken directly from people with each of the five conditions, and selecting patients based on how severe their fatigue is, rather than just the diagnosis written in their medical records.