Study Finds Shared Biological Networks Across Five Fatigue-Linked Illnesses

The study examined five clinically different conditions: myalgic encephalomyelitis/chronic fatigue syndrome, often called ME/CFS; long COVID; post-traumatic stress disorder, or PTSD; rheumatoid arthritis; and multiple sclerosis.

The authors focused on symptoms that can overlap across these conditions, including persistent fatigue, cognitive impairment, autonomic dysfunction and immune dysregulation. Cognitive impairment means difficulties with thinking or concentration. Autonomic dysfunction refers to problems in the body systems that work automatically, such as those involved in heart rate and blood pressure.

Rather than looking only at the order of DNA letters, the researchers used a method designed to study the three-dimensional arrangement of DNA in cells. DNA is folded inside cells, and that folding can help control which genes are active. The team combined chromosome-conformation signatures, which describe aspects of this three-dimensional structure, with information from genome-wide association studies. These studies look for genetic differences that are more common in people with a condition.

For the ME/CFS dataset, the researchers identified 552 unique three-dimensional genomic anchors, which they mapped to 567 genes. The abstract says that comparable condition-specific sets were created for long COVID, PTSD, rheumatoid arthritis and multiple sclerosis. It does not provide the number of people included in the datasets or the size of the sets for the other four conditions.

At the level of individual genes, there was limited direct overlap between the five conditions. That means the same genes did not simply appear again and again across all of them. However, the picture changed when the researchers used network analysis, a computer-based approach that examines how proteins and genes may be connected in larger systems.

Those analyses found substantial interconnection across conditions. The shared pathways included immune and cytokine signaling, interferon responses, mitochondrial function, metabolic regulation and neuroendocrine processes. Cytokines and interferons are immune-system signaling molecules. Mitochondria are structures in cells that help make energy. Metabolic regulation refers to processes that manage energy and other chemical activity in the body. Neuroendocrine processes link the nervous system and hormones.

The authors also highlighted highly connected genes and pathways, including LAG3 and parts of the mTOR signaling pathway. They proposed that patterns involving long-lasting immune activity, changes in immune-cell function and disrupted links between immunity and metabolism could be common mechanisms across the conditions.

This is not evidence that any one pathway causes fatigue, brain fog or other symptoms in every person with these diagnoses. It is also not a clinical trial, and it did not test a medicine, a diagnostic test or a strategy for improving symptoms. The results come from integrating and analyzing existing genomic datasets, so they should be viewed as a research model that needs further testing.

The work may help researchers ask more focused questions about whether people with different diagnoses can have related biological patterns. Future studies would need to confirm these network findings in well-described groups of patients and determine whether they can reliably identify subgroups, predict outcomes or point to treatments that improve health.