Huge study of ME/CFS reveals genetic 'hotspots' linked to the debilitating syndrome

Researchers have conducted the largest-ever genetic analysis of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), a typically lifelong condition that affects people's ability to exert physical effort and can be debilitating.

The DecodeME study, which recruited over 15,000 people of European ancestry with the condition, revealed that eight stretches of the genome were tied to the syndrome. These had not previously been linked to ME/CFS. The gene variants found in these locations are also found in some healthy individuals, the research suggests. But in people with ME/CFS, the variants are likely to act alongside environmental factors to increase people's risk of the condition, the researchers said.

The findings "provide the first robust evidence for genetic contributions to ME risk," study co-author Chris Ponting, a bioinformatician at the University of Edinburgh, said at a news conference Wednesday (Aug. 6).

The new study has been released as a preprint by the University of Edinburgh and has not been peer-reviewed yet.

Estimates suggest ME/CFS may affect 67 million people worldwide, although the exact prevalence is uncertain and research into how the disease manifests and how to treat it has been glacially slow. This is partly because of disputes in the field about what characterizes the disease's key symptoms.

For years, leading psychiatrists positioned ME/CFS as a psychological condition. These discredited theories suggested that the syndrome — whose symptoms include brain fog, fatigue that is not relieved by rest, and chronic pain — was driven by patients' mental states and lack of exercise. These ideas emerged, in part, because the few clinical investigations done on ME/CFS could not pinpoint biological changes tied to the syndrome or a clear trigger for the observed symptoms.

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Now, the new work adds to mounting evidence that links the condition to dysfunction in the nervous and immune systems.

"Our findings will provide credibility and validity to the experience of people with ME," study co-author Sonya Chowdhury, CEO of the ME/CFS charity Action for M.E., said at the news conference.

DecodeME involved genome-wide association studies (GWAS), which are genetic analyses that look for links between common variations in the genome and other traits, such as the presence of a given disease. The study conducted two separate GWAS on about 15,600 ME/CFS patients.

The patients' genomes were compared with those of people without ME/CFS whose genetic information was previously recorded in the UK Biobank, which includes data from 500,000 U.K. adults. Together, the two GWAS identified eight loci — locations in the genome — that were strongly associated with whether or not a person had ME/CFS. At these key locations, they marked out the genes most likely to influence a person’s risk of developing the condition.

These genes included several linked to immune function. One was BTN2A2, which a previous study showed could influence the function of T cells, which are key to fighting germs. One locus contained the gene CA10, which was previously linked to pain. The authors say this link may help to explain ME/CFS patients' hypersensitivity to light, sound and touch.

The genetic links do not reflect changes wrought by the disease — instead, they hint at the biological systems that influence how vulnerable people are to developing ME/CFS.

The authors made some efforts to replicate their data by looking at whether these same associations could be drawn using 13,800 ME/CFS cases recorded in the UK Biobank and in the Netherlands' Lifelines database, another large cohort study. However, after statistical correction, none of the associations were replicated.

"This may reflect poor or inconsistent diagnosis data in those other datasets, rather than flaws in the DecodeME findings themselves," said Amy Mason, a research associate at the University of Cambridge who was not involved with the study, told the U.K. Science Media Center.

Long COVID — a long-lasting condition that emerges after a COVID-19 infection and affects many systems in the body — has been noted to share symptoms with ME/CFS. However, DecodeME didn't identify any of the same genetic signals found in a similarly sized GWAS analysis of long COVID published earlier this year, Ponting said. At this point, it's unknown why that might be.

ME/CFS is a highly sex-biased disorder; roughly 80% of patients are female. The DecodeME study didn't identify any strong sex links, but Mason pointed out that the team did not look at the X or Y chromosomes, where sex-linked traits might be found. The analysis also focused entirely on people of European descent, which may limit its value towards patients from other ancestries.

The authors hope that DecodeME will be a jumping-off point for further research, which could explore the genetic signals in more detail and pinpoint the biological mechanisms they suggest are involved in ME/CFS. For now, the findings cannot advance diagnostics or screening for the condition, Ponting said.

"There is an urgent need for studies that target these regions that dig down … to determine why each of these signals is linked to ME," he said, "so that we cannot just move towards, but accelerate towards, future diagnostics and treatments."