Chronic fatigue syndrome seems to have a very strong genetic element

We are beginning to understand the role that genetics plays in the development of chronic fatigue syndrome, or myalgic encephalomyelitis (ME/CFS). According to the largest study of its kind to date, more than 250 genes are involved, six times the number identified earlier this year. Not only could this help us develop treatments that get to the root of ME/CFS, but the study also adds to our knowledge of how it differs from long covid, a very similar illness.

“This opens up a lot of new avenues, either for the development of new therapies or for the repurposing of drugs,” says Steve Gardner, a member of the Precision Life team in Oxford.

ME/CFS is a chronic illness that is often debilitating. It has many symptoms, but a key feature is post-exertion malaise, where even small amounts of activity lead to prolonged exhaustion. ME/CFS is usually triggered by an infection, but it is unclear why many people can get such an infection without developing the disease.

To learn more, Gardner’s team examined genomic data from more than 10,500 people diagnosed with ME/CFS. This data was previously collected by a project called DecodeME, which revealed in August that people with ME/CFS have key genetic differences from people without the condition.

Now, Gardner and colleagues compared this data with that of people without ME/CFS from the UK Biobank. They focused on genetic variants called single nucleotide polymorphisms (SNPs), in which only one letter of the genome is changed.

A standard analysis would look at one SNP at a time, but “complex disease biology is just not like that,” Gardner says. “Several genes are involved and they interact with each other. Some amplify each other’s effects, others inhibit each other.”

Instead, researchers looked for clusters of SNPs associated with ME/CFS risk. They found 22,411 such groups, made up of combinations of 7,555 SNPs, out of the more than 300,000 they identified in total. Researchers also found that the more SNP groups a person has, the greater their chances of developing ME/CFS.

“This is where they start to move things forward,” says Jacqueline Cliff of Brunel University in London.

Next, the team mapped SNPs to 2,311 genes, each playing a small role in a person’s risk. Of these, they identified 259 “core” genes that had the strongest links to ME/CFS and had the most common SNPs. This represents a big advance from the August study, which found 43 genes.

“If you are really interested in drugability and want to benefit as many patients as possible, the [variants] with higher prevalence and higher effect sizes are obviously the ones you would choose to study first,” says Gardner. There are currently no specific medications to treat ME/CFS, but people can be offered painkillers or antidepressants, as well as being trained in energy management.

Danny Altmann of Imperial College London is optimistic that studies like these will shine a light on the serious harms of ME/CFS, which he says have been misunderstood and overlooked for decades. “We have come of age in terms of genomics and pathophysiology.”

Several studies have already attempted to identify genetic risk factors for ME/CFS. “Some have reproduced [each other’s findings] and others don’t,” says Altmann. “It’s all about scale and power.” Studies with too few participants will likely miss real genetic signals.

In August, researchers behind DecodeME also identified variants in eight regions of the genome, including all 43 genes that contribute to ME/CFS risk, but they could not replicate them all in independent datasets. PrecisionLife, however, has rediscovered all eight regions, supporting the idea that they are real risk factors for the disease.

ME/CFS is also frequently compared to long covid, which is also triggered by infection and also frequently leads to post-exertional malaise. In the new study, the researchers attempted to clarify the relationship between these conditions by comparing the list of genes they had linked to ME/CFS with those they had previously linked to long covid. “About 42 percent of the genes we found in long covid also appear reproducibly in multiple EM cohorts,” says Gardner. “These are obviously two partially overlapping diseases.”

But we can’t be too confident about the long covid results, Cliff says, because these individuals were analyzed differently than those with ME/CFS. In the paper, the researchers say the genetic overlap they identified is “a minimum estimate,” suggesting the conditions may be more genetically similar than we think.

Altmann and colleague Rosemary Boyton, also at Imperial, have just secured £1.1 million in funding to study how ME/CFS and long covid are linked. Altmann says they aim to recruit people with both diseases and perform “high-tech, high-resolution analyses,” including of participants’ immune systems, any latent viruses lingering in their bodies, and their gut microbiomes — all of which have been implicated in these conditions.

By understanding the mechanisms behind ME/CFS and long covid, and understanding how they vary from person to person, we can hopefully target them directly, says Altmann.