Massive Study Links 8 Genetic Signals to Chronic Fatigue Syndrome

Chronic fatigue syndrome, also known as myalgic encephalomyelitis (ME/CFS), is a severely disabling condition that was overlooked for years, with specialists often writing it off as psychosomatic for decades. Even now, some clinicians continue to treat it as something that exists only in a patient’s mind. However, the largest genetic investigation of its kind indicates that ME/CFS has genuine biological roots.

DecodeME and ME/CFS: the largest genetic analysis to date

A UK research programme known as DecodeME has examined genome-wide associations and identified eight potential genetic signals linked to ME/CFS. The results are currently available as a preprint and have not yet been published in a journal or peer reviewed, but they indicate that a person’s genetic make-up contributes, at least in part, to the likelihood of developing ME/CFS.

Neuropsychiatrist Alan Carson from the University of Edinburgh, who did not participate in the work, describes it as "by someway the largest study ever conducted on genetics of CFS/ME."

Who was included and how ME/CFS was defined

DecodeME’s study combined data from more than 16,000 patients, the majority of whom are women and of European ancestry. The diagnostic standards were strict, ensuring that only the most unambiguous cases were selected.

To be eligible, participants needed both a formal ME/CFS diagnosis and a hallmark symptom known as post-exertional malaise. This refers to disproportionate exhaustion after exercise or other activities that use energy, including mental effort such as concentrating or taking part in social activities.

What the researchers found in the genome-wide associations

The analysis initially uncovered more than a dozen genetic signals associated with ME/CFS, but only eight of these could be replicated in a second dataset comprising more than 13,000 cases.

A third dataset including more than 14,000 cases did not reproduce the findings. The researchers suggest this could reflect variation in how ME/CFS was defined and diagnosed across datasets.

Although the eight genome-wide associations are not unique to people with ME/CFS, the results imply that these variants occur more often among those with the condition.

Links to pain, infection response, and the brain

Chris Ponting, a bioinformatician at the University of Edinburgh and the DecodeME project lead, says one of the eight genetic variants "nicely overlays" a signal previously associated with chronic pain, which is frequently reported by people living with ME/CFS.

The study also reports that three of the eight signals are recognised for acting as first responders to viral or bacterial infections. This may help clarify why many patients describe an infection preceding the onset of symptoms, as well as why case numbers have increased since the pandemic.

Several of the eight signals were expressed in brain tissue, including those tied to pain and immune function.

The authors propose: "Drugs targeting these genes' proteins might help protect against the consequences of microbial infection and therefore could reduce the risk of acquiring ME/CFS,"

How experts interpret the significance

The DecodeME team-made up of more than 50 researchers-argues that their results strengthen the biological basis for future work: "DecodeME's results, grounded in the principles of statistical genetics, now place ME/CFS research on a firm biological foundation," adding that this "should help to reduce the stigma of the illness,"

At the same time, the detected signals are relatively modest, and their implications are not yet clear. Alena Pance, a geneticist at the University of Hertfordshire who was not involved, says the study is a "great advance towards understanding the illness better."

Carson likewise considers the research significant but emphasises that progress may be slow. He notes that in conditions such as depression, identifying a small number of associated genes has not yet transformed understanding of disease mechanisms or led directly to improved treatments.

The role of patients and what comes next

Despite the uncertainties, Ponting and colleagues contend that these findings help account for the inherited component of ME/CFS, increase the chances of discovering effective medicines, and position the condition more comparably alongside other common genetic disorders.

Sonya Chowdhury, a study contributor and CEO of the UK health charity Action for ME, says: "We've gone from knowing almost nothing about the causes of ME to having specific genetic information to delve much deeper into,"

She adds: "For decades people with ME have asked to be heard, and now science is catching up."

The research is available via preprint here.