A genome-wide association study of myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS)

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a chronic disease characterised by substantial reduction or impairment of activity levels associated with high levels of disability and poor quality of life. It affects an estimated 250,000 people in the UK who often face stigma because of misconceptions. Despite its high cost to patients, the economy and the NHS, we know less about the causes of ME/CFS and how to treat it effectively than we do about many rarer and less disabling diseases. This situation is not helped by ME/CFS research findings from small studies often not being confirmed by other researchers.

Our project seeks to reveal differences in a person’s DNA (including their genes) that alter their risk of developing ME/CFS. These changes in risk are typically small and so to find them we need to study a large number – at least 20,000 – of people with ME.

We propose using a genome-wide association study (GWAS) design because it has already helped uncover the biological roots of many other complex diseases. GWAS’s major strength is that it is unbiased, so it is ideal for discovering genetic causes of disease and new biology. Next, we will find out whether the genetics of ME/CFS overlaps with other diseases. Then we will predict genes, biological pathways and cell-types directly implicated in ME/CFS. In this way we intend to generate strong scientific leads that researchers can pursue with new experiments. We hope this work will ultimately lead to the development of diagnostic tests and targeted treatments.

Using orchestrated marketing and PR campaigns developed with Patient and Public Involvement (PPI), we will build a research cohort of 20,000 people – each clinically diagnosed with ME/CFS and who meet the widely-used Canadian Consensus or IOM/NAM criteria. A system will give researchers easy access to this cohort’s DNA data, questionnaire answers and other information, to allow them to design better and cheaper experiments. The data will be appropriately anonymised and held safely and securely.

Our experience is that most patients consent to be re-contacted about taking part in future studies. This will make it easier for researchers to deliver high quality studies. The Research Partnership links research institutions with people with ME and their carers. Our PPI team includes representatives from Forward-ME (covering ten UK ME/CFS charities) and Science for ME. This proposal was initiated, planned and written by everyone across this Partnership in accordance with the NIHR’s National Standards for Public Involvement.

ME/CFS is a chronic and fluctuating condition that may affect many body systems. People with ME/CFS
experience severe, persistent fatigue associated with post-exertional malaise. Few recover, most remain ill
for many years. Risk for ME/CFS is known, in part, to be inherited. Biomolecular research into the causes of
ME/CFS has long suffered from a replication crisis caused by most studies being considerably underpowered.
Studies also often suffer from ill-defined disease criteria, cohort heterogeneity and failure to distinguish
aetiology from symptomology.
Our Partnership aims to reveal causal biomolecular mechanisms of ME/CFS and to create focused
opportunities for development of diagnostic tests and targeted treatments. We will build a re-contactable
research cohort of 20,000 people – each clinically diagnosed with ME/CFS and who meet either Canadian
Consensus or IOM/NAM criteria – with DNA genotypes obtained by spit-and-post to allow a case-control
genome-wide association study. Genotypes of control individuals will be obtained primarily from UK Biobank.
Statistically significant association of loci to ME/CFS status would then provide objective and testable
hypotheses with which to illuminate ME/CFS disease aetiology. We will also test for genetic concordance with
other complex traits. Importantly, we expect genetic associations to provide the evidence base necessary to
substantially improve the perception of ME/CFS among health care professionals and the general public, and
reduce some of the stigma currently experienced by pwME.
Our expertise ranges from interdisciplinary science (cohort building, genomics and statistical genetics) to the
lived experience of ME/CFS of patients and carers. The considerable reach of our Patient and Public
Involvement team (containing representatives of ten UK charities and from Science for ME) and our planned
marketing and PR campaigns will optimise recruitment of the 20,000 ME/CFS cases.