Approved Research

Genome-wide association study of Myalgic Encephalomyelitis / Chronic Fatigue Syndrome (ME/CFS)

University of Edinburgh

Lay summary

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 125,000 to 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. 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/CFS.

Our focus will be on DNA differences that add to a person's ME/CFS predisposition. We will use 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: its results are not affected by pre-existing biological assumptions or hypotheses. This means that 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, and also predict genes, biological pathways and cell-types that are directly implicated in ME/CFS. We hope this work will ultimately lead to the development of diagnostic tests and targeted treatments.

To meet our goals, we formed a Multidisciplinary Research Partnership linking researchers with people with ME/CFS and their carers. Our Patient and Public Involvement (PPI) team includes representatives from ten UK ME/CFS charities and Science for ME. The funded proposal was initiated, planned and written by everyone across this Partnership in accordance with the NIHR's National Standards for Public Involvement.

Using orchestrated marketing and PR campaigns developed with PPI, we will build a research cohort of 20,000 people - each clinically diagnosed with ME/CFS and who meet established criteria. Within two weeks of our funding announcement, 17,660 individuals with a self-reported ME/CFS diagnosis signed up to support our project. A system will give researchers easy managed access to DNA data, questionnaire answers and other information on this large number of people, to allow them to design better and more effective experiments. The data will be appropriately anonymised and will be held and made available safely and securely.

We have received a £3.2m award from the MRC and NIHR (MC_PC_20005) to undertake the world's first well-powered (20,000 case) genome-wide association study (GWAS) of Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome (ME/CFS). The project seeks to robustly identify multiple genetic risk variants for ME/CFS. Such variants are expected to provide a strong evidential foundation for gene- and cell type-specific mechanistic hypotheses that can then be tested experimentally. Prior to the start of the project, we have built a digital registry of 21,200 (April 2021) adults (>16yrs) who live in UK and with a diagnosis of ME/CFS who have expressed a wish to take part. Following project launch in late 2021, we anticipate acquiring the genotypes of 20,000 people with ME using an Affymetrix Axiom array under contract with the NIHR National Biosample Centre. Our case-control GWAS will require a suitable set of matched control genotypes. For quality control and GWAS analysis we thus here request access to all UK Biobank processed genetic data and raw files for Axiom array data. To define controls we will also make use of UK Biobank's extensive phenotype data (including Baseline participant characteristics, general and specific (pain) questionnaires, Linked health-related and returned datasets).

New scope requested: We wish to (1) Use newly-available UKB whole exome and genome data to explore rare genetic variation associated with ME/CFS; (2) Take advantage of UKB molecular data to explore phenotypic differences characteristic of ME/CFS, which could provide insight into genetic disease processes and/or identify a diagnostic biomarker or potential therapeutic target; and (3) Take advantage of data (when made available) from two new questionnaires (Health and Well-being 2022 and COVID-19: Mental Well-Being 2022) in order to compare the genetics of ME/CFS with that of post-acute sequelae SARS-CoV-2 infection (Long COVID).

Scope extension:

New scope requested (i): We wish to (1) Use newly-available UKB whole exome and genome data to explore rare genetic variation associated with ME/CFS; (2) Take advantage of UKB molecular data to explore phenotypic differences characteristic of ME/CFS, which could provide insight into genetic disease processes and/or identify a diagnostic biomarker or potential therapeutic target; and (3) Take advantage of data (when made available) from two new questionnaires (Health and Well-being 2022 and COVID-19: Mental Well-Being 2022) in order to compare the genetics of ME/CFS with that of post-acute sequelae SARS-CoV-2 infection (Long COVID).

New scope requested ii) We wish to assess the genetic associations and pathogenesis of ME/CFS and fibromyalgia, both jointly and severally, in UKB and DecodeME, and combinations thereof.