Frequently Asked Questions

A genome-wide association study (GWAS) is a very large genetic study that seeks to uncover some of the biological roots of ME/CFS. By probing small DNA differences between people, a GWAS can help to pinpoint the genetic causes of disease and guide drug development. This design has previously been helpful in identifying genes together with molecular and cellular pathways that contribute to disease risk. (Read more about the science of GWAS.)

To work well, the study needs to recruit around 20,000 people with an ME/CFS diagnosis whose DNA will be compared with that of a similar number of non-ME/CFS matched controls. These will be people from a similar population who do not have ME/CFS drawn from the half-million-strong UK ME/CFS Biobank.

We take diagnosis very seriously. Participants will be diagnosed using the CureME questionnaire that has been in use for the UK ME/CFS Biobank for several years. This is additional to participants reporting that they have been diagnosed with ME or CFS by a clinician.

CureME will apply its diagnostic algorithm (a very specific set of rules) to assess people according to well accepted diagnostic criteria: the Institute of Medicine 2015 or the 2003 Canadian Consensus criteria, but not the Oxford or NICE criteria. Post-exertional malaise (PEM) will be a mandatory symptom. This is because patients, patients’ organisations, and ME/CFS biomedical researchers all regard it as a defining symptom of the disease. Using these definitions will help to ensure that findings are compatible with those from biomedical research around the world, which uses these criteria.

We undertook an online survey and the majority of people supported this. These criteria were also agreed at the MRC/NIHR Workshop with researchers, patients and carers.

No, we won’t be asking them to send in evidence: making a declaration that they have a clinical diagnosis and completing the questionnaire is sufficient (see previous question). This does mean that someone could falsely claim to have an ME diagnosis and access the questionnaire part of the study. But: (1) we feel that the number of people who might do so will be too small to be significant, and (2) we would anyway prefer to keep the barriers to taking part to a minimum for patients.

Our goal is to identify causes of ME/CFS. For this we will first isolate and analyse patients’ DNA from the saliva sample. We will then look at around a million common variants in DNA and see if any of the variants are more or less common in patients than seen in control individuals. Survey data such as age, type of onset and symptoms will be used to gain a better understanding of patients’ background and illness and we will link this survey data to their genetic data.

We may also ask patients if they are willing to provide us access to their electronic health record, with personal clinical information kept by their GPs. This would help us to get a more detailed understanding of patients’ illness, progression and symptoms, but would be entirely optional and will not affect eligibility for the study.

Until the first GWAS study for an illness is done, it is just not possible to know how meaningful its findings will be. However, we’ve chosen to study 20,000 people with ME/CFS because other projects of this size commonly found around five causal links between DNA and disease diagnosis. ME/CFS could have many independent genetic causes and a study of this size will have a chance of revealing part of this potential spectrum of genetic causes.

Findings from such studies have helped to:

• establish the identity of numerous genes involved in Type II diabetes, such as those affecting the action of insulin on fat cells and liver cells. These studies have also helped to identify an unsuspected role in Type II diabetes for a protein that transports zinc into cells, and scientists are developing drugs that target this protein.
• reveal that microglia, the immune cells of the brain, play a key role in Alzheimer’s disease.
• demonstrate that thermogenesis, where “brown fat” cells burn off fat to produce heat, is an important pathway impacting on obesity.
• show that high levels of “good” HDL-cholesterol is simply associated with lower levels of heart disease — but is not actually protective. This explains why the pharmaceutical industry’s $5 billion investment in drugs that increase HDL-cholesterol came to nothing. Instead, GWAS helped to show that a different type of fat, the triglyceride group, does increase the risk of heart disease.
• establish that many different diseases often share some common biological mechanisms. An immune-regulating molecule called IL-23 plays a significant role in numerous autoimmune diseases. As a result of this insight, existing drugs that are used to inhibit the IL-23 pathway in other diseases have become a mainstay treatment for several autoimmune conditions, including psoriasis and ankylosing spondylitis.

We are looking to learn all the (good) lessons that previous projects can teach us. One good example that we are aware of is the UK GLAD study, which has used predominantly online recruitment. One year in, 79,000 people had registered online, 47,400 had given consent and 20,000 people had returned saliva samples to become study participants.

The GLAD study is recruiting from the 1 in 3 people aged 16+ who have ever had anxiety or depression (18 million), while we have the much more challenging task of recruiting from the approximately 1 in 250 people who have ME/CFS. Even so, the GLAD study’s recruitment is at least a proof of concept, and also gives examples of ways of engagement that will be useful to us in our study, though the disease focus of the research is very different.

A GWAS has the major advantage that its results indicate root causes of illness, because DNA doesn’t change with ME onset, so GWAS findings reflect causes rather than effects of illness. With most other approaches, it is not usually possible to know if findings indicate the effects of illness, or the cause. For example, people who are unable to exercise are likely to show molecular changes that are solely due to being sedentary, rather than highlighting the root causes of their disease.

GWAS have been successfully applied to many different diseases (asthma, schizophrenia, diabetes, pulmonary disease etc – see a comprehensive list here) and traits. We believe that it is time that ME/CFS science took full advantage of this cutting-edge genetics approach which is entirely complementary to approaches taken by other ME/CFS researchers.

Existing samples from the UK ME/CFS Biobank will be used. However, we need a very large number of people for a GWAS study, typically at least 10,000–20,000 patients. This will require a significant expansion of the Biobank, and collaboration with the NIHR Biosample Centre in Milton Keynes.

As yet, there is no such biomarker and despite some promising research, there is still no test that can reliably separate people with ME/CFS from people with other, similar diseases. We know that others around the world (e.g. Stanford, Harvard and Uppsala) are actively pursuing biomarker research, and we hope they are successful. But there is no guarantee of success and the timescale to development is uncertain. So, it is our view that we should press ahead with our complementary approach.

In total, four years but we will release preliminary results as soon as we can, prior to publication. The sooner we can recruit participants, the sooner the results will be released.

We welcome participation by all people with ME, whether or not others in their family are affected. Our project is not to identify such large-effect, family-specific DNA variants, but smaller-effect, general-population DNA variants.

There will be no attempt at identifying related individuals, other than as a routine part of the statistical analyses.

Yes, genetic associations to ME/CFS will be looked at first. The next step is unlikely to be “tracking in families” because we expect there to be not one or two DNA differences, but rather dozens or hundreds of DNA differences that tilt the balance one way or another, changing someone’s risk of having ME/CFS. Having one DNA difference is unlikely to be sufficient to change that risk.

Instead, the second step – once the type of cell or metabolic process that is disrupted in ME/CFS has been identified – will be to chase down what immediate effect this root cause has on the body and then see whether it can be reversed.

When we approached the potential funders earlier this year, we presented an indicative budget. Unfortunately, when the full budget was calculated, we realised that there was limited space for any biobanking work. At a workshop organised by the funders, which people with ME and scientists attended, there was overall agreement that the GWAS should be prioritised and that a proposal to extend the UK ME/CFS Biobank should be developed separately.

If funded, we hope to launch very early in 2021. We plan for recruitment to take up to two or three years, but the sooner the better!

This is highly likely. The risk of having a complex disease such as an autoimmune condition is altered by many, many different DNA letters scattered around the human genome, and we think it is likely that it will be the same for ME/CFS. The genetic variants all could have the same effect (for example, muting the body’s immune system) but might have separate effects on different bodily processes.

Modern biomedical science tries not to compartmentalise. The body’s health is like a tune that can become discordant because of faults in any of the musical instruments, being played by many different parts of the body’s orchestra!

Your information and samples will only be used by researchers who have relevant scientific and ethical approval for research. This could include researchers working in other countries or with commercial companies who are looking for new treatments or lab tests.

You’re providing your sample as a gift. You won’t receive any payment for your contribution. The Partnership won’t sell your data or sample.  Samples and data may be made available to other research institutions, in the public and private sector, in the UK and overseas, to help researchers make an invention. If an invention is created from research on your data or sample, you won’t receive any compensation or payment.

No — the lead investigators are a specialist in human genetics (Chris Ponting, Professor for Medical Bioinformatics at the MRC Human Genetics Unit), and a clinician (Dr Luis Nacul, who heads up the CureME team and the UK ME/CFS Biobank). All researchers in this project are focused on biomedical research.