CMRC researchers propose deep trawl of DNA to uncover causes of ME/CFS | 28 June 2019

June 28, 2019

In a major new blog from Simon McGrath, he explains how a Genome-Wide Association Study (GWAS) has been proposed by researchers at the CMRC to help uncover possible causes of ME/CFS.

The blog has been created with comment and input from Professor Chris Ponting (Deputy-Chair, CFS/ME Research Collaborative). The ME Association is an active member of the CMRC Executive.

The largest ME/CFS study in the world!

The GWAS study would require the support of c.20,000 patients – potentially all from the UK – providing postal samples of their DNA together with information relating to their diagnosis – making it the largest ever study of ME/CFS in the world!

CMRC researchers are currently in advanced discussions about funding with the Medical Research Council (MRC) and National Institute of Health Research (NIHR).

We will of course update you with any further news as soon as it occurs – but in the meantime, you might like to keep an eye on the CMRC meeting summaries.

We have selected highlights from Simon's blog – with his kind permission – but strongly recommend that if you want to learn more about GWAS and how this kind of large-scale study has led to the discovery of causes and treatments in other diseases, you read his work in full.

Extracts from Simon McGrath's blog

A new and very different type of genetic research has emerged this millennium – the genome-wide association study (GWAS, pronounced “gee-was”).

By probing small genetic differences between people, such studies can help to uncover the biological roots of disease and have already helped to guide drug development.

Researchers including Professor Chris Ponting, an expert in biomedical genomics, are asking the main UK research funders to finance a large GWAS for ME/CFS.

How do GWAS work?

GWAS need very large samples if they are to discover the very small effects that influence the likes of height and Type II diabetes. Even a study with 2,000 patients is now considered small and so studies typically use at least 10,000 patients to generate robust results. Studies of diseases include similar numbers of healthy patients to aid comparison.

Researchers use genetic probes mounted on special chips to identify which version each person has of each of the roughly million SNPs in a GWAS, similar to the information provided to individuals by companies such as 23andMe. Researchers then look to see if any of these SNPs are significantly more or less common in people with the disease than in those without.

The results are displayed in Manhattan plots, so named because they look like the Manhattan skyline. Each spot represents the probability that a SNP is associated with disease. The higher up the plot the result, the more confident scientists can be that the association with disease is real. Only a very few of the DNA differences will reach significance: typically, a study of 10,000 patients might generate anywhere between a few and 50 significant hits.

The power of GWAS

Normally in science, researchers form a theory about what the problem is (a hypothesis) and then devise an experiment to test that theory. But if no one guesses (hypothesises) what the problem is, they can’t find it.

GWAS are different: there is no need to guess what the problem is first. By scanning across the whole genome, scientists are effectively searching through all the biological processes in the body, looking for issues. And that means the researchers can find previously unsuspected problems. This makes the technique particularly suitable for studying ME/CFS.

With ME/CFS, scientists have pursued many different hypotheses about its cause over the years but have yet to make a breakthrough. University College London’s emeritus Professor Jonathan Edwards argues that it is time for broad approaches like GWAS with the potential to generate new avenues to explore. He told me in a recent email,

“The success of research into causes of disease hinges on someone suddenly having a brilliant idea… yet for ME/CFS nobody has a strong enough lead to show everyone the way forward. So it makes sense to set up a comprehensive fishing trip to see if we can trawl up some clues. Genetic screening [a GWAS] is probably the best bet for finding such clues.”

In addition, compared with most other techniques, a GWAS holds a distinct advantage: its significant results reflect cause rather than effect.

To see this, let’s compare GWAS results with changes in blood levels of cytokines (immune messenger molecules). Cytokine levels might go up or down as a downstream effect of an illness rather than being the underlying cause. But DNA doesn’t change with ME onset – it’s the same before and after the illness starts. So, because the DNA association with disease cannot be an effect of illness it must instead reflect its cause.

And that means that clues emerging from GWAS are particularly valuable.

GWAS are coming of age

What’s currently limiting GWAS as a research tool is the difficulty in going from the SNPs that are significant in a GWAS to the genes that are having an impact on the disease.

Yet researchers are rapidly developing analytical techniques to identify the causal genetic changes that drive disease risk, such as the fiendishly titled two-sample Mendelian randomisation and its proteome-by-phenome spin-off.

Chris Ponting’s lab is among many groups working on innovative methods. As a result of all these developments, says Ponting,

“We could be on the brink of a surge of GWAS-based discoveries about diseases. ME could and should be part of that.”

GWAS can sweep across the whole of human biology looking for potential mechanisms that might cause ME/CFS, even unsuspected mechanisms. It’s a remarkable technique and this is the ideal time for an ME/CFS study.

UK researchers, including Chris Ponting, colleagues from the CMRC and the CureME (ME Biobank) team are aiming to put a proposal in for a large GWAS later this year. The study might need as many as 20,000 patients.

But recruiting so many ME/CFS patients would pose an unprecedented challenge for the researchers. The study would be the largest ever conducted in ME/CFS.

However, recent years have seen rapid growth of an action orientated patient community around the world. MillionsMissing events, for example, have shown what patients can come together to achieve.

“We can get this done, and done fast – but it will be people with ME who make it happen,” Professor Chris Ponting.

It’s rare that any patient can take part in research about their illness, but this study gives us all this chance. It would be an incredible project, the world’s biggest ME/CFS study, that could help uncover the biological roots to our disease.

I’d love to take part in this research. If it is funded, and when the time comes, I hope you’ll join me.

Read the complete blog from Simon McGrath:
Researchers propose deep trawl of DNA to help uncover the causes of ME/CFS

Image credit: DNA/Crowd (c) Can Stock Photo / tai11

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