A Norwegian team has published the largest analysis yet to look for DNA differences that could pinpoint what goes wrong in ME (also known as chronic fatigue syndrome, CFS). Such differences would be a first step toward finding effective treatments.

Unfortunately, the new study doesn’t find any DNA differences that reach the accepted standard for statistical significance. Even so, as Professor Chris Ponting and I comment in a companion piece, their paper helps to move forward the field of ME genetics.

Ruling out dead ends

Study leader Dr Riad Hajdarevic and colleagues found no support for DNA differences that others had linked to ME. We feel it is critical they reported these negative results to help ME research refocus on the most promising leads.

The authors conclude that all previous genetic studies have not been big enough to find true associations between DNA differences and ME.

No new findings reach statistical significance.

The researchers ran a “discovery analysis” on 427 Norwegian patients and looked to replicate the findings from this in 2,105 UK Biobank participants. They did not find any new links of DNA differences to ME that reach the accepted threshold for significance (p < 5 x 10^-8).

We agree with the authors that, to pinpoint and tease apart ME’s various causes, researchers will need to create much larger studies, such as DecodeME (which aims for 25,000 ME participants). Scientists will also need to pool the data from many studies to analyse even larger numbers of patients.

Research studies need effective diagnosis

Hajdarevic and colleagues express concern about the accuracy of diagnosis in the UK Biobank sample. Almost all the Norwegian cohort met the Canadian Consensus Criteria. UK Biobank participants were asked if they had a diagnosis of CFS from a doctor.

With no diagnostic test, there is always the risk of including people who do not have ME and failing to include those who do. We argue that future studies need to be inclusive (to make them as large as possible) and exclusive — by excluding any individual who doesn’t have the core symptoms of ME, particularly post-exertional malaise.

A possible link to a gene

The Norwegian study does find a link between some DNA differences and ME, though even the strongest link (p = 8.5 x 10^-7), in the Norwegian cohort, falls short of the accepted target for significance. This potential link is to TPPP, the gene for tubulin polymerisation promoting protein, which plays a role in cell structure. This link deserves attention when bigger studies are analysed.

Studies need large numbers of participants to reliably detect individual DNA differences, which often have only a very small effect. (Note: the first ‘big DNA’ studies, which were smaller and used less-strict levels of statistical significance, usually produced unreliable results.)

The latest view is that, in most cases, studies need at least 10,000 participants to produce reliable results.

The critical role of those with ME

Finally, Chris and I say that people who live with ME should be at the heart of ME studies because their experience will always improve scientific quality and delivery. People with ME can also consent for their data to be shared ethically to allow researchers to analyse data from even larger numbers of participants. This is the fastest route to robust genetic results.

Simon McGrath

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