New study links 14 genes to ME/CFS

New study links 14 genes to ME/CFS

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A study has analysed existing genetic data in a new way to link 14 genes to ME/CFS and identify many patient subgroups. If the new approach pans out, it could transform ME research and turbocharge the development of treatments.

Paper: Genetic Risk Factors for ME/CFS Identified Using Combinatorial Analysis

Authors: Sayoni Das, Krystyna Taylor, James Kozubek, Jason Sardell, Steve Gardner

The paper has been submitted to a scientific journal and is being considered for publication. For now, the submitted draft is available as a preprint. Its findings were presented at the ME Genetics Research Summit on 14th September 2022

The study comes from Oxford-based tech company PrecisionLife. It aims to find better treatments for chronic illnesses that have few or no treatment options – such as ME.

PrecisionLife uses a technique called combinatorial analysis. Big DNA studies look for differences in single DNA’ letters’, called single nucleotide polymorphisms or SNPs, pronounced “snips”. But PrecisionLife looks for combinations of these differences. They call these combinations disease signatures.

Big DNA studies look at SNPs one by one. Combinatorial analysis looks for combinations of SNPs, which should make it easier to find links to disease.,

The study looked at DNA data from nearly 2,400 people in the UK Biobank who reported in a questionnaire that a doctor had diagnosed them with ME or CFS. The analysis found 84 statistically significant disease signatures. Each was a combination of three to five SNPs, and 199 different SNPs were involved altogether.

Of the 199, the researchers focused on 25 critical SNPs that appeared in many different disease signatures. The research team used the critical SNPs to identify14 genes connected with ME.

To put this in perspective, the only previous genetic link found to ME is for an immune-system gene, a finding that, like these new ones, needs replication.

The 14 genes affect (amongst many things) energy metabolism, susceptibility to viruses and bacteria, and sleep – all of which have an obvious link to ME.

The subgroup problem

Crucially, the study looked at how the disease signatures were shared. Many disease signatures overlapped, and the researchers combined the disease signatures into 15 subgroups. The subgroups ranged in size from 5% to 30% of the biobank ME sample. 91% of patients fell into a subgroup.

Graphic showing the 15 subgroups
A graphic taken from the new paper showing the 15 subgroups. Each dot represents one of the 199 SNPs clustered into subgroups. Disease signatures are not shown in an obvious way.

This is consistent with the belief of most researchers that ME/CFS is a mix of many different subgroups of patients. Each subgroup could be a different subtype of disease or even a completely different disease. This makes it very hard to find out what’s going on.

It’s as if each subgroup is a different colour: red, green, blue. If they are mixed together, we get a muddy brown, and it’s hard to see the picture.

PrecisionLife’s approach treats subgroups as the solution rather than a problem. It aims to identify groups of patients who share the same disease signature (or overlapping disease signatures). The focus on combinations of SNPs, instead of single ones, and looking for subgroups generates a stronger signal.

Big DNA studies look at how common a single SNP is in patients compared with healthy controls. Typically, there is only a small difference, and having a single SNP might increase the risk of disease by a modest 10-20%.

But the links between combinations of SNPs and the subgroups they define increase the risk of disease by far more – typically fourfold – compared with healthy controls. These stronger associations are easier to find, allowing PrecisionLife to find differences that other genetic approaches can only find with far larger samples.

Dramatic findings awaiting confirmation

Compared with everything published to date, these are spectacular findings. They also come from analysing a very small sample by the standards of genetic research – just 2,400 patients.

Limited success with replication

These are striking results produced by a new method, so it’s natural to be check if the results can be repeated.

The authors tried to do this, using a separate UK Biobank group. This was made up of around 1,300 people who reported in an interview that they had a diagnosis of CFS (rather than being asked if they had ME or CFS).

Success was limited. Five of the 25 critical SNPs were also statistically significant in the replication group, but none of the 84 disease signatures was. The five critical SNPs identified 2 of the 14 genes from the first group.

The paper says that technical reasons meant they were likely to miss at least some of the disease signatures or critical SNPs in the second group of patients. This is something the researchers intend to address in future studies.

The authors also pointed to the slightly different diagnoses for the two groups, which meant that they might not have been comparing like with like.

For now, though, it’s unclear how well these findings replicate.

We should also note that while the researchers describe the method in some detail, PrecisionLife uses a patented process. Effectively, it’s a black box, and other scientists can’t look inside to check its workings. (The authors told me their patented approach reduces the time taken to do these calculations by millions of years!)

Success with other illnesses

But what makes PrecisionLife’s approach so interesting are the results they report for other diseases.

PrecisionLife made the first genetic analysis of Covid, which ran on just 725 patients from the UK Biobank. They found 68 genes of interest and reported that 48 have since been associated with Covid in published papers from other groups.

Examples of the association include:

  • Five of their genes of interest were also found by a much larger genetic study of Covid.
  • They suggested versions of a gene they identified could play a role in Covid inflammation and a particular drug could reduce inflammation. The gene was shown to be active in the lung cells of severely ill Covid patients and the drug did reduce inflammation.
  • The genetic signals they found pointed to the potential of 29 drugs to treat Covid. Thirteen of these have been tested. Most results are not yet available, but one drug has proved effective in a clinical trial.

Issues about the UK Biobank sample

PrecisionLife used data from the UK Biobank as it currently has the largest available of people with ME/CFS. However, it is far from ideal.

The UK Biobank’s diagnosis of ME or CFS might not be very accurate. It is solely based on people saying that a doctor has said that’s what they have, and there are no questions to check that people meet research criteria.

Also, the sample might not be representative. In the first group, the average age was 69, and only 71% were women, compared with 80–85% in most research studies of ME/CFS.

What do the 14 genes do, and can they explain ME?

Back to the study findings. The researchers identified 14 genes associated with ME/CFS. Can these genes – and their biological function – explain why people with particular versions of them are more likely to get ill? Or why people have the symptoms they do?

The authors point out that linking genes to biological function is somewhat open to interpretation. But there is evidence linking the genes to ME/CFS:

1. Autoimmunity

Seven of the 14 genes are linked to autoimmune diseases (there is a lot of genetic overlap between autoimmune diseases), particularly to multiple sclerosis. There is already some published evidence of autoimmune problems in at least some people with ME.

2. Energy metabolism

Several of the genes affect energy metabolism, including one that affects the power stations of the cell, mitochondria, including mitochondria activity after exercise. The effect happens via AMPK, an important molecule that acts as the master regulator of cells’ energy balance. Professor Julia Newton’s team has linked AMPK to ME/CFS.

3. Sleep

Two of the genes affect sleep through our 24-hour circadian rhythms. Poor sleep is a core symptom of ME.

4. Infection

Five of the genes are linked to viral and bacterial infection. Around 70% of people with ME report that their illness began with an infection.

Next moves

Professor Chris Ponting told me he was very interested in these findings. He also said the ME/CFS gene variants identified in this study would “need further genetic support from more conventional studies such as genome-wide association studies”.

As an alternative, he said, he’d like to see if “PrecisionLife’s method can validate the same combinations of DNA variants in independent cohorts of people with ME”.

Happily, DecodeME is already collecting data for a large DNA study, which might confirm some of the genetic links identified here.

And PrecisionLife is in discussions with DecodeME about its own analysis of DecodeME data. DecodeME can provide larger samples with a more accurate diagnosis of ME/CFS.

How these new findings could change the landscape

If the findings from this new study do pan out, we might see rapid progress in ME research and the development of treatments.

Researchers could use the genes highlighted as clues pointing to what is going wrong in ME. That’s a key step to developing new treatments.

Using SNPs to split patients into subgroups could lead to more focused research and clearer findings.

In the same way, SNPs could be used as biomarkers, helping to diagnose ME and even identify which type of ME someone has.

And PrecisionLife has much expertise in identifying drug targets and evaluating which drug candidates are most likely to succeed.

The next critical step is confirmation of these remarkable findings. It could come as soon as next year, depending on DecodeME data availability. And if it does, it will be very good news for people with ME.

I thank Drs Sayoni Das and Krystyna Taylor of PrecisionLife for talking to me about their study.

PrecisionLife presented the findings of this study at the ME Genetics Research Summit on 14th September 2022. A video of the presentation will be available shortly.

The summit marks the launch of a new Genetics Centre of Excellence. Founded by Action for ME and the MRC Human Genetics Unit at the University of Edinburgh, the aim is to create a network of researchers and increase high-quality genetic research and funding for it.

Image credits. DNA, Canstock Photo. Subgroups, PrecisionLife.

14 thoughts on “New study links 14 genes to ME/CFS

  1. Thank you so much for this and making complicated data and methodology more easily understood by my addled ME brain.

  2. Thank you for this,which I have read and will need to read again a few times,due to 27 years of ME.I always felt there might be some genetic link,partciularly with my father..
    My ME started after a nasty virus at a time of extreme stress.

  3. Interesting news.
    AMPK also regulates breathing – which makes sense since cellular respiration needs to be coordinated with O2 supply (PMC7279029). Also affects immune function.

  4. At last a study that attempts to look at both phenotyoing and causation. Not recognising that ME is heterogeneous and more of a disease family is why attempt to get a biomarker or to a single root cause or replicate study findings among different populations have failed for so long, perpetuating the psychogenic myth. Great to hear they are in conversation with Decode ME. By the way. I submitted samples to Biobank several years ago and in addition to the self reported diagnosis there was a detailed symptom questionnaire which was clearly designed to enable confident classification by all the main ME definitions and a specialist nurse visit for the blood draw who also asked questions, so I’m a little surprised at the suggestion that Biobank’s ME diagnosis confidence would be any less accurate than Decode ME which is also a self reported questionnaire but with no nurse visit.

    1. Hi. Yes, just the approach we need.

      Sounds like you joined the UK ME/CFS Biobank run by the London School of Hygiene and Tropical Medicine? This study took data from the much larger UK Biobank 9covering many illnesses, which has less data on each person.

  5. Exactly what ive said for years, that until we can identify all the subgeoups we wll never get anywhere by trying to lump us all together, when patently this just does not work. Well done everyone, just hope this can be replicated.

  6. This sounds like a tremendous breakthrough. But given its complexity won’t it be something that will help far down the road as opposed to soon enough to benefit patients suffering today?

    Thank you.

    1. We don’t know. If the results hold up, identifying subgroups (each likely to have different causes) will make it easier to find treatments. And if we know which genes play a role in causing ME, it’s a starting point for finding treatments. That’s a speciality of PrecisionLife.

      The fasted help will come if it turns out an existing drug – approved for another disease – can help people in some subgroups. Looking for this kind of drug repurposing is something PrecisionLife specialise in.

      But of course, first we need replicated results. And there is no guarantee on the drug front. But finding causes is the surest way to finding treatments.

  7. Thanks for bringing this paper to my attention. I plan to wrestle with it tonight. Gene to gene interactions more important than single isolated SNPs in complex multifactorial diseases like ME/CFS.

  8. ME/CFS is a waste basket diagnosis. A London clinic reported over 50% of referrals actually had something else – MS, Addisons, depression, burnout, sleep disorders etc. As many clinics are psychology led, it is unlikely misdiagnosis are routinely picked up. There are over 30 conditions with chronic fatigue symptoms. PEM has always been a requirement for ME, but has only recently been a requirement for ME/CFS and is not clearly defined for reliable diagnosis. As a result any group of ME/CFS patients will contain a mixed bag of conditions. This does not mean ME has sub groups or is an umbrella.
    Herpes viruses stay in the body, so lack of an apparent viral trigger does not mean a resident virus is not the underlying cause.
    I think it is more likely that ME is mostly an immune reaction, like hay fever is to pollen, but the underlying virus that triggers it is not necessarily the same. The viruses themselves also may cause damage, which results in different symptoms independently. I really hope these dna studies will be able to unravel a lot of this.

  9. very interesting .
    once upon a time i was a medical technologist before this illness hit.
    in college biochemistry & genetics were my favorite classes.

    But i am 35 years behind the times !

    i would be interested in reading additional developements

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