Today, we know almost nothing for sure about what causes ME/CFS. We do know that the illness can be triggered by certain infectious diseases, such as glandular fever. But we don’t know why most people recover from those infections but a minority instead develop ME/CFS.
There are many competing hypotheses about what causes the illness, all with some evidence to support them. But nothing has yet been nailed down.
A scientific paper reviewed the available evidence about ME/CFS genetics and explained how big new DNA studies can help find causes of the disease.
The paper was written by Joshua Dibble, the PhD student of DecodeME’s lead scientist Professor Chris Ponting. He was funded by Action for ME and Scotland’s Chief Scientist Office. The other authors were Chris himself and Simon McGrath, who has ME/CFS and is also on the DecodeME team. In this blog post, we summarise our review.
Genetic studies offer a way forward because if genes are linked to ME/CFS, they must be a cause of the illness and not simply an effect of it. This is because diseases don’t change our DNA. In contrast, for studies looking at other molecules, any differences between patients and controls might simply be a consequence of the illness rather than a cause that drives it.
A very large genetic study can identify causes that have not previously been considered. In Alzheimer’s disease, for example, researchers were initially focusing on nerve cells in the brain. But big genetic studies drew researchers’ attention to other brain cells called glia that support the normal functioning of nerve cells.
In rheumatoid arthritis, genetic studies have helped to identify what goes wrong at the molecular level to set off the disease.
Comparing findings between different autoimmune diseases found that some of them shared a disease mechanism. As a result, drugs already used successfully in some autoimmune diseases are now used to treat patients with other autoimmune diseases that share a common mechanism.
Progress in all these diseases came from a type of genetic research called genome-wide association studies (GWAS).
GWAS shed light on many diseases that are caused not by a single gene but by many. In simple genetic diseases, such as cystic fibrosis, the illness is caused by a fault in a single gene. However, the role of genetics in most diseases is weaker, and usually the result of many different genetic differences, each having a small effect. Non-genetic factors, such as environmental influences and infections, also play a big role in most illnesses.
To reliably find the small genetic differences that occur in most diseases, we need very large studies: typically with at least 10,000 participants.
Evidence of a role for genetics in ME/CFS
Although usually just one person in a family gets ME/CFS, quite often more than one person is affected. This indicates that an increased risk of becoming ill with ME/CFS can run in families. Several studies have now provided evidence of an inherited, genetic role in ME/CFS, though the studies don’t agree on how big the role is.
ME/CFS genetics studies so far
Several studies of the genetics of ME/CFS have linked the disease to particular genes. However, none of these specific genetic links have yet been independently confirmed. Our paper critically reviews these studies.
The strongest genetic evidence to date
Human leucocyte antigens (HLA) proteins allow the immune system to target cancerous cells and cells infected by viruses and other bugs.
The situation with HLA genes (and proteins) is unusually complex. There are many genes for HLA proteins and often many versions of each gene. The upshot of this is that we each have a set of HLA genes and while we will share individual HLA gene versions with other people, we are unlikely to have exactly the same set as anyone else.
(HLA genes also determine whether or not an organ transplant will be rejected. For an organ to be accepted, there must be a good match between the organ donor’s set of HLA genes and those of the person receiving the transplant.)
Certain versions of HLA genes increase the risk of autoimmune disease. Recently, two versions of HLA genes were linked to ME/CFS and each roughly doubled the risk of having ME/CFS. The study was large (458 patients, 4,500 controls) and done well, though the finding will need replication.
The largest genetic studies to date used data from the UK Biobank of over half a million individuals. Nearly 2,000 of these individuals said they had a CFS diagnosis from a doctor (but it is not clear if they would meet specific ME/CFS criteria).
One analysis of these people with CFS found a link to a protein that transports an amino acid into mitochondria, the mini-power-stations of the cell. There is some evidence to support this finding. However, other slightly different analyses of the same data didn’t confirm this finding.
Our review also examines several other ME/CFS genetic studies. Most of them are rather small and some also appear to have technical shortcomings that we cover in the paper. For our review, we looked to see if the gene versions linked to ME/CFS in these studies were also linked to CFS using data from the UK Biobank. But disappointingly, they did not.
Benefits expected from ME/CFS Genome Wide Association Studies (GWAS)
Our review of available genetic studies and findings provides limited evidence that particular genes play a role in ME/CFS. It also highlights the need for larger and more rigorous studies that give more robust results. ME/CFS GWAS can do that.
GWAS have already helped to improve our understanding of the causes of many diseases and have helped to develop new treatments. GWAS for ME/CFS are long overdue. DecodeME will be the first study of this kind, and a Norwegian group is planning a separate ME/CFS GWAS. Replicated results from such studies would have four important benefits:
1. Finding causes
Positive results would help provide much needed insight into the biological causes of ME/CFS. In combination with other technologies, GWAS can pinpoint variations in DNA that change the activity of genes and as a result alter the risk of ME/CFS.
It is likely that many genes will be involved in increasing the risk of ME/CFS, each in a small way. If the genes turn out to have an activity in common (such as a particular immune function or the functioning of a certain type of brain cell), then that effectively flags up possible cellular or molecular causes of the disease. This would provide strong leads for further research.
2. Learning from other diseases
Researchers could investigate if the genetics of ME/CFS is shared with any other disease, indicating possible shared disease mechanisms. This provides the potential for reusing existing treatments to treat ME/CFS.
3. Subtypes and targeted treatments
GWAS findings could help split ME/CFS into different groups. This could eventually lead to identifying distinct subtypes of ME/CFS, each with a different cause and potentially a different treatment.
Lastly, discovering genetic factors that play a role in causing ME/CFS might improve how the disease is seen by both health professionals and society at large.
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