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Scientists comment on an unpublished preprint on the DecodeME genome-wide association study of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).
Dr Jackie Cliff, Senior Lecturer, Brunel University of London, said:
“Although there have previously been genetics studies of ME/CFS, the DecodeME study is on a much-larger scale, ensuring greater validity and confidence in the findings. It is very interesting to me, as an immunologist, to see that genes involved in the immune response have been identified: this will guide us to understand better the role of infection and the mechanism of disease-susceptibility. Another fascinating finding is the identification of genes related to mitochondrial function: mitochondria are vital for producing cellular energy, and mitochondrial dysfunction has been implicated previously in ME/CFS. I would also like to see analysis of the X and Y chromosome data, to see if they yield insight into the sex-differences observed in ME/CFS incidence, although the role of hormones may be more important than genetics. It would also be of interest to see if people with different disease severity and presentation have different genetic sequences, and potentially different pathogenesis mechanisms. Replication of these results is an important next step. By providing solid biological evidence of disease-susceptibility, this study should stimulate vigorous research in the ME/CFS area. Substantial functional research is required to translate these findings into new treatments for ME/CFS, and this will take considerable investment in academia and by industry.”
Prof Alan J Carson, Professor in Neuropsychiatry, University of Edinburgh and Consultant Neuropsychiatrist, Royal Infirmary Edinburgh, said:
“This study is by someway the largest study ever conducted on genetics of CFS/ME. To date there is reasonable evidence of familial clustering which suggests but does not confirm a likely genetic contribution to the condition. Most clinicians in the field believe a genetic contribution is likely but one would say that of the majority of disorders.
“This study shows a number of modest linkages. Interestingly they are different to previously suggested candidate genes, this may be because of greater power but it also emphasises why replication will be key, chance findings are commonplace in such studies even when authors take steps to control for that.
“More importantly however no-one really knows what is wrong with the patients. Diagnosis was done by questionnaire and this has a significant error rate. The National Institute of Health in the US has suggested diagnostic error rates of around one third. Whilst much is made of patients having post exertional malaise it should be remembered that this does not have a definition, and it is found across multiple disorders not just ME. Finally, there were significant co-morbidities within the sample with disorders known to have a genetic contribution like depression, chronic pain and irritable bowel syndrome.
“So what does it all mean- the honest answer is who knows? First the findings need replicated. Then it needs to be established that they code for ME and not one of the co-morbidities; for example CSE1L has been associated with depressive illness previously. Even if we cross these hurdles, finding a few associated genes has not advanced understanding of mechanism or novel treatments to date in disorders like depression which raise similar challenges. Will it one day- maybe? But that is a long way off.”
Dr Alena Pance, Senior Lecturer in Genetics, University of Hertfordshire, said:
“This is study uses an enormous cohort of samples from healthy and patient donors to conduct a Genome Wide Association Study (GWAS) with the aim to identify genetic traits associated with and potentially causal to ME/CFS (myalgic encephalomyelitis/chronic fatigue syndrome). This is a debilitating, incapacitating disease that has been underestimated and even dismissed for a long time, because of the complexity of the disease and the lack of diagnostic tools. Aided by the statistical power of the big cohort of samples, the study identified genetic variants present in samples from people affected by the disease. This is a great advance towards understanding the illness better and most importantly towards developing diagnostic tools to facilitate appropriate healthcare.
“As any genomic study, this work has limitations highlighted by the inability to detect the sex-bias, as is observed clinically that females are more highly affected. This is due to the difficulties presented by this particular disease, mainly that diagnosis is not always clear due to the lack of precise tools and the fact that it is a multigenic and multifactorial disease meaning that is it determined by several genes and environmental factors. These characteristics of the disease make it difficult to select and discriminate patients and healthy donors, which will have an impact on the analysis of the data. Much more research is needed to continue this opening path, particularly in the search of expression quantitative trait loci (eQTLs) for the variants found, to associate the genes pinpointed in the study with differences in their expression levels in patients. This is fundamental because ultimately it is the genes affected that will produce more or less of the protein they encode, which will affect cell function. But this is totally dependent on the type of tissue examined because genes are expressed differently in distinct tissues. While the study used the most complete data available for tissue-specific gene expression, it is not exhaustive.
“The identification of specific genes as potentially involved in this disease in this study guides and enables further research to be carried out bringing the perspective of accurate diagnosis and therapy development so much closer.”
Dr Amy Mason, Research Associate, British Heart Foundation Cardiovascular Epidemiology Unit, University of Cambridge, said:
“This is a well-designed study with large numbers and careful case selection. It is particularly notable for how well it has recruited ME/CFS patients, who are usually hard to identify in existing national biobanks. The results identify specific genetic areas linked to developing ME/CFS. This is solid genetic evidence pointing to potential biological pathways that cause ME/CFS, with multiple new targets for future study.
“However, the study did not show strong replication of these results in other biobanks, although there was some suggestive evidence when using more specific definitions of ME/CFS. This may reflect poor or inconsistent diagnosis data in those other datasets, rather than flaws in the DecodeME findings themselves.
“Interestingly they find no evidence that depression and ME/CFS have shared genetic links, but do find evidence of both pain and the immune system being involved. This fits with what patients often report and helps shift the narrative; ME/CFS is not psychosomatic but linked to measurable differences in genes affecting pain and immunity.
“One limitation of this study is that it is in people of European ancestry only, due to the global lack of more diverse genetic data sets – this is a common problem with GWAS studies. However, the results are still likely to be relevant more broadly, as humans are overwhelmingly genetically similar. Another limitation is that they have not yet looked at the X and Y chromosomes, which may be why their results cannot help explain why ME/CFS diagnoses are more common in women. This doesn’t affect the validity of the signals they have found.
“This study identifies some key potential areas for future study. It lays the groundwork for other researchers and pharmaceutical companies to follow, by identifying the areas to look at both for understanding the causes of ME/CFS and for developing new drugs to treat it.”
The unpublished preprint ‘Initial findings from the DecodeME genome-wide association study of myalgic encephalomyelitis/chronic fatigue syndrome’ was available from 19:00 UK time Wednesday 6th August.
Declared interests
Dr Jackie Cliff: I have research grants from the National Institutes for Health and from ME Research UK/ME Association for ME/CFS research. I do not have any industrial funding.
Prof Alan Carson:
I am past president of British Neuropsychiatry Association and the past president of the (international) Functional Neurological Disorders Society
I am an associate editor of Journal of Neurology Neurosurgery and Psychiatry
I have given independent testimony on Court on Neuropsychiatric topics.
Dr Alena Pance: I have no conflict of interest regarding this work.
For all other experts, no reply to our request for DOIs was received.