ME Research UK attended the ME Genetics Research Symposium held recently at the Human Genetics Unit at the University of Edinburgh. Here is our second article reporting on some of the research presented there. (You can read part 1 here.)
The symposium was chaired by Prof. Chris Pointing, Director of the Medical Research Council Genetics Unit at Edinburgh, and research lead of the new DecodeME study which is investigating potential genetic causes of why some people develop ME/CFS.
However, given that decades of research looking for a gene, or genes, involved in ME/CFS have returned inconsistent results, we might ask how likely it is that ME/CFS holds any genetic risk association at all.
Prof. Ponting and co-authors published a paper in 2020 that reviewed the scientific literature in search of evidence for genetic risk factors in ME/CFS. Disappointingly, they found that multiple genome-wide studies using UK Biobank patients had failed to find any consistent associations.
Despite a lack of clear genetic biomarkers, the authors feel that prior studies suffered from inconsistency in study methods and low participant numbers. They believe that a genome-wide association study (or GWAS) using much larger numbers of participants may reveal some as yet unknown genetic links. A GWAS is an approach used to identify genomic variants associated with a risk for a disease or a particular trait.
This desire to ‘go big’ is a major rationale behind the DecodeME project being led by Prof. Ponting in Edinburgh. He hopes to collect as many as 25,000 DNA samples, including 5,000 from people who may have developed ME/CFS after a COVID-19 infection.
While no clear causal genetic mutation in a single gene has been found in ME/CFS to date, researchers in this area have long suspected some genetic component, given that ME/CFS appears to present slightly more often in other family members.
The obvious question is whether or not these ME/CFS cases result from linked genes or some acquired risk factor, such as shared exposure to a particular pathogen like a virus, or, controversially, some social factors shared by family members.
In 2014, Drs Shimosako and Kerr published a paper identifying 21 SNPs (single nucleotide polymorphisms) that were significantly associated with ME/CFS (compared with healthy subjects and those with depression). SNPs are the most common type of genetic variation among people, where each SNP represents a difference in a single DNA building block, called a nucleotide. In this study, 148 SNP alleles had a significant association with one or more ME/CFS subtypes.
Dr Kerr believed some ME/CFS patients could be subtyped based on their genetic SNP profiles but, again, study numbers were small and other researchers have been unable to easily genetically profile ME/CFS patients.
A private sector company called PrecisionLife based in the UK has taken an interest in this area and presented some of their findings at the Edinburgh Symposium. Company CEO Dr Steve Gardener spoke about how his company is using computational mathematics, large database analysis and computer modelling to generate insights into the biological mechanisms underpinning complex chronic diseases.
The company appears to have been attracted to this area by the funding available for long COVID research and a potentially lucrative market for diagnostics and therapeutics, and Dr Gardener said they viewed ME/CFS as a useful analogue to better understand long COVID.
Dr Sayoni Das, one of their lead bioscientists, gave more information about a new publication (not yet peer-reviewed) reporting results from PrecisionLife’s case-control GWAS study exploring samples from ME/CFS cohorts in the UK Biobank.
They report finding 199 SNPs, mapping to 14 specific genes, that they say were significantly associated with 91% of the cases in the ME/CFS population analysed. These SNPs were stratified into 15 clusters. Many of the genes identified are linked to key cellular mechanisms thought to underpin ME/CFS, including stress and/or infection, mitochondrial dysfunction, sleep disturbance, and autoimmune development.
Dr Das said their results show similarities with genes associated with multiple sclerosis and long COVID, which may both be triggered by viral infections.
Making sense of the results
It is important to note that the term ‘association’ does not necessarily mean there is a causal relationship, only that some SNPs have been identified that may be involved and that require more research.
One possibility is that ME/CFS is not actually a genetic disorder inherited at birth (like sickle cell disease), since many ME/CFS sufferers live perfectly normal and healthy lives up to the point they develop the illness. However, there may still be some inherited susceptibility, such as a reduced ability to fight off infections.
Problems fighting off infections or keeping them under control may help explain why a small subgroup (around 10%) of people who contract Epstein-Barr virus remain unwell for up to a year, while a smaller subgroup remain unwell for longer and meet ME/CFS diagnostic criteria – as noted in a longitudinal study conducted in the USA by Prof. Jason at DePaul University.
The possibility of an immune deficiency might lead us to consider inherited illnesses such as Immunoglobulin Deficiency Syndrome – this is a reduced ability to produce an effective antibody response to infections. There are five types of immunoglobulin (IgG, IgA, IgM, IgD and IgE), and sometimes patients may not have a primary disorder of immunoglobulins, but rather a subtle deficiency in one type that goes undetected yet lowers the antibody response to specific infections.
Staying with genetic blood disorders, one might think of a person who, while not having outright thalassaemia (a genetic blood disorder of haemoglobin), still carry the gene for it, and thus can be considered to have a thalassaemic trait. Could it be that many humans carry similar traits for immunological disorders that are not fully expressed but make an individual more vulnerable to ME/CFS?
Another potential area of interest is allergy and inflammatory responses to infections. Perhaps some people carry a genetic propensity to produce a strong inflammatory response to infections that upregulates specific cellular activities, such as producing the ‘cytokine storm’ we hear so much about in ME/CFS and long COVID. Such a response might dysregulate the immune system meaning that a return to normal is lost.
Finally, rather than search for the silver bullet of one gene or a series of genes, many researchers in this field appear to favour an epigenetic theory. Epigenetics is the study of how human behaviour and environment interact with biology and affect the way our genes function. Crudely, we can think of genes switching on and off as a result of diet, lifestyle, stress, chemical exposure or infection.
There may still be an inherited chink in the armour that increases a person’s risk of developing ME/CFS carried in the DNA, but it is more likely that a combination of factors – including age, sex, stress and exposure to one or more infections – ultimately results in a person going on to develop ME/CFS.