ME Research UK attended the ME Genetics Research Symposium held recently at the Human Genetics Unit in the University of Edinburgh. Over the course of two articles we will report on some of the research presented there.
The symposium was chaired by Prof. Chris Ponting, 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.
Prof. Ponting opened the meeting with a talk about his background in genetic research, the work of the MRC Genetics Unit, and how he became involved in the UK CFS/ME Research Collaborative, taking over a leadership role from Prof. Stephen Holgate.
He also talked about a successful partnership grant application to the Medical Research Council and the National Institute for Health Research to fund DecodeME, and study which aims to sample the saliva of 25,000 people with ME/CFS to analyse for genetic profiles that might differ from healthy controls.
A significant portion of the day was given over to discussion about the role of patient-priority-partnerships and involvement (so-called PPI), with information about how ME/CFS patients were involved in devising 10 core research questions they would most like to see addressed by scientists and clinicians working on the illness. This project was funded by the James Lind Alliance and you can see the 10 questions here.
Prof. Ponting believes genetics will play a significant part in helping to unravel some of the mysteries about what causes ME/CFS, and may also help in the development of more targeted treatments.
The search for genetic clues
Prof. Marte Viken of the University of Olso detailed the work of her team and the findings of one of the largest ME/CFS genetic studies undertaken to date, involving cohorts totalling 2,500 patients. Her talk discussed some of the finer details of genetics research (at times difficult to fully appreciate given the technical terminology used by geneticists) about the identification of possible regions of the human genome that could be important in ME/CFS.
Prof. Viken started off by saying that there appears to be a slightly increased heritability risk in ME/CFS, given the illness sometimes presents in more than one family member or relative.
She said that genetics research in this field has been hampered by a lack of scalability – genetics work really needs to be done on a large scale and should involve as many samples as possible, but funding shortages often mean researchers undertake smaller pilot studies that hold less statistical power.
To date, no established risk loci exist that point to a single genetic mutation involved in ME/CFS.
In one of the studies undertaken by Prof. Viken’s team, they analysed samples from three ME/CFS cohorts: a Norwegian discovery cohort (427 patients) with almost 41% bedbound (severe illness presentation), a Danish replication cohort (460 patients) and a replication dataset from the UK biobank (2,105 patients). This was one of the first ME/CFS genome-wide association studies of this magnitude, incorporating 2,532 patients for the genome-wide analyses and 460 patients for a targeted analysis.
Genome-wide association studies involve scanning markers across the genomes of many people to find genetic variations associated with a particular disease. The completion of the Human Genome Project in 2003 and the International HapMap Project in 2005 has allowed researchers access to a reference database of information on the human genome they can use to compare with individuals with specific illnesses and diseases such as ME/CFS.
Prof. Viken aims to explore the entire set of DNA (the genome) of ME/CFS and healthy control samples, searching for small variations called single nucleotide polymorphisms or SNPs (pronounced ‘snips’). Using computer-aided methods, this approach can look at hundreds or thousands of SNPs at the same time. The aim is to identify SNPs that occur more frequently in people living with ME/CFS and not in controls.
SNPs have been associated with several complex conditions including diabetes, heart disease, Parkinson’s disease and Crohn’s disease. While individual SNPs account for only a small percentage of disease risk, large numbers of SNPs across the genome can help determine an increased risk of developing a disease such as ME/CFS (an added risk rather than a clear cause and effect).
Prof. Viken recently published a paper on their findings. They did not find any ME/CFS risk loci displaying genome-wide significance. In the Norwegian cohort, the TPPP gene region showed the most significant association, but they could not replicate the top SNP.
Several other SNPs in the TPPP gene were associated with ME/CFS in the UK biobank cohort, and also in a combined analysis of the Norwegian and UK cohorts. Interestingly, the protein encoded by the TPPP gene is expressed in brain tissues, which is why Prof. Viken believes this gene requires further investigation on a much larger patient population.
As has been shown before, no clear gene could be identified as a strong associative factor in ME/CFS, but some clues have emerged that will inform future studies.
Prof. Viken is currently looking at genes that help code for proteins differentiating between self and non-self (human leukocyte antigens). They play a significant role in disease and immune defence, and may be involved in autoimmune responses in ME/CFS, perhaps triggered by an infection. Early experiments have identified a possible gene, DQB1, that Prof. Viken and her team wish to investigate further.
The complex work in this area continues at pace in the search for genetic markers in ME/CFS. Meanwhile, ME Research UK continue to fund research into the genetic risk factors for the disease, and in April we announced our first PhD award to Gemma Sams for a project at the University of Edinburgh under the supervision of Prof. Chris Ponting.
ME Research UK has also funded a wide range of projects in this area and continues to support genetics research in ME. In particular, ME Research UK funded a study by Dr Jonathan Kerr which also investigated SNPs and ME/CFS.