Currently, there is no consensus on the genetic foundations of ME/CFS, although its heritability estimated at up to
50%. While a large-scale GWAS is ongoing in a dedicated ME/CFS cohort (DECODE-ME), our project will complement
this by focusing on rare genetic variants. Thus, the aim of this research project is to provide a list of causal genes for
ME/CFS to facilitate further testing and characterization in collaboration with clinical researchers and wet lab
biologists.
This opportunity arises from the recent availability of whole genome sequencing data from large-scale biobanks
such as UK Biobank. We can now categorize all protein-altering variants within a gene or other
genomic structures like transcription factor binding sites and evaluate their collective impact on ME/CFS. We will
utilize the International Consensus Criteria to define cases, however we will also conduct sensitivity analyses
around the phenotype definition, and extend our analyses to include long COVID phenotypes within the cohorts
mentioned above.
Our primary analysis will be a meta-analysis of data from the UK Biobank and All of Us, which we will, depending on
availability, also attempt to replicate using imputed data from the DECODE-ME cohort. This will not only provide
the most extensive analysis of rare variants in ME/CFS to date enhancing our knowledge of the condition’s causal
genes and pathways, but it will also establish a dataspace and collaborative framework for clustering, factor
analysis, and other exploratory and epidemiological studies, which we think are essential to fully understand this
complex condition. These analyses could also inform subsequent rounds of genetic association tests. Ultimately,
the outcomes of these tests may enable stratification of patients and facilitate the categorization of patients into
specific subgroups.
