Genetic association study in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) identifies several potential risk loci, by Riad Hajdarevic, Asgeir Lande, Jesper Mehlsen, Anne Rydland, Daisy D Sosa, Elin B Strand, Olav Mella, Flemming Pociot, Øystein Fluge, Benedict A Lie, Marte K Viken in Brain, Behavior, and Immunity Vol 102, May 2022, Pages 362-369 [doi.org/10.1016/j.bbi.2022.03.010]
Research highlights
- Largest ME/CFS genetic study to date.
- Three different cohorts totaling more than 2500 patients.
- First Immunochip study in ME/CFS.
- Possible implication of TPPP genetic region.
Research abstract:
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a disease of unknown etiology and pathogenesis, which manifests in a variety of symptoms like post-exertional malaise, brain fog, fatigue and pain. Hereditability is suggested by an increased disease risk in relatives, however, genome-wide association studies in ME/CFS have been limited by small sample sizes and broad diagnostic criteria, therefore no established risk loci exist to date.
In this study, we have analyzed three ME/CFS cohorts: a Norwegian discovery cohort (N=427), a Danish replication cohort (N=460) and a replication dataset from the UK biobank (N=2105). To the best of our knowledge, this is the first ME/CFS genome-wide association study of this magnitude incorporating 2532 patients for the genome-wide analyses and 460 patients for a targeted analysis. Even so, we did not find any ME/CFS risk loci displaying genome-wide significance.
In the Norwegian discovery cohort, the TPPP gene region showed the most significant association (rs115523291, P=8.5×10-7), but we could not replicate the top SNP. However, several other SNPs in the TPPP gene identified in the Norwegian discovery cohort showed modest association signals in the self-reported UK biobank CFS cohort, which was also present in the combined analysis of the Norwegian and UK biobank cohorts, TPPP (rs139264145; P= 0.00004). Interestingly, TPPP is expressed in brain tissues, hence it will be interesting to see whether this association with time will be verified in even larger cohorts.
Taken together our study, despite being the largest to date, could not establish any ME/CFS risk loci, but comprises data for future studies to accumulate the power needed to reach genome-wide significance.
Discussion – excerpt
Using genome-wide array data and large ME/CFS cohorts (>2900 patients in total), we have identified several chromosomal regions with suggestive ME/CFS associations that warrants follow-up in subsequent studies towards the future establishment of the first ME/CFS genetic risk loci at genome-wide significance…
Despite the current lack of large cohorts of phenotypically stringent and well-characterized ME/CFS patients, this study represents, to the best of our knowledge, the largest and most homogenous genetic study performed in ME/CFS so far. Ongoing projects like the DecodeME project (https://www.decodeme.org.uk) will enable future studies of larger and more powerful cohorts, which are warranted to produce the desired statistical power to definitively investigate the genetic architecture of ME/CFS.
In conclusion, we identified several potential risk loci for ME/CFS, which encourage further investigations. Future genetic studies should be performed in large cohorts of several thousand patients and strive to use strict and comprehensive phenotyping to enable analyses of homogenous sub-phenotypes.
