No replication of previously reported association with genetic variants in the T cell receptor alpha (TRA) locus for (ME/CFS), 2022, Ueland et al

Andy

Andy

Retired committee member
Full title: No replication of previously reported association with genetic variants in the T cell receptor alpha (TRA) locus for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)

Abstract

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a disease with a variety of symptoms such as post-exertional malaise, fatigue, and pain, but where aetiology and pathogenesis are unknown. An increasing number of studies have implicated the involvement of the immune system in ME/CFS. Furthermore, a hereditary component is suggested by the reported increased risk for disease in relatives, and genetic association studies are being performed to identify potential risk variants.

We recently reported an association with the immunologically important human leucocyte antigen (HLA) genes HLA-C and HLA-DQB1 in ME/CFS. Furthermore, a genome-wide genetic association study in 42 ME/CFS patients reported significant association signals with two variants in the T cell receptor alpha (TRA) locus (P value <5 × 10−8). As the T cell receptors interact with the HLA molecules, we aimed to replicate the previously reported findings in the TRA locus using a large Norwegian ME/CFS cohort (409 cases and 810 controls) and data from the UK biobank (2105 cases and 4786 controls).

We investigated numerous SNPs in the TRA locus, including the two previously ME/CFS-associated variants, rs11157573 and rs17255510. No associations were observed in the Norwegian cohort, and there was no significant association with the two previously reported SNPs in any of the cohorts. However, other SNPs showed signs of association (P value <0.05) in the UK Biobank cohort and meta-analyses of Norwegian and UK biobank cohorts, but none survived correction for multiple testing. Hence, our research did not identify any reliable associations with variants in the TRA locus.

Open access, https://www.nature.com/articles/s41398-022-02046-1
 
Oh, that's disappointing. But thanks to the researchers for their careful work following up a lead.
A 1% difference in allele frequencies between cases and controls was seen for some of the tested SNPs in our dataset, which, if representing a genuine difference, could reach significance in a much larger population. Hence, the lack of association in this study cannot be used to conclude that TRA is not involved in the pathogenesis of ME/CFS. This is underpinned by the signs of association observed in the self-reported UK cohort, which did not withstand correction for multiple testing. Further studies and meta-analyses are necessary to either confirm or reject an association between TRA and ME/CFS. Reliable findings will be achieved both by including more patients and controls as well as a denser set of SNPs across the TRA region. The DecodeME initiative (https://www.decodeme.org.uk/), with the goal of recruiting 20,000 ME/CFS patients, will hopefully enable robust association studies with good statistical power.
Click to expand...
No pressure, DecodeME! :)
 
I note that the same team using the same patient sample have also published in March this year the study discussed on this thread:
Genetic association study in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) identifies several potential risk loci, 2022,Hajdarevic et al
Does this mean they are gradually working their way through the data from their GWAS to home in on different regions of the genome that have previously been thought to be significant, and publish them in separate papers?
 
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