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). — CFSMEATLAS
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).
Ueland, Marthe, Hajdarevic, Riad, Mella, Olav et al. · Translational psychiatry · 2022 · DOI
Quick Summary
Researchers wanted to confirm whether certain genetic changes in a gene called TRA (involved in immune system function) were linked to ME/CFS, based on earlier findings. They tested this in large groups of people from Norway and the UK, but found that the genetic changes previously reported were not reliably associated with ME/CFS. While they found some other genetic variations that showed weak signals of association, none were strong enough to be considered genuine findings.
Why It Matters
This study is important because it demonstrates the challenges in identifying genetic risk factors for ME/CFS and highlights the need for robust replication of genetic findings before drawing conclusions. Understanding genetic components of ME/CFS could eventually help with diagnosis, prognosis, and treatment development, making careful validation essential for the field.
Observed Findings
No significant association was found between rs11157573 and rs17255510 (the two previously reported variants) and ME/CFS in either the Norwegian or UK Biobank cohorts
No associations were observed across the entire TRA locus in the Norwegian cohort
Some SNPs showed uncorrected associations (P<0.05) in UK Biobank data and meta-analyses, but none withstood correction for multiple testing
The combined sample size across cohorts (2,514 cases and 5,596 controls) was substantially larger than the original study that reported the association (N=42)
Inferred Conclusions
The previously reported association signals in the TRA locus likely represent false positives or population-specific findings that do not generalize to larger, well-characterized cohorts
Genetic association studies in ME/CFS require large sample sizes and independent replication to distinguish true associations from spurious findings
Alternative genetic loci and pathways should continue to be investigated, as the TRA locus does not appear to be a reliable genetic marker for ME/CFS
Remaining Questions
Why did the original small study report such strong associations if they do not replicate in larger cohorts—was it a statistical artifact or population-specific effect?
Are there other immune-related genetic loci that would be more promising to investigate for ME/CFS susceptibility?
What This Study Does Not Prove
This study does not prove that the TRA locus has no role in ME/CFS—it only shows that these specific genetic variants are not reliably associated in these populations. Negative replication studies do not exclude other variants in the region or other genes from contributing to disease risk. The study also cannot determine causation or explain the biological mechanisms of ME/CFS.