Genetic variants associated with chronic fatigue syndrome predict population-level fatigue severity and actigraphic measurements, 2024, Liu et al.

Genetic variants associated with chronic fatigue syndrome predict population-level fatigue severity and actigraphic measurements
Liu, Patrick Z; Raizen, David M; Skarke, Carsten; Brooks, Thomas G; Anafi, Ron C

STUDY OBJECTIVES
The diagnosis of myalgic encephalomyelitis/chronic fatigue syndrome (CFS) is based on a constellation of symptoms which center around fatigue. However, fatigue is commonly reported in the general population by people without CFS. Does the biology underlying fatigue in patients with CFS also drive fatigue experienced by individuals without CFS?

METHODS
We used UK Biobank actigraphy data to characterize differences in physical activity patterns and daily temperature rhythms between participants diagnosed with CFS compared to controls. We then tested if single nucleotide variants (SNVs) previously associated with CFS are also associated with the variation of these actigraphic CFS correlates and/or subjective fatigue symptoms in the general population.

RESULTS
Participants diagnosed with CFS (n = 295) had significantly decreased overall movement (Cohen’s d = 0.220, 95% CI of -0.335 to -0.106, p-value = 2.42x10-15 ), lower activity amplitudes (Cohen’s d = -0.377, 95% CI of -0.492 to -0.262, p-value = 1.74x10-6 ), and lower wrist temperature amplitudes (Cohen’s d = -0.173, 95% CI of -0.288 -0.059, p-value = 0.002) compared to controls (n = 63,133). Of 30 tested SNVs associated in the literature with CFS, one was associated in the control population with subjective fatigue and one with actigraphic measurements (FDR < 0.05).

CONCLUSIONS
The genetic overlap of CFS risk with actigraphy and subjective fatigue phenotypes suggests that some biological mechanisms underlying pathologic fatigue in CFS patients also underlie fatigue symptoms at a broader population level. Therefore, understanding the biology of fatigue in general may inform our understanding of CFS pathophysiology.

Link | PDF (Sleep) [Open Access]

 

Regarding SLC15A4 and ATP9A, see also —

Genetic risk factors for severe and fatigue dominant long COVID and commonalities with ME/CFS identified by combinatorial analysis (2023, Journal of Translational Medicine) —

[86] is Human SLC15A4 is crucial for TLR-mediated type I interferon production and mitochondrial integrity (2021, International Immunology)

 

"Members of the CFS group must have met both of two criteria: 1) they must have answered “Yes” to the 2019 UKBB pain supplement questionnaire question “Have you ever been told by a doctor that you have had Chronic Fatigue Syndrome or Myalgic Encephalomyelitis (M.E.)?” and 2) they must have self-reported having CFS prior to 2013 during a verbal interview by a trained nurse on past and current medical conditions."

Hmm..

The findings are certainly interesting, and the overlap with findings from other studies.

But 295 is a tiny sample for a study like this when UKB has a few thousand cases. The recent blood biomarker study from Edinburgh also required CFS peeps to declare fair/poor health and HC to be average/good, which apparently made a big difference.

The small Cohen's d effect sizes for CFS vs actigraphy also casts doubt on the severity for this CFS cohort.

 

Statement of Significance

Objective metrics characterizing symptomatology in chronic fatigue syndrome are scarce and would provide insight into phenotypic presentation, pathophysiology, and fatigue in general. How genetic risk for chronic fatigue syndrome influences phenotypic manifestations of fatigue also remains uncharacterized. This study utilizes large-scale datasets to demonstrate that individuals with chronic fatigue syndrome exhibit reduced total physical activity, lower physical activity amplitudes, and altered wrist temperature rhythms. Moreover, genetic variants associated with CFS modulate these phenotypic manifestations in a control population. These findings suggest the potential of characterizing objective actigraphic parameters in chronic fatigue syndrome patient populations and of linking genetic risk to symptomology, providing insights for understanding chronic fatigue syndrome and fatigue in general and establishing potential mechanistic routes for further investigation.

 

The conclusion of the paper writes:

Which I found rather confusing because the content of their paper suggest rather the opposite. Of 30 single nucleotide variants (SNVs) previously associated with CFS, only one was associated with subjective fatigue severity in the control group. The authors argue that this is unlikely to be due to lack of statistical power:

So where does this statement come from that "some biological mechanisms underlying pathologic fatigue in CFS patients also underlie fatigue symptoms at a broader population level". It is a plausible hypothesis but I don't see anything in this paper that provides evidence for it.