DHCR7 Mutation Carriers and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: No Associations According to DecodeME Data, 2026, Sverdrup et al

[forestglip]

DHCR7 Mutation Carriers and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: No Associations According to DecodeME Data

Spoiler: Authors

Sverdrup, Antoniy Elias; Akhmetzyanova, Elvira R.; Molchun, Anna M.; Liaudanski, Aleh D.; Rizvanov, Albert A.

Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating multi-system disorder whose pathogenesis is associated with metabolic and immune dysfunction. Dysfunction of cholesterol metabolism and vitamin D deficiency are considered potential path-ogenic factors.

The DHCR7 gene, encoding 7-dehydrocholesterol reductase, catalyzes the final step in cholesterol biosynthesis and simultaneously determines the availability of provitamin D. Pathogenic DHCR7 mutations, leading to the development of Smith-Lemli-Opitz syndrome (SLOS) in the homozygous state, are characterized by a high prevalence in the population as heterozygous carriers (~1%). Therefore, it was hypothesized that heterozygous carriage of DHCR7 mutations may be associated with an increased predisposition to the development of ME/CFS.

Materials and Methods
We used open-source genetic data from the DecodeME project (n = 15,579 ME/CFS patients, 259,909 controls). We analyzed the frequency of 11 pathogenic DHCR7 mutations: IVS8-1G>C, W151X, T93M, V326L, R404C, R352W, E448K, R352Q, G410S, R242C, and F302L. The association with the ME/CFS phenotype was assessed using a χ² test in six datasets (the overall sample (gwas_1), subsamples of men (gwas_1_male), women (gwas_1_female), spontaneous CFS development (gwas_1_non-infectious_onset), CFS development with infectious onset (gwas_1_infectious_onset), and a subsample with a 1:10 patient: control ratio (gwas_2)).

Results
Only the IVS8-1G>C mutation was detected in the DecodeME data (carrier frequency ~1%). A statistically significant association (p-value ≈ 0.013) was observed in only one subsample (gwas_2) but was not replicated in the others. The remaining mutations were not detected in the DecodeME data.

Conclusions
The obtained results do not support the hypothesis of a link between carriage of SLOS-inducing DHCR7 mutations and ME/CFS. This negative result is important for the correct refinement of metabolic hypotheses regarding pathogenesis and the prioritization of research areas. Further study of sterol metabolism and metabolomic biomarkers in patient subgroups is recommended.

Web | DOI | PDF | Personalized Psychiatry and Neurology | Open Access

 

[ScoutB]

This negative result is important for the correct refinement of metabolic hypotheses regarding pathogenesis and the prioritization of research areas.

Appreciate this, if only we saw this kind of comment more often.

 

[Simon M]

I agree that it's fantastic to have a negative results like this published. Right now, everything has been proposed, almost nothing ruled out. I know that Chris Ponting thought one of the benefits of.DecodeME , and making the data publicly available, was that researchers could use it for just this: testing out hypotheses.

If something doesn't hold up with genetic data, maybe it's time to move on, or refine the hypothesis. This way, we are more likely to get progress.

 

[Utsikt]

Yet another reason to fund a WGS (especially the Germans): it enables you to avoid spending limiting resources on red herrings.

 

[Hutan]

From a Russian (Kazan) and Belarus team

Smith–Lemli–Opitz syndrome (SLOS) is a rare autosomal recessive disorder caused by mutations in the DHCR7 gene on chromosome 11 (locus 11q12–q13). DHCR7 defects result in a deficiency of the enzyme 7-dehydrocholesterol reductase, the final step in cholesterol synthesis. As a result, patients with SLOS have dramatically reduced cholesterol levels and an accumulation of its intermediate precursors (e.g., 7-dehydrocholesterol).

So, the defects that were looked for reduce cholesterol and increase 7-dehydrocholesterol.

A number of metabolomics studies have shown changes in the lipid profile in ME/CFS – disturbances in the levels of phospholipids, triglycerides, cholesteryl esters, and cholesterol itself [5]. A decrease in high-density lipo-protein (HDL) levels was also noted in patients with chronic fatigue compared to healthy controls [6]. These data suggest a possible role for lipid and sterol metabolism (including cholesterol) in the pathogenesis of ME/CFS[5].

References

5. Nkiliza A., Parks M., Cseresznye A., et al. Sex-specific plasma lipid profiles of ME/CFS patients and their association with pain, fatigue, and cognitive symptoms. J Transl Med. 2021; 19: 370. https://doi.org/10.1186/s12967-021-03035-6​

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6. Tseng C., Huang Y., Lee Y., et al. High-density lipoprotein cholesterol abnormalities correlate with severe fatigue in major depressive disorder: A cross-sectional study. Journal of Psychosomatic Research. 2024; 184: 111835 https://doi.org/10.1016/j.jpsy-chores.2024.111835​

I don't think we have seen a pattern of low cholesterol in people with ME/CFS (or, for that matter, particularly high cholesterol)? That reference there suggesting a decrease in people with chronic fatigue (Ref #6) is for people with fatigue as part of major depressive disorder. I'm therefore a bit puzzled as to why this investigation was selected as a priority, although, like others, I appreciate the publishing of a null result.

A very recent study of post-COVID-condition (unfortunately a very small study) reported that HDL was lower in their PCC sample.
A 2024 study on the UK Biobank data (and its probably poorly characterised ME/CFS cohort) found some differences in free cholesterol (also lower HDL and slightly lower LDL, but higher VLDL.
I'm sure that there have been plenty of other studies that have measured cholesterol e.g. the NIH Deep phenotyping study?

Since the original hypothesis was biologically sound (through the role of cholesterol and vitamin D in the nervous system), documenting its refutation helps clarify the direction of further research. In the future, it would be worthwhile to study more subtle aspects of sterol metabolism in ME/CFS: for example, by directly measuring the levels of 7-dehydrocholesterol, cholesterol, and its metabolites (oxysterols) in patients compared to healthy controls. It also remains an open question whether non-genetic factors influencing DHCR7 enzyme activity (e.g., hormonal, dietary, or environmental influences) could influence the course or symptoms of ME/CFS.

I guess it would be good to have more measurements of cholesterol and related metabolites in a large samples of people with well-characterised ME/CFS. But I think that if these things were low in the blood of people with ME/CFS, we'd have an idea that that is so by now.