Uncovering the genetic architecture of ME/CFS: a precision approach reveals impact of rare monogenic variation, 2025, Birch, Younger et al

[Jonathan Edwards]

then wouldn’t it be helpful to have information from people with rare variants which cause larger or more clear susceptibilities

Absolutely, I think everyone is agreed on that. But if rare variants are really rare it is hard to get statistical data on relative prevalence. i think people are just arguing about how much weight one can give to rare variants that look a bit like what you were expecting to find when we cannoot be sure they are actually conferring risk rather than showing up by chance.

 

[hotblack]

i think people are just arguing about how much weight one can give to rare variants that look a bit like what you were expecting to find when we cannoot be sure they are actually conferring risk rather than showing up by chance

Ah! Gotya. Thanks for clarifying.

 

[Sly Saint]

Ok pulled together a starter set of both the studies and a few reviews of studies

• Altered Fatty Acid Oxidation in Lymphocyte Populations of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, 2023, Maya et al
• AI-driven multi-omics modeling of Myalgic Encephalomyelitis / Chronic Fatigue Syndrome, 2025, Xiong et al.
• Heightened innate immunity may trigger chronic inflammation, fatigue and [PEM]…, 2025, Che, Hornig, Bateman, Klimas, Komaroff, Lipkin+
• Initial findings from the DecodeME genome-wide association study of myalgic encephalomyelitis/chronic fatigue syndrome, 2025, DecodeMe Collaboration
• Heightened innate immunity may trigger chronic inflammation, fatigue and [PEM]…, 2025, Che, Hornig, Bateman, Klimas, Komaroff, Lipkin+
• Metabolic adaptation and fragility in healthy 3-D in vitro skeletal muscle tissues exposed to [CFS] and Long COVID-19 sera, 2025, Mughal+
• Decreased Fatty Acid Oxidation and Altered Lactate Production during Exercise in Patients with Post-acute COVID-19 Syndrome, 2022, de Boer et al
• Dissecting the genetic complexity of myalgic encephalomyelitis/chronic fatigue syndrome via deep learning-powered genome analysis, 2025, Zhang+
• Heightened innate immunity may trigger chronic inflammation, fatigue and [PEM]…, 2025, Che, Hornig, Bateman, Klimas, Komaroff, Lipkin+
• Signatures of Mitochondrial Dysfunction and Impaired Fatty Acid Metabolism in Plasma of Patients with Post-Acute Sequelae of COVID-19 (PASC), 2022, Va
• Multi-omics identifies lipid accumulation in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome cell lines: a case-control study, 2026, Missailidis et
• Sex-specific plasma lipid profiles of ME/CFS patients and their association with pain, fatigue, and cognitive symptoms, 2021, Nkiliza, Klimas et al
• Metabolic profiling reveals anomalous energy metabolism and oxidative stress pathways in CFS, 2017, Armstrong et al
• An Isolated Complex V Inefficiency and Dysregulated Mitochondrial Function in Immortalized Lymphocytes from ME/CFS Patients Missailidis et al. 2019
• A map of metabolic phenotypes in patients with myalgic encephalomyelitis/chronic fatigue syndrome, 2021, Fluge, Mella et al
• Exploring a genetic basis for the metabolic perturbations in ME/CFS using UK Biobank, 2025, Armstrong et al
• Transcriptional reprogramming primes CD8+ T cells toward exhaustion in Myalgic encephalomyelitis/chronic fatigue syndrome, 2024, Iu, Hanson et al
• Tryptophan Metabolites, Cytokines, and Fatty Acid Binding Protein 2 in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, 2021, Simonato et al
• Metabolic profiling of an ME cohort reveals disturbances in fatty acid and lipid metabolism, Hanson, Levine et al, 2018
• Myalgic encephalomyelitis/chronic fatigue syndrome patients exhibit altered T cell metabolism and cytokine associations - [new article 2020]
• Conceptual foundations of acetylcarnitine supplementation in neuropsychiatric long COVID syndrome: a narrative review, 2024, Helbing

 

[jnmaciuch]

Oh yes I agree; and the point was not that there isn't a unifying mechanism, just that in some cases it can be caused by a rare variant. Totally agree.

Ah okay, thanks for clarifying. I think a lot of the pushback comes from myself and several others on the thread interpreting the comment below and others from your posts as you arguing against a unifying mechanism. [Edit: I think everyone here is on board with the idea that rare variants could contribute strongly to someone developing ME/CFS]

I absolutely feel that - at the molecular level - ME/CFS is not one, but rather perhaps even hundreds of disease with convergent symptoms...

 

[Utsikt]

Of interest; do you think that there is no role for a mito defect in ME/CFS?

See below.

NIH-funded work has documented increased ME/CFS diagnoses following covid infection and increased rates of ME/CFS since COVID.

There are going to be more new ME/CFS cases if people get infected far more often than they used to. That’s different from covid having an increased rate of new onset ME/CFS compared to other viral infections.

Edited for clarity.

If mitochondrial dysfunction is only one pathway to ME/CFS, you’d expect related findings in just a subset of cases; not seeing it in everyone doesn’t refute the hypothesis. In heterogeneous cohorts, rare events like rhabdomyolysis could be missed (could be underpowered for this group of folks, testing to see the issue could be time-point specific, etc.). I’m not claiming it’s common or even proven; only that its absence at group level doesn’t disprove the hypothesis. I looked hard at rhabdo for a while, and there are case reports of rhabdo in ME/CFS/Long COVID patients - one I recall was an autopsy case from the UK; there were some other mentions on reddit and ME/CFS long hauler sites. So like all of these; they remain to be proven, but IMO anyway remain a plausible, if uncommon, path.

I don’t understand what you mean «pathway to ME/CFS». Can you clarify?

How do you (or others who discussed it) define broken mitochondria?

Good question. Reduced ability to generate ATP. If that was the case, we’d have seen it on the day 1 CPETs. Those results are about normal.

Other stuff related to mitochondria might be going wrong, but I have no idea if that’s upstream or downstream or just part of a self-sustaining cycle.

So can I ask; what would be your take on rare causes of ME/CFS? honestly interested in general.

I’m not sure I understand what you mean by rare causes of ME/CFS.

My layman’s thinking is that you need some kind of pathology that everyone with ME/CFS has in common. I’m sure there are hundreds of factors that make it more or less likely that you end up with ME/CFS, including rare genes.

It might be that there are two or three diseases that would all fit what we now think of as ME/CFS, but I don’t think I’ve ever heard about a syndrome that was based on reasonable clinical and scientific judgement that turned out to be dozens or hundreds of different diseases. (So excluding FND, etc. that are just territory-grabbing attempts by the BPS crowd - they are not reasonable).

———

Thank you for all for all of the studies, and thank you @Sly Saint for linking the threads!