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Which study does this refer to?

I also read that the intercept of an LD score regression can be interpreted in a similar way (an indicator of inflation). But I don't see this measure reported in the DecodeME preprint: anyone saw it somewhere?

Don't think we have discussed this plot yet: Basically, the idea is that if the difference between groups is driven by selection bias, stratification effects, ancestry differences etc., then there will be lower p-values across the board. It would look like a systematic shift where many SNPs are...

Yes, the theory isn't very specific, but I don't think anyone can be at this stage. It does predict that studying the neural pathways that cause sickness behavior and synapse communication involved in this will be more fruitful for ME/CFS than all the things the field is pursuing now. I think...

I don't think so. I think if we found strong evidence of things like this, it would refute the theory. It leaves some room for subtle peripheral pathology because biology likes to recycle things in different parts of the body. So whatever is causing the synapses to go wrong might cause some...

Could be both, I guess. My hunch is that they are different. For example that post-viral fatigue results in pressing the button of the symptom signal a bit longer, while ME/CFS is mainly about the button being broken (and constantly on).

For simplicity, I would place the pathology in (or as close to) the symptom-causing pathway itself. The pathways that interpret/evaluate signals coming from the body or help with the transmission of those signals seem less crucial. A major difference is that thoughts and behavior do not really...

I don't think it does; merely wanted to suggest how it leaves room for it. It would view overexertion as the body not responding to the symptom signal. Hence, the need to make the symptoms worse and cause PEM. This would help explain why any type of exertion (cognitive tasks, physical exercise...

Yes, many patients also report early muscle weakness/cramping/lactic acid feeling that seems similar to what Ramsay described in his descriptions of ME. Anecdotally, severe patients also seem to suffer from muscle weakness that does not appear to be due to deconditioning. I'm not sure if these...

My hunch is to follow Ockham's razor, keep things simple, and only add things if we really need to. At this point, I think there is strong evidence of an immune trigger, but not necessarily of immune pathology maintaining the illness.

Thanks for all the useful comments and suggestions! Lowered intelligence, drop in IQ level. But I generally meant that ME/CFS does not suggest brain damage or a neural development disorder. The cognitive problems are disabling but more vague and diffuse in nature, such as brain fog. Like Jo...

Conclusion Overall, I think this is convincing evidence that should make this the most plausible framework for understanding ME/CFS. When I think about other theories for ME/CFS, they often fit into this concept as an addition (for example, by giving a plausible explanation of how the signaling...

Genetic data Let’s now move on to some actual data. The best evidence that we have is from genetic studies because of large sample sizes that control for population differences and that are not confounded by other factors such as diet, behavior, or the illness itself. If we look at all the...

I wanted to make a thread to discuss the theory that ME/CFS is a signaling problem, located in the synapses of neurons in the brain. I think it fits and would help explain the few findings and observations that we have about the illness. The clinical picture First of all, there is no clear...

For the hits on chromsome 1 and 20, there are so many potential genes on the location it's harder to guess which one might be relevant.

For the hit on chromosome 17, CA10 is the only candidate and it also clearly linked to neurons and synapses. So if we focus on the close-by genes, the clearest hits seem to point to neurons/synapses. The exceptions are OLFM4 on chromosome 13, which has a clear immune connection (linked to...

PEBP1 seems like the second closest to the hit on chromosome 12, next to TAOK3, which seems very stretched out. EDIT: added the image below

Another gene that hasn't been discussed yet but that seems the closest to the hit on chromosome 6q is POU3F2 POU3F2 Gene - GeneCards | PO3F2 Protein | PO3F2 Antibody EDIT: added the image below

Highlighting gene UNC13C, which seems the closest to the hits on chromosome 15. The gene card reads as follows: UNC13C Gene - GeneCards | UN13C Protein | UN13C Antibody EDIT: added the image below

This lecture is interesting and relevant to our discussion: MPG Primer: Linking SNPs with genes in GWAS (2022) Don't understand everything, but there's some discussion that eQTL data and GWAS hits often do not match very well. Genes that are likely to be causally related to disease often do not...