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

[jnmaciuch]

But if these numbers are representative, then - assuming my math is correct - one out of eight ME/CFS cases alone can be attributed to a single variation of channelopathy

One out of eight. Are these not-ME/CFS? Are there more of what we call ME/CFS that are not ME/CFS? Is that just the ratio for a single brand of ME/CFS? Or an indicator that true ME/CFS is rarer still? Or is it not even a thing??

I don't think we can really answer any of those questions from this data--they were specifically looking for variants that were common between their ME/CFS cases to highlight in the results, not doing an unbiased search. And they're only guessing it's relevant here because it's relevant in some other disease contexts when it's a homozygous, rather than a heterozygous, mutation.

What they're doing here is the same level of causal inference as if I went to the homes of a bunch of people that suffered a heart attack looking for something which would "explain" the connection between them and found that a handful always bought the same brand of deli meat, which I thought was important because processed meats have sodium and that's been linked to heart disease.

 

[alex3619]

I am not sure why 'genetic heterogeneity' is problematic.

Agree. High genetic heterogeneity is only a problem is there is high downstream causal heterogeneity. If a huge number of genes have potentially a small impact on the pathological mechanisms, but the mechanisms are conserved, the focus should be on those mechanisms. Now metabolomic, RNA and proteomic sequencing are still relevant until we have identified and understood the mechanisms.