[graboy]

I think maybe you are saying that there may be some way that the genes affect heart disease not through LDL, and therefore MR does not apply because the "exclusion restriction" [1] fails here? Or are you talking about a different assumption?

The cited study addresses this, which is why I pointed to figure 3. They argue that if genes were causing heart disease not through LDL in any meaningful way, you wouldn't expect such a clean dose-response consistency across different genetic variants - it would be more jagged.

[1] https://en.wikipedia.org/wiki/Mendelian_randomization#Defini...

[daveguy]

It seems you are confusing mendelian randomization for specific alleles associated with LDL-C production and conflating that with mendelian randomization somehow controlling genetic confounding of heart disease. The control is for the LDL production, not heart disease.

Here is a simple primer on mendelian randomization: https://www.psomagen.com/blog/what-is-mendelian-randomizatio...

Please review the key principles and assumptions section. Using MR to control for genetic confounding of heart disease fails all assumptions. Thats why it quite directly does not follow.

This is why the paper presented does not support the claim that LDL is the sole source of heart disease. I'd be interested to hear what the authors of that paper (which is legitimate) think about it being used to support the OP's claim because "mendelian randomization".

[graboy]

> This is why the paper presented does not support the claim that LDL is the sole source of heart disease

Is that what we were arguing about? I guess it was. At some point in thinking about this my frame must have shifted into agreement with you. Of course there are other causes of heart disease besides LDL, like blood pressure, duh. The smooth dose response is about the particular gene not being linked to heart disease through something other than LDL, roughly.