1) A thread for people worrying that the DecodeME effect sizes are too small… In an interview with David Tuller, Prof. Chris Ponting pointed out that "just because the human genetics gives a small effect size, does not predict the effect size of an intervention like a drug."
2) it might sound counterintuitive, but it make sense if you think about these genetic differences, not as measurements of the problem itself, but as mere pointers to the problem. They are just clues to what might be going wrong in the body.
3) The genetic effect size found says something about how much the relevant gene influences pathology. That might be really small: the gene might only have a small contribution. But the problem it contributes to might be big and central to the disease.
4) There’s some evidence to back this up. A recent Nature paper (Minikel et al. 2024) examined data on drug development and found that the effect size from genetic studies did not influence the chance that a drug will be successful.
5) Here’s a quote from the paper: “here we provide systematic evidence that small effect size, […] do not diminish the value of GWAS evidence to differentiate clinical success rates.”
6) They give the example of HMGCR, an enzyme involved in cholesterol synthesis. Variants in the HMGCR gene identified by GWAS have only a small effect. However, drugs such as statins, which inhibit HMGCR, produce substantial reductions in cholesterol land cardiovascular risk.
7) Here’s an analogy we made up that might help to understand the issue. It shows why effect sizes found by GWAS aren’t crucial and why interventions based on genetic hits might also help patients who do not have the risk genes.
8) Suppose an illness is caused by a structure somewhere in the body that lets cells through that it should hold back, like a dam that is breaking. There is one gene X that helps to create a simple protein that acts as one of many support structures in the dam.
9) One variant of the gene creates a slightly stronger protein than the other variant to support the dam. The difference between the two proteins is minor and this protein is only a minuscule part of what holds the dam.
10) There are many other mechanisms involved in the strength of the dam that involves feedback loops and complex interactions. These are much more important but gene X is simple and straightforward. It only has one job.
11) In GWAS of the illness, gene X might show up with a small effect size. The others don't show up because the mechanisms are too complex and intertwined or there is a signal but it's ambiguous and hard to interpret. Luckily gene X points to the problem: the dam is breaking!
Thank you for this thread.