tooluniverse-mendelian-randomization
Mendelian Randomization (Causal Inference from Genetic Instruments)
MR estimates the CAUSAL effect of an exposure on an outcome using genetic variants as instrumental variables. Because alleles are randomized at conception, MR is largely robust to the confounding and reverse causation that bias observational associations. It is not a free lunch: the causal claim rests on three assumptions, and violating them (especially horizontal pleiotropy) silently biases the estimate.
LOOK UP, DON'T GUESS: never assert a causal MR estimate from memory. Genetic-instrument results are updated as new GWAS are published — always retrieve current evidence with EpiGraphDB_get_mendelian_randomization. Do not invent beta/p-values.
Correlation ≠ causation, and genetic correlation ≠ causation. A high genetic correlation (rg) means two traits share heritability — it does NOT establish a causal direction. Only MR (with valid instruments) speaks to causality. Report them as different kinds of evidence.
The three instrumental-variable assumptions
| Assumption | Statement | How it fails | Check |
|---|---|---|---|
| Relevance | Instrument is robustly associated with the exposure | Weak instruments (low F-stat) → bias toward the confounded observational estimate | MOE score; instruments selected at GWAS significance |
| Independence | Instrument shares no common cause with the outcome | Population stratification, assortative mating | Ancestry-matched GWAS; report population |
| Exclusion restriction | Instrument affects the outcome ONLY through the exposure | Horizontal pleiotropy — the variant influences the outcome via another path | MR-Egger intercept ≈ 0; agreement across methods |
If you cannot speak to these, your causal claim is provisional. Say so.