Mendelian Randomization pQTL Drug-Target Validation Methodology
Mendelian randomization using protein quantitative trait loci (pQTLs) is used to validate drug targets, but the instrument measures protein abundance while many drugs act on protein activity. We test whether this mismatch predicts a measurable validity boundary.
Mechanism-Dependent Validity of Cis-pQTL Mendelian Randomization
Abundance or Activity? Mechanism-Dependent Validity of Cis-pQTL Mendelian Randomization
Zenodo 10.5281/zenodo.21207253
A cis-pQTL instrument measures lifelong variation in circulating protein abundance, yet evaluations of pQTL-based Mendelian randomization for drug-target validation report composite accuracy across all drug mechanisms. This conflation predicts a mechanism-dependent domain of validity: MR should be informative when drug and instrument act on the same causal axis (protein level) and uninformative when they do not (protein function). Pre-registered, outcome-blind evaluation of a zero-parameter classifier against 195 Phase III drug-target pairs across 24 diseases confirms the prediction. For activity-blocking targets (n = 82), MR is uninformative (balanced accuracy = 0.515, 90% CI [0.460, 0.579]). For abundance-modulating targets (n = 72), MR is informative (BA = 0.610, [0.530, 0.694]; AUC = 0.599, permutation p = 0.024). The pooled BA of 0.578 is a mixture of these strata, consistent with benchmarks reporting lower pQTL enrichment than GWAS-only approaches. The instrument class has a definable validity boundary set by drug mechanism.