Study explains why both loss-of-function and duplication variants affect complex traits in the same direction

Summary

Milind et al. investigate a paradox in human genetics: why loss-of-function variants (which decrease gene expression) and duplications (which increase expression) tend to have effects in the same direction on 94 complex traits, rather than opposite effects as intuition would suggest. Using gene dosage response curves (GDRCs), they gather evidence for two explanatory models and interpret what these observations imply about the genetic architecture of complex traits. The findings suggest that for most complex traits, the genome-wide burden of both types of variants push phenotypes in the same direction, challenging simple assumptions about gene dosage effects.