To see if our approach provides well-calibrated p-values, we simulated random phenotypes and calculated association p-values for all 1KG SNPs. We then employed our pathway analysis pipeline and checked if pathway p-values were uniformly distributed, as expected for random phenotypes. We found that without the gene-fusion strategy, pathway p-values are indeed inflated and, as expected, this inflation is stronger for pathways with many proximal genes (Fig 3A). In contrast, applying the gene-fusion strategy corrects the distribution of pathway score p-values to be uniform irrespective of the number of proximal genes (Fig 3B). Importantly, we did not see inflation for very small p-values with the gene-fusion strategy, which is essential for type I error control.
