In this study we identified modifiers of meconium ileus susceptibility, encompassing the previously identified SLC26A9 and SLC6A14, and two new loci ATP12A and PRSS1. To understand the mechanism by which these modifier genes impact CF severity we developed a new statistical method that assesses colocalization with regulatory information. Here, PRSS1 is linked to intestinal obstruction in the newborn due to guanylate cyclase 2C deficiency.