Acute appendicitis is a common disease with a causative mechanism that is likely multifactorial. Existing evidence1-4 is suggestive of a familial predisposition to acute appendicitis, with heritability estimates ranging from 27% to 56%. In a multi-institutional genome-wide association study in this issue of JAMA Surgery, Gaitanidis and colleagues5 identified a polymorphism at 18q, located in the NEDD4-like E3 ubiquitin protein ligase (NEDD4L) gene, which was associated with the development of acute appendicitis. They validated this finding by demonstrating differential expression of NEDD4L in appendiceal tissue from donors with vs without acute appendicitis. This study5 identifies only the second polymorphism known to be associated with acute appendicitis. The locus 4q25, adjacent to the paired-like homeodomain 2 (PITX2) gene, was the first (to our knowledge) to be associated with an increased risk of acute appendicitis.1,6,7 Within the cohorts analyzed in the study by Gaitanidis et al,5 however, 18q demonstrated a larger effect size than 4q25, suggesting the possibility of a more causal link between perturbation of NEDD4L and the pathogenesis of acute appendicitis. These types of polymorphisms may be associated with secretion quality or appendiceal luminal quality that may predispose to appendicitis.