Importance The familial aspect of acute appendicitis (AA) has been proposed, but its hereditary basis remains undetermined.
Objective To identify genomic variants associated with AA.
Design, Setting, and Participants This genome-wide association study, conducted from June 21, 2019, to February 4, 2020, used a multi-institutional biobank to retrospectively identify patients with AA across 8 single-nucleotide variation (SNV) genotyping batches. The study also examined differential gene expression in appendiceal tissue samples between patients with AA and controls using the GSE9579 data set in the National Institutes of Health’s Gene Expression Omnibus repository. Statistical analysis was conducted from October 1, 2019, to February 4, 2020.
Main Outcomes and Measures Single-nucleotide variations with a minor allele frequency of 5% or higher were tested for association with AA using a linear mixed model. The significance threshold was set at P = 5 × 10−8.
Results A total of 29 706 patients (15 088 women [50.8%]; mean [SD] age at enrollment, 60.1 [17.0] years) were included, 1743 of whom had a history of AA. The genomic inflation factor for the cohort was 1.003. A previously unknown SNV at chromosome 18q was found to be associated with AA (rs9953918: odds ratio, 0.99; 95% CI, 0.98-1.00; P = 4.48 × 10−8). This SNV is located in an intron of the NEDD4L gene. The heritability of appendicitis was estimated at 30.1%. Gene expression data from appendiceal tissue donors identified NEDD4L to be among the most differentially expressed genes (14 of 22 216 genes; β [SE] = −2.71 [0.44]; log fold change = −1.69; adjusted P = .04).
Conclusions and Relevance This study identified SNVs within the NEDD4L gene as being associated with AA. Nedd4l is involved in the ubiquitination of intestinal ion channels and decreased Nedd4l activity may be implicated in the pathogenesis of AA. These findings can improve the understanding of the genetic predisposition to and pathogenesis of AA.