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.

重要性 急性阑尾炎 (AA) 的家族性已被提出，但其遗传基础仍未确定。

目的 鉴定与 AA 相关的基因组变异。

设计、设置和参与者 这项全基因组关联研究于 2019 年 6 月 21 日至 2020 年 2 月 4 日进行，使用多机构生物库对 8 个单核苷酸变异 (SNV) 基因分型批次的 AA 患者进行回顾性鉴定。该研究还使用美国国立卫生研究院基因表达综合库中的 GSE9579 数据集检查了 AA 患者和对照组之间阑尾组织样本中的差异基因表达。统计分析于 2019 年 10 月 1 日至 2020 年 2 月 4 日进行。

主要结果和措施 使用线性混合模型测试具有 5% 或更高的次要等位基因频率的单核苷酸变异与 AA 的关联。显着性阈值设置为P  = 5 × 10 ^-8。

结果 共纳入 29 706 名患者（15 088 名女性 [50.8%]；入组时平均 [SD] 年龄，60.1 [17.0] 岁），其中 1743 名有 AA 病史。该队列的基因组膨胀因子为 1.003。发现染色体 18q 上的一个先前未知的 SNV 与 AA 相关（rs9953918：优势比，0.99；95% CI，0.98-1.00；P  = 4.48 × 10 ^-8）。该 SNV 位于NEDD4L基因的内含子中。阑尾炎的遗传率估计为30.1%。来自阑尾组织供体的基因表达数据确定NEDD4L是最差异表达的基因之一（22 216 个基因中的 14 个；β [SE] = -2.71 [0.44]；对数倍数变化 = -1.69；调整后的P  = .04）。

结论和相关性 本研究确定 NEDD4L 基因内的SNV与 AA 相关。Nedd4l 参与肠道离子通道的泛素化，降低的 Nedd4l 活性可能与 AA 的发病机制有关。这些发现可以提高对 AA 的遗传易感性和发病机制的理解。