Objective Colonic diverticulosis is a prevalent condition among older adults, marked by the presence of thin-walled pockets in the colon wall that can become inflamed, infected, haemorrhage or rupture. We present a case–control genetic and transcriptomic study aimed at identifying the genetic and cellular determinants underlying this condition and the relationship with other gastrointestinal disorders. Design We conducted DNA and RNA sequencing on colonic tissue from 404 patients with (N=172) and without (N=232) diverticulosis. We investigated variation in the transcriptome associated with diverticulosis and further integrated this variation with single-cell RNA-seq data from the human intestine. We also integrated our expression quantitative trait loci with genome-wide association study using Mendelian randomisation (MR). Furthermore, a Polygenic Risk Score analysis gauged associations between diverticulosis severity and other gastrointestinal disorders. Results We discerned 38 genes with differential expression and 17 with varied transcript usage linked to diverticulosis, indicating tissue remodelling as a primary diverticula formation mechanism. Diverticula formation was primarily linked to stromal and epithelial cells in the colon including endothelial cells, myofibroblasts, fibroblasts, goblet, tuft, enterocytes, neurons and glia. MR highlighted five genes including CCN3, CRISPLD2, ENTPD7, PHGR1 and TNFSF13 , with potential causal effects on diverticulosis. Notably, ENTPD7 upregulation was confirmed in diverticulosis cases. Additionally, diverticulosis severity was positively correlated with genetic predisposition to diverticulitis. Conclusion Our results suggest that tissue remodelling is a primary mechanism for diverticula formation. Individuals with an increased genetic proclivity to diverticulitis exhibit a larger numbers of diverticula on colonoscopy. Data are available in a public, open access repository (dbGap assession number phs003556.v1.p1).

中文翻译：

---

结肠憩室病的遗传和转录组景观

目的 结肠憩室病是老年人中的一种常见疾病，其特点是结肠壁上存在薄壁憩室，这些薄壁憩室可能会发炎、感染、出血或破裂。我们提出了一项病例对照遗传和转录组研究，旨在确定这种情况背后的遗传和细胞决定因素以及与其他胃肠道疾病的关系。设计 我们对 404 名患有 (N=172) 和不患有 (N=232) 憩室病的患者的结肠组织进行了 DNA 和 RNA 测序。我们研究了与憩室病相关的转录组变异，并将这种变异与来自人类肠道的单细胞 RNA-seq 数据进一步整合。我们还使用孟德尔随机化 (MR) 将我们的表达数量性状位点与全基因组关联研究相结合。此外，多基因风险评分分析评估了憩室病严重程度与其他胃肠道疾病之间的关联。结果我们识别出与憩室病相关的 38 个具有差异表达的基因和 17 个具有不同转录物使用的基因，表明组织重塑是憩室形成的主要机制。憩室的形成主要与结肠中的基质细胞和上皮细胞有关，包括内皮细胞、肌成纤维细胞、成纤维细胞、杯状细胞、簇状细胞、肠上皮细胞、神经元和神经胶质细胞。 MR 强调了五个基因，包括 CCN3、CRISPLD2、ENTPD7、PHGR1 和 TNFSF13，它们对憩室病具有潜在的因果影响。值得注意的是，在憩室病病例中证实了 ENTPD7 上调。此外，憩室病的严重程度与憩室炎的遗传易感性呈正相关。结论我们的结果表明组织重塑是憩室形成的主要机制。憩室炎遗传倾向增加的个体在结肠镜检查中表现出更多的憩室。数据可在公共、开放访问存储库中获取（dbGap 评估编号 phs003556.v1.p1）。