Vanderbilt University School of Medicine, Nashville, Tennessee, USA
Department of Internal Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
BMJ Open Gastroenterol. 2024 Sep 23;11(1):e001474. doi: 10.1136/bmjgast-2024-001474.
Polygenic risk scores (PRS) for diverticular disease must be evaluated in diverse cohorts. We sought to explore shared genetic predisposition across the phenome and to assess risk stratification in individuals genetically similar to European, African and Admixed-American reference samples.
A 44-variant PRS was applied to the Research Program. Phenome-wide association studies (PheWAS) identified conditions linked with heightened genetic susceptibility to diverticular disease. To evaluate the PRS in risk stratification, logistic regression models for symptomatic and for severe diverticulitis were compared with base models with covariates of age, sex, body mass index, smoking and principal components. Performance was assessed using area under the receiver operating characteristic curves (AUROC) and Nagelkerke's R.
The cohort comprised 181 719 individuals for PheWAS and 50 037 for risk modelling. PheWAS identified associations with diverticular disease, connective tissue disease and hernias. Across ancestry groups, one SD PRS increase was consistently associated with greater odds of severe (range of ORs (95% CI) 1.60 (1.27 to 2.02) to 1.86 (1.42 to 2.42)) and of symptomatic diverticulitis ((95% CI) 1.27 (1.10 to 1.46) to 1.66 (1.55 to 1.79)) relative to controls. European models achieved the highest AUROC and Nagelkerke's R (AUROC (95% CI) 0.78 (0.75 to 0.81); R 0.25). The PRS provided a maximum R increase of 0.034 and modest AUROC improvement.
Associations between a diverticular disease PRS and severe presentations persisted in diverse cohorts when controlling for known risk factors. Relative improvements in model performance were observed, but absolute change magnitudes were modest.
必须在不同的队列中评估用于憩室病的多基因风险评分 (PRS)。我们旨在探索表型之间的共同遗传易感性，并评估在遗传上与欧洲、非洲和混合美洲参考样本相似的个体中的风险分层。
应用 44 个变异的 PRS 进行 研究计划。表型全基因组关联研究（PheWAS）确定了与憩室病遗传易感性升高相关的疾病。为了评估 PRS 在风险分层中的作用，比较了用于有症状和严重憩室炎的逻辑回归模型与包含年龄、性别、体重指数、吸烟和主成分的协变量的基础模型。使用接收者操作特征曲线下的面积 (AUROC) 和 Nagelkerke 的 R 评估性能。
该队列包括 181719 名进行 PheWAS 和 50037 名进行风险建模的个体。PheWAS 确定了与憩室病、结缔组织病和疝气的关联。在不同的祖先群体中，PRS 每增加一个标准差，与严重憩室炎（比值比 (OR) (95% CI) 1.60 (1.27 至 2.02) 至 1.86 (1.42 至 2.42)）和有症状憩室炎的几率更高（比值比 (OR) (95% CI) 1.27 (1.10 至 1.46) 至 1.66 (1.55 至 1.79)）相关。欧洲模型获得了最高的 AUROC 和 Nagelkerke 的 R（AUROC (95% CI) 0.78 (0.75 至 0.81)；R 0.25）。PRS 提供了最大 0.034 的 R 增量和适度的 AUROC 改善。
在控制已知风险因素的情况下，憩室病 PRS 与严重表现之间的关联在不同的队列中仍然存在。观察到模型性能的相对改善，但绝对变化幅度较小。
