Multiancestry transferability of a polygenic risk score for diverticulitis

Abstract

Objective: 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.

Methods: A 44-variant PRS was applied to the All of Us 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 R².

Results: 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 R² (AUROC (95% CI) 0.78 (0.75 to 0.81); R² 0.25). The PRS provided a maximum R² increase of 0.034 and modest AUROC improvement.

Conclusion: 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.

Keywords: DIVERTICULAR DISEASE; GENETIC POLYMORPHISMS; SURGICAL RESECTION.

Figure 1. Overview of study design. AFR, EUR, AMR, individuals with genetic similarity to 1000Genomes African, European and Admixed American reference samples; PheWAS, phenome-wide association study; PRS, polygenic risk score.

Figure 2. Phenome-wide association studies of a diverticular disease polygenic risk score in the All of Us Research Program. Cohorts comprised of individuals with genetic similarity to 1000Genomes reference samples in the following groups: (A) European (EUR), (B) African (AFR), (C) Admixed-American (AMR) and (D) Combined (EUR+AFR + AMR).

Figure 3. Nagelkerke’s R² in the All of Us Research Program. Covariates in the base model include age, sex, the first 10 genetic principal components, body mass index and any smoking status. The full model additionally includes the polygenic risk score. The Nagelkerke’s R² was converted to the liability scale as recommended by Lee et al. AFR, EUR, AMR: individuals with genetic similarity to 1000Genomes African, European and Admixed American reference samples. Combined group includes AFR + EUR + AMR participants.