Associations of polygenic risk scores with intestinal surgery, gastrointestinal cancer, and all-cause mortality in 5,021 individuals with inflammatory bowel disease

Polygenic risk scores (PRS) predict inflammatory bowel disease (IBD) susceptibility, but their associations with outcomes after diagnosis are uncertain. We studied 5,021 UK Biobank participants with Crohn’s disease (CD; n = 1,427) or ulcerative colitis (UC; n = 3,594). Cox-model estimates for disease-specific standardized PRS were pooled across 20 imputed datasets. A clinically extended model included disease duration, log-transformed C-reactive protein, previous intestinal surgery, and baseline aminosalicylate, corticosteroid, and immunomodulator use in addition to demographic and lifestyle covariates. Benjamini–Hochberg false-discovery rate (FDR) correction covered six disease–outcome tests. In CD, each 1-SD higher PRS was associated with intestinal surgery (HR = 1.61, 95% CI 1.31–1.99; P < 0.001; FDR < 0.001); the high versus low tertile estimate was HR = 2.70 (95% CI 1.58–4.62; FDR = 0.004). CD PRS was not associated with gastrointestinal cancer or mortality. In UC, associations with surgery ( P = 0.482), gastrointestinal cancer (HR = 1.21, 95% CI 0.99–1.48; P = 0.065; FDR = 0.130), and mortality (HR = 1.10, 95% CI 1.00–1.22; P = 0.058; FDR = 0.130) were nonsignificant. The CD surgery association persisted among participants without previous surgery (HR = 1.62, 95% CI 1.29–2.04; P < 0.001). These genetic epidemiology associations do not establish incremental prediction or clinical utility and require external validation.