Polygenic Risk Scores Show Distinct Genetic Architectures of IBD-Associated Comorbidities

Patients with inflammatory bowel disease (IBD) have a higher prevalence of various immune and non-immune comorbidities. Whether this reflects shared genetic susceptibility or is an effect of chronic inflammation remains unclear.

We systematically assessed genetic risk underlying 20 IBD-comorbidity associations using polygenic risk scores (PRS) in 853 patients with IBD (542 Crohn's disease, 311 ulcerative colitis) and 4333 non-IBD controls from the Mass General Brigham Biobank. PRS were generated by clumping-and-thresholding approach in PLINK2.0 using largest available genome-wide association studies. Associations between PRS and IBD were tested with logistic regression adjusted for age, sex, and principal components. Bonferroni correction was applied for multiple testing.

Patients with IBD showed a significantly higher genetic risk for colorectal cancer (p = 4.1 × 10^-11), primary sclerosing cholangitis (p = 1.6 × 10^-5), and celiac disease (p = 0.0035), which may be consistent with partial shared polygenic architecture among these conditions. Conversely, patients showed significantly lower genetic risk for depression (p = 3.6 × 10^-7) and atopic dermatitis (p = 0.0016), suggesting co-occurrence may reflect factors other than shared inherited risk including shared environment or effect of chronic inflammation. Quartile analyses showed dose-response patterns for genetically mediated comorbidities. Patients with Crohn's disease had higher PRS for primary sclerosing cholangitis (p = 0.029) and type 1 diabetes (p = 0.038) compared to patients with ulcerative colitis.

IBD comorbidities show selective, rather than uniform genetic overlap. These patterns are consistent with involvement of epithelial-immune related loci, although PRS data alone do not allow causal inference. Further work is needed to clarify relative contributions of inherited risk, inflammation, and environmental factors to comorbidity patterns in IBD. These findings support PRS-based precision medicine approaches for risk stratification and personalized screening.