Unveiling Novel Traits Associated with Ulcerative Colitis via Phenome-Wide Associations Enhanced by Polygenic Risk Statistics.

Background

Ulcerative colitis (UC) is a major form of inflammatory bowel disease affecting the gastrointestinal tract. Increasing evidence suggests UC is predisposed to co-occurring with other autoimmune diseases, yet its pathogenesis remains insufficiently understood. Large-scale biobank-based cross-trait genetic analyses may provide insights into the origins of UC and its comorbidities.

Methods

Using the UK Biobank and Mount Sinai BioMe Biobank, we conducted genome-wide association studies (GWASs) in individuals of European ancestry. High-impact rare variants were aggregated for collapsing analysis. Genome-wide significant variants were tested in a phenome-wide association study (PheWAS) to explore UC comorbidities. Polygenic risk scores (PRSs) were derived from large-scale GWASs under different thresholds and functionalities, and the best-performing PRS was further applied in a PRS-based PheWAS. Genetic correlation between UC and highly associated traits was evaluated.

Results

GWASs identified four genome-wide significant loci, including two novel variants (rs2314757, p = 4.82 × 10-11, OR = 0.81; rs6869382, p = 2.48 × 10-8, OR = 0.83) and two previously reported UC-associated sites (rs4654925, p = 1.85 × 10-8, OR = 0.84; rs2836882, p = 1.23 × 10-11, OR = 0.78) outside the HLA region. The optimal PRS, constructed with SNPs at p < 0.05, conferred an odds ratio of 5.86 (95% CI: 5.05-6.86) for UC in individuals with the highest versus lowest quintile. Both variant- and PRS-based PheWASs consistently highlighted type 1 diabetes (T1D) as the most significant comorbidity, confirmed by genetic correlation analysis.

Conclusions

This study reveals novel loci contributing to UC and highlights comorbidities with shared genetic bases. UC PRSs demonstrated strong utility beyond risk prediction, effectively identifying UC-associated traits. A robust genetic correlation was established between UC and T1D.