| Title: | Unveiling Novel Traits Associated with Ulcerative Colitis via Phenome-Wide Associations Enhanced by Polygenic Risk Statistics |
| Journal: | Genes |
| Published: | 30 Nov 2025 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/41465104/ |
| DOI: | https://doi.org/10.3390/genes16121431 |
Publication 16817
WARNING: the interactive features of this website use CSS3, which your browser does not support. To use the full features of this website, please update your browser.
Abstract
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.</p>
12 Keywords
- Colitis, Ulcerative
- Female
- Genetic Predisposition to Disease
- Genome-Wide Association Study
- Humans
- Male
- Middle Aged
- Multifactorial Inheritance
- Phenotype
- Polymorphism, Single Nucleotide
- Risk Factors
- United Kingdom
6 Authors
- Yiming Wu
- Ling Liu
- Meltem Ece Kars
- Rui Li
- Menglong Li
- Yuval Itan
1 Application
| Application ID | Title |
|---|---|
| 53074 | Identifying novel high-impact rare disease-causing mutations, genes and pathways in inflammatory bowel disease patients |
Enabling scientific discoveries that improve human health