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Purpose <p>The genetic component of ulcerative colitis (UC) remains largely unexplained in non-European populations. This study aimed to investigate the polygenic architecture of UC in an Indian population.</p> Methods <p>Whole-exome sequencing was performed in 160 UC patients and 379 ethnically matched controls. Gene-based rare variant burden tests (SKAT-O, CMC) and exome-wide association testing of coding and noncoding common variants using allelic chi-square testing were performed.</p> Results <p>Burden analysis identified 85 previously unreported genes significantly enriched for rare variants in UC, of which 22 showed suggestive associations (<i>P</i> ≤ 5 × 10⁻³; odds ratio 2.6–10.9). These genes were primarily involved in epithelial integrity, immune signalling, DNA repair, and vesicle trafficking pathways. Exome-wide association analysis identified 55 common variants surpassing the Bonferroni-corrected significance threshold (<i>P</i> ≤ 5.57 × 10⁻⁷), mapping to 44 unreported and two known susceptibility genes, with most belonging to functional categories similar to those observed in the rare variant analysis. Logistic regression analysis showed that variants significant in the allelic test remained significant after adjustment for covariates. STRING network analysis revealed functional interactions between eight genes identified in this study and known inflammatory bowel disease–related genes. Sub-phenotype analysis further indicated genetic heterogeneity among clinically defined UC subgroups.</p> Conclusion <p>This first exome-based study of Indian UC patients expands the genetic landscape of the disease and identifies population-specific associations that appear distinct from those reported in Western cohorts, suggesting potential differences in underlying disease mechanisms. Most identified genes map to disease-relevant pathways. However, given the modest sample size and limited statistical power, these findings should be considered exploratory and require further validation to clarify their contribution to UC pathogenesis. The study also underscores the importance of conducting genetic investigations in genetically diverse and understudied populations to improve the broader applicability of genetic findings.</p>

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Exome analysis of Indian ulcerative colitis reveals novel genes affecting epithelial integrity, DNA repair, trafficking, and immune signalling

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年8月5日

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  • Radhika Chauhan,
  • Bhawna Sharma,
  • Ajit Sood,
  • Vandana Midha,
  • Arshdeep Singh,
  • Jibin John,
  • Garima Juyal

摘要

Purpose

The genetic component of ulcerative colitis (UC) remains largely unexplained in non-European populations. This study aimed to investigate the polygenic architecture of UC in an Indian population.

Methods

Whole-exome sequencing was performed in 160 UC patients and 379 ethnically matched controls. Gene-based rare variant burden tests (SKAT-O, CMC) and exome-wide association testing of coding and noncoding common variants using allelic chi-square testing were performed.

Results

Burden analysis identified 85 previously unreported genes significantly enriched for rare variants in UC, of which 22 showed suggestive associations (P ≤ 5 × 10⁻³; odds ratio 2.6–10.9). These genes were primarily involved in epithelial integrity, immune signalling, DNA repair, and vesicle trafficking pathways. Exome-wide association analysis identified 55 common variants surpassing the Bonferroni-corrected significance threshold (P ≤ 5.57 × 10⁻⁷), mapping to 44 unreported and two known susceptibility genes, with most belonging to functional categories similar to those observed in the rare variant analysis. Logistic regression analysis showed that variants significant in the allelic test remained significant after adjustment for covariates. STRING network analysis revealed functional interactions between eight genes identified in this study and known inflammatory bowel disease–related genes. Sub-phenotype analysis further indicated genetic heterogeneity among clinically defined UC subgroups.

Conclusion

This first exome-based study of Indian UC patients expands the genetic landscape of the disease and identifies population-specific associations that appear distinct from those reported in Western cohorts, suggesting potential differences in underlying disease mechanisms. Most identified genes map to disease-relevant pathways. However, given the modest sample size and limited statistical power, these findings should be considered exploratory and require further validation to clarify their contribution to UC pathogenesis. The study also underscores the importance of conducting genetic investigations in genetically diverse and understudied populations to improve the broader applicability of genetic findings.