Fine-mapping inflammatory bowel disease loci to single-variant resolution

Area of Science:

• Genetics
• Gastroenterology
• Immunology

Background:

• Inflammatory bowel diseases (IBD) are chronic gastrointestinal disorders affecting millions globally.
• Genome-wide association studies (GWAS) have identified numerous IBD-associated genetic loci, but causal variants remain largely unresolved.
• Understanding the genetic basis of IBD is critical for developing targeted therapies.

Purpose of the Study:

• To perform high-resolution fine-mapping of 94 IBD-associated loci in a large cohort.
• To pinpoint specific causal variants responsible for IBD susceptibility.
• To investigate the functional implications of identified causal variants in disease mechanisms.

Main Methods:

• Fine-mapping of 94 IBD loci using high-density genotyping.
• Analysis of 67,852 individuals to increase statistical power.
• Statistical analysis to pinpoint causal variants with high certainty.

Main Results:

• Identified 18 associations pinpointed to a single causal variant (>95% certainty) and 27 more (>50% certainty).
• These 45 variants are enriched for protein-coding changes, disruption of transcription-factor binding sites, and tissue-specific epigenetic marks.
• Epigenetic marks showed enrichment in immune cells for Crohn's disease and gut mucosa for ulcerative colitis.

Conclusions:

• High-resolution fine-mapping in large cohorts effectively identifies statistically convincing causal variants for IBD.
• These identified variants provide a strong foundation for experimental studies to elucidate IBD pathogenesis.
• The findings advance our understanding of the genetic architecture underlying inflammatory bowel diseases.