IBD risk loci are enriched in multigenic regulatory modules encompassing putative causative genes.

Area of Science:

• Genetics
• Genomics
• Immunology

Background:

• Genome-wide association studies (GWAS) have identified over 200 risk loci associated with Inflammatory Bowel Disease (IBD).
• The majority of these IBD-associated genetic variants are regulatory, influencing gene expression rather than protein sequence.
• Identifying the specific genes affected by these regulatory variants is crucial for understanding IBD pathogenesis.

Purpose of the Study:

• To identify causative genes perturbed by regulatory variants associated with Inflammatory Bowel Disease (IBD).
• To characterize the regulatory modules driving IBD risk loci.
• To validate candidate genes through sequencing in a large cohort of Crohn's disease patients.

Main Methods:

• Generation of a large transcriptome dataset across nine disease-relevant cell types.
• Identification and analysis of cis-expression quantitative trait loci (cis-eQTL) and regulatory modules.
• Sequencing of candidate genes in a large cohort of Crohn's disease (CD) cases and controls.

Main Results:

• Identification of 23,650 cis-eQTLs, organized into approximately 9720 regulatory modules.
• Discovery that approximately 3000 modules operate in multiple tissues and 970 modules affect multiple genes.
• Determination that regulatory modules drive disease associations for 63 out of 200 IBD risk loci, with enrichment in multigenic modules.
• Identification of likely causative genes through burden tests on resequenced candidate genes in 6600 CD cases and 5500 controls.

Conclusions:

• Regulatory modules, particularly multigenic ones, play a significant role in driving IBD genetic associations.
• This study successfully identified likely causative genes for a subset of IBD risk loci.
• Substantially larger sample sizes (at least 10-fold increase) are necessary to definitively establish the causality of individual genes using current genetic approaches.