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Exome sequencing directly implicates 68 genes in inflammatory bowel disease
Preprint

Exome sequencing directly implicates 68 genes in inflammatory bowel disease

Ruifei Zhu, Qian Zhang, Kai Yuan, Rui Zhang, Alexandra K Turvey, Christine R Stevens, Laura Fachal, Tariq Ahmad, Klaartje Bel Kok, Charles N Bernstein, …
medRxiv
Cold Spring Harbor Laboratory Preprints
2026-05-20
DOI: https://doi.org/10.64898/2026.05.08.26352648

Abstract

Inflammatory bowel disease (IBD) is a chronic immune-mediated disorder of the gastrointestinal tract whose genetic basis is only partly resolved because most risk variants identified by genome-wide association studies (GWAS) lie in non-coding regions, limiting direct gene assignment and biological interpretation1,2. Here we analysed whole-exome and whole-genome sequencing data from 86,213 IBD cases and 478,363 controls of European ancestry. We identified 68 IBD genes directly implicated by conditionally independent protein-coding associations across the allele frequency spectrum. Many newly implicated IBD genes are supported by orthogonal genomic or pleiotropic evidence, pointing to disease-related pathways and nominating targets with therapeutic relevance. We further identified allelic series and non-additive effects at key loci such as NOD2 and TYK2. These results show that large-scale sequencing can resolve disease genes and pathways that remain ambiguous from non-coding association alone, providing a more direct route from human genetics to biological insight and therapeutic hypotheses.

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