Exome sequencing directly implicates 68 genes in inflammatory bowel disease

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 cases and 478,363 controls to define the contribution of protein-altering variation to IBD susceptibility. We identify 68 genes directly implicated by coding variation, including genes supported by single-variant associations and ultra-rare mutational burden. 57 of these genes lie within regions previously highlighted by GWAS, indicating convergence of regulatory and protein-altering evidence in IBD. The implicated genes point to coherent biological themes, including post-transcriptional control of inflammatory programmes, epithelial restitution, and calibrated immune pathway signalling, and nominate targets with therapeutic relevance. 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.